Telomere length is an independent prognostic marker in MDS but not in de novo AML.

PubMed

Williams, Jenna; Heppel, Nicole H; Britt-Compton, Bethan; Grimstead, Julia W; Jones, Rhiannon E; Tauro, Sudhir; Bowen, David T; Knapper, Steven; Groves, Michael; Hills, Robert K; Pepper, Chris; Baird, Duncan M; Fegan, Chris

2017-07-01

Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS. © 2017 John Wiley & Sons Ltd.

MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation

PubMed Central

Figueroa, Maria E.; Skrabanek, Lucy; Li, Yushan; Jiemjit, Anchalee; Fandy, Tamer E.; Paietta, Elisabeth; Fernandez, Hugo; Tallman, Martin S.; Greally, John M.; Carraway, Hetty; Licht, Jonathan D.; Gore, Steven D.

2009-01-01

Increasing evidence shows aberrant hypermethylation of genes occurring in and potentially contributing to pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDSs), are responsive to DNA methyltransferase inhibitors. To determine the extent of promoter hypermethylation in such tumors, we compared the distribution of DNA methylation of 14 000 promoters in MDS and secondary acute myeloid leukemia (AML) patients enrolled in a phase 1 trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu-poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. This trial was registered at www.clinicaltrials.gov as J0443. PMID:19652201

Rescue of TET2 Haploinsufficiency in Myelodysplastic Syndrome Patients Using Turbo Cosubstrate

DTIC Science & Technology

2016-07-01

prevalent in a number of myeloid malignancies such as MDS- myeloproliferative neoplasms (MDS-MPN) and acute myeloid leukemia derived from MDS and MDS-MPN...Myelodysplastic syndromes (MDS), MDS- myeloproliferative neoplasms (MDS-MPN), Acute myeloid leukemia (AML), 5-methylcytosine (5mC), Mutation

Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children's Oncology Group.

PubMed

Barnard, Dorothy R; Alonzo, Todd A; Gerbing, Robert B; Lange, Beverly; Woods, William G

2007-07-01

Myelodysplastic syndromes (MDS), acute erythroleukemia (FAB M6), and acute megakaryocytic leukemia (FAB M7) have overlapping features. Children without Down syndrome or acute promyelocytic leukemia who were newly diagnosed with primary myelodysplastic syndrome or acute myeloid leukemia (AML) M6 or M7 were compared to children with de novo AML M0-M5. All children were entered on the Children's Cancer Group therapeutic research study CCG 2891. The presentation and outcomes of the 132 children diagnosed with MDS (60 children), AML FAB M6 (19 children), or AML FAB M7 (53 children) were similar. Children with AML FAB M7 were diagnosed at a significantly younger age (P = 0.001). Children with MDS, M6, or M7 had significantly lower white blood cell (WBC) counts (P = 0.001), lower peripheral blast counts (P < 0.001), and an increased frequency of -7/7q- (P = 0.003) at presentation. All three groups had significantly inferior overall survival (OS) (P < 0.001) and event free survival (P < 0.001) compared with the 748 children diagnosed with AML FAB M0-M5 when assessed from entry on study. This poor survival was largely attributable to induction death and failure. However, when assessed from successful completion of induction therapy, the 5-year OS (P = 0.090)(49.1 vs. 56.9%) and disease-free survival (DFS) (P = 0.113)(38.0 vs. 46.3%) therapy were not significantly different from other children with AML. Childhood AML FAB M6 and AML M7 resemble MDS in presentation, poor induction success rates, and outcomes.

Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990-2005.

PubMed

Kaplan, Henry G; Malmgren, Judith A; Atwood, Mary K

2011-06-21

Our objective was to measure myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) risk associated with radiation and/or chemotherapy breast cancer (BC) treatment. Our study cohort was composed of BC patients diagnosed from 1990 to 2005 and followed up for blood disorders, mean length of follow up = 7.17 years, range 2-18 years. 5790 TNM stage 0-III patients treated with surgery alone, radiation and/or chemotherapy were included. Patients without surgery (n = 111), with stem cell transplantation (n = 98), unknown or non-standard chemotherapy regimens (n = 94), lost to follow up (n = 66) or 'cancer status unknown' (n = 67) were excluded. Rates observed at our community based cancer care institution were compared to SEER incidence data for rate ratio (RR) calculations. 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period, crude rate .29% (95% CI = .17, .47), SEER comparison RR = 3.94 (95% CI = 2.34, 6.15). The RR of MDS in patients age < 65 comparing our cohort incidence to SEER incidence data was 10.88 (95% CI = 3.84, 24.03) and the RR of AML in patients age < 65 was 5.32 (95% CI = 1.31, 14.04). No significant increased risk of MDS or AML was observed in women ≥ 65 or the surgery/chemotherapy-only group. A RR of 3.32 (95% CI = 1.42, 6.45) was observed in the surgery/radiation-only group and a RR of 6.32 (95% CI = 3.03, 11.45) in the surgery/radiation/chemotherapy group. 3 out of 10 MDS cases died of disease at an average 3.8 months post diagnosis and five of seven AML cases died at an average 9 months post diagnosis. An elevated rate of MDS and AML was observed among breast cancer patients < 65, those treated with radiation and those treated with radiation and chemotherapy compared to available population incidence data. Although a small number of patients are affected, leukemia risk associated with treatment and younger age is significant.

The natural history of trilinear myelodysplastic syndrome and erythroleukemia.

PubMed

Michiels, J J; van der Meulen, J; Brederoo, P

1997-01-01

A case of Di Guglielmo's syndrome passed through the three stages of chronic erythromyelosis, erythroleukemia and acute myeloid leukemia (AML). According to the FAB classification the subsequent stages of this syndrome were refractory anemia (RA), RA with excess of blasts (RAEB), AML-M6, AML-M2 and undifferentiated AML-MO as the end-stage disease. Light- and electronmicroscopice findings on peripheral blood and bone marrow slides showed a pronounced trilineage myelodysplastic syndrome (MDS) during the RA, RAEB, AML-M6 and M2 phases of the disease, i.e. dysplastic erythropoiesis with PAS-positive erythroblasts, agranular and hypogranular neutrophils and dysplastic megakaryocytes. It is concluded that this case of Di Guglielmo's syndrome with chronic erythromyelosis, erythroleukemia and AML appears to be a continuum of trilineage MDS, AML-M6 and M2 with dyserythropoiesis which evolved into AML-M0.

Rescue of TET2 Haploinsufficiency in Myelodysplastic Syndrome Patients Using Turbo Cosubstrate

DTIC Science & Technology

2015-07-01

myeloproliferative neoplasms (MDS-MPN) and acute myeloid leukemia derived from MDS and MDS-MPN (sAML). One of the fundamental causes of these diseases is the...the activity of TET2 can be modified using 2-oxoglutarate analogs. 2. KEYWORDS: Myelodysplastic syndromes (MDS), MDS- myeloproliferative neoplasms (MDS

Iron overload promotes erythroid apoptosis through regulating HIF-1a/ROS signaling pathway in patients with myelodysplastic syndrome.

PubMed

Zheng, Qing-Qing; Zhao, You-Shan; Guo, Juan; Zhao, Si-da; Song, Lu-Xi; Fei, Cheng-Ming; Zhang, Zheng; Li, Xiao; Chang, Chun-Kang

2017-07-01

Erythroid apoptosis increases significantly in myelodysplastic syndrome (MDS) patients with iron overload, but the underlying mechanism is not fully clear. In this study, we aim to explore the effect of HIF-1a/ROS on erythroid apoptosis in MDS patients with iron overload. We found that iron overload injured cellular functions through up-regulating ROS levels in MDS/AML cells, including inhibited cell viability, increased cell apoptosis and blocked cell cycle at G0/G1 phase. Interestingly, overexpression of hypoxia inducible factor-1a (HIF-1a), which was under-expressed in iron overload models, reduced ROS levels and attenuated cell damage caused by iron overload in MDS/AML cells. And gene knockdown of HIF-1a got the similar results as iron overload in MDS/AML cells. Furthermore, iron overload caused high erythroid apoptosis was closely related with ROS in MDS patients. Importantly, the HIF-1a protein levels of erythrocytes elevated obviously after incubation with desferrioxamine (DFO) from MDS patients with iron overload, accompanied by ROS levels inhibited and erythroid apoptosis reduced. Taken together, our findings determine that the HIF-1a/ROS signaling pathway plays a key role in promoting erythroid apoptosis in MDS patients with iron overload. Copyright © 2017 Elsevier Ltd. All rights reserved.

Extended exposure to alkylator chemotherapy: delayed appearance of myelodysplasia.

PubMed

Chamberlain, Marc C; Raizer, Jeffrey

2009-06-01

A case series of gliomas treated with alkylator-based chemotherapy who subsequently developed myelodysplastic syndrome (tMDS) or acute myelocytic leukemia (AML). Alkylator-based chemotherapy is recognized to be leukemogenic; however, it is infrequently described as a delayed consequence of anti-glioma treatment. Seven patients (4 men; 3 women) ages 34-69 years (median 44), with gliomas (3 Grade 2; 4 Grade 3) were treated with surgery, all but one with involved-field radiotherapy and all with alkylator-based chemotherapy (temozolomide; 6 patients, nitrosoureas; 5 patients, both agents; 5 patients). Exposure to alkylator-based chemotherapy ranged from 8 to 30 months (median 24). The diagnosis of tMDS was determined by bone marrow biopsy in 7 patients. Seven patients showed chromosomal abnormalities consistent with chemotherapy induced MDS. Three patients were diagnosed with AML as well (in two determined by bone marrow and one at autopsy). Interval from last chemotherapy exposure to diagnosis of tMDS/AML ranged from 3 to 31 months (median 24 months). Two patients were treated with bone marrow transplantation and 5 received supportive care only. Five patients have died, 2 as a consequence of recurrent brain tumor, 1 as a complication of transplantation, and 2 due to AML. Although rare, induction of tMDS/AML following extended use of alkylator-based chemotherapy may become more relevant with the evolving practice to treat gliomas for protracted periods. Future work to determine at risk patients would be important.

Perturbed hematopoietic stem and progenitor cell hierarchy in myelodysplastic syndromes patients with monosomy 7 as the sole cytogenetic abnormality.

PubMed

Dimitriou, Marios; Woll, Petter S; Mortera-Blanco, Teresa; Karimi, Mohsen; Wedge, David C; Doolittle, Helen; Douagi, Iyadh; Papaemmanuil, Elli; Jacobsen, Sten Eirik W; Hellström-Lindberg, Eva

2016-11-08

The stem and progenitor cell compartments in low- and intermediate-risk myelodysplastic syndromes (MDS) have recently been described, and shown to be highly conserved when compared to those in acute myeloid leukemia (AML). Much less is known about the characteristics of the hematopoietic hierarchy of subgroups of MDS with a high risk of transforming to AML. Immunophenotypic analysis of immature stem and progenitor cell compartments from patients with an isolated loss of the entire chromosome 7 (isolated -7), an independent high-risk genetic event in MDS, showed expansion and dominance of the malignant -7 clone in the granulocyte and macrophage progenitors (GMP), and other CD45RA+ progenitor compartments, and a significant reduction of the LIN-CD34+CD38low/-CD90+CD45RA- hematopoietic stem cell (HSC) compartment, highly reminiscent of what is typically seen in AML, and distinct from low-risk MDS. Established functional in vitro and in vivo stem cell assays showed a poor readout for -7 MDS patients irrespective of marrow blast counts. Moreover, while the -7 clone dominated at all stages of GM differentiation, the -7 clone had a competitive disadvantage in erythroid differentiation. In azacitidine-treated -7 MDS patients with a clinical response, the decreased clonal involvement in mononuclear bone marrow cells was not accompanied by a parallel reduced clonal involvement in the dominant CD45RA+ progenitor populations, suggesting a selective azacitidine-resistance of these distinct -7 progenitor compartments. Our data demonstrate, in a subgroup of high risk MDS with monosomy 7, that the perturbed stem and progenitor cell compartments resemble more that of AML than low-risk MDS.

Accelerate Genomic Aging in Congenital Neutropenia

DTIC Science & Technology

2016-08-01

transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital neutropenia. We hypothesize that...colony-stimulating factor; Acute myeloid leukemia; Myelodysplastic syndrome 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION OF ABSTRACT 18. NUMBER OF...responsible for the markedly increased risk of transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with

Iron overload may promote alteration of NK cells and hematopoietic stem/progenitor cells by JNK and P38 pathway in myelodysplastic syndromes.

PubMed

Hua, Yanni; Wang, Chaomeng; Jiang, Huijuan; Wang, Yihao; Liu, Chunyan; Li, Lijuan; Liu, Hui; Shao, Zonghong; Fu, Rong

2017-08-01

The objective of the study was to examine levels of intracellular iron, reactive oxygen species (ROS) and the expression of JNK and p38MAPK in NK cells and hematopoietic stem/progenitor cells (HSPCs) in MDS patients, and explore potential mechanisms by which iron overload (IOL) promotes MDS progression. Thirty-four cases of MDS and six cases of AML transformed from MDS (MDS/AML) were included. HSPCs and NK cells were isolated by magnetic absorption cell sorting. We used flow cytometry to detect the levels of ROS and intracellular JNK and P38 in NK cells and HSPCs. Total RNA and protein were extracted from NK cells and CD34 + cells to examine the expression of JNK and p38MAPK using RT-PCR and Western blotting. Intracellular iron concentration was detected. Data were analyzed by SPSS 21 statistical software. Intracellular iron concentration and ROS were increased in both NK cells and HSPCs in MDS patients with iron overload (P < 0.05). MDS patients with iron overload had higher JNK expression and lower p38 expression in NK cells, and higher p38 expression in HSPCs compared with non-iron overload group. IOL may cause alterations in NK cells and HSPCs through the JNK and p38 pathways, and play a role in the transformation to AML from MDS.

Role of Hypomethylating Agents in the Treatment of Bone Marrow Failure

DTIC Science & Technology

2015-10-01

and clonal somatic mutations that occur in myeloid malignancies. 15. SUBJECT TERMS Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML...Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), hypomethylating agents (HMA), azacitidine, decitabine, TET2 mutations 3...of this project is to develop novel approaches to the treatment of acute myeloid leukemia based on combinations of lenalidomide with additional

MDS/AML del(11)(q14) Share Common Morphological Features Despite Different Chromosomal Breakpoints.

PubMed

Dambruoso, Irene; Invernizzi, Rosangela; Boni, Marina; Zappatore, Rita; Giardini, Ilaria; Cavigliano, Maria Paola; Rocca, Barbara; Calvello, Celeste; Bastia, Raffaella; Caresana, Marilena; Pasi, Francesca; Nano, Rosanna; Bernasconi, Paolo

2017-02-01

In myelodysplatic syndromes and acute myeloid leukemia (MDS/AML) deletion of the 11q14 region is a rare chromosomal defect (incidence: 0.6-1.0%), included within the intermediate risk criteria by the International Prognostic Scoring System. No fluorescence in situ hybridization (FISH) study has yet been performed to identify a common breakpoint region (CBR). In our study through FISH with bacterial artificial chromosomes and commercial probes, we analyzed seven patients with MDS/AML harboring 11q14 deletion on conventional cytogenetic analysis. FISH revealed deletions in five patients and amplifications in two. Three patients with deletion carried a CBR, two had a deletion involving a more centromeric breakpoint. These five patients exhibited multilineage dysplasia, blast cells with large round nuclei, loose chromatin, small and abundant nucleoli, and vacuolated cytoplasm with very thin Auer bodies. In conclusion, the morphological features which occur independently of the extent of the deletion are of multilineage dysplasia in MDS and leukemic blasts strongly reactive to peroxidase in AML; despite the variable size of the deleted area, some patients harbor a CBR. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia.

PubMed

Sperling, Adam S; Gibson, Christopher J; Ebert, Benjamin L

2017-01-01

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome.

PubMed

Volkert, Sarah; Kohlmann, Alexander; Schnittger, Susanne; Kern, Wolfgang; Haferlach, Torsten; Haferlach, Claudia

2014-05-01

We analyzed 1,200 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a 5q deletion in order to clarify whether the type of 5q loss is associated with other biological markers and prognosis. We investigated all patients by chromosome banding analysis, FISH with a probe for EGR1 (5q31) and, if necessary, to resolve complex karyotypes with 24-color-FISH. Moreover, 420 patients were analyzed for mutations in the TP53 gene. The patient cohort was subdivided based on type of 5q loss: Patients with interstitial deletions and patients with 5q loss due to unbalanced rearrangements or monosomy 5. Loss of the long arm of chromosome 5 due to an unbalanced rearrangement occurred more often in AML (286/627; 45.6%) than MDS (188/573; 32.8%; P < 0.001). In both entities, patients with 5q loss due to unbalanced translocations showed complex karyotypes more frequently (MDS: 179/188; 95.2% vs. 124/385; 32.2%; P < 0.001; AML: 274/286; 95.8% vs. 256/341; 75.1%; P < 0.001). Moreover, in MDS unbalanced 5q translocations were associated with clonal evolution (109/188; 58.0% vs. 124/385; 32.2%; P < 0.001), mutation of TP53 (64/67; 95.5% vs. 40/120; 40.0%; P < 0.001), and shorter survival (15.3 months vs. not reached; P < 0.001). In MDS, complex karyotype was an independent adverse prognostic factor (HR = 5.34; P = 0.032), whereas in AML presence of TP53 mutations was the strongest adverse prognostic factor (HR = 2.21; P = 0.026). In conclusion, in AML and MDS, loss of the long arm of chromosome 5 due to unbalanced translocations is associated with complex karyotype and in MDS, moreover, with clonal evolution, mutations in the TP53 gene and adverse prognosis. Copyright © 2014 Wiley Periodicals, Inc.

BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders.

PubMed

Damm, Frederik; Chesnais, Virginie; Nagata, Yasunobu; Yoshida, Kenichi; Scourzic, Laurianne; Okuno, Yusuke; Itzykson, Raphael; Sanada, Masashi; Shiraishi, Yuichi; Gelsi-Boyer, Véronique; Renneville, Aline; Miyano, Satoru; Mori, Hiraku; Shih, Lee-Yung; Park, Sophie; Dreyfus, François; Guerci-Bresler, Agnes; Solary, Eric; Rose, Christian; Cheze, Stéphane; Prébet, Thomas; Vey, Norbert; Legentil, Marion; Duffourd, Yannis; de Botton, Stéphane; Preudhomme, Claude; Birnbaum, Daniel; Bernard, Olivier A; Ogawa, Seishi; Fontenay, Michaela; Kosmider, Olivier

2013-10-31

Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.

High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia

PubMed Central

Pasquet, Marlène; Bellanné-Chantelot, Christine; Tavitian, Suzanne; Prade, Naïs; Beaupain, Blandine; LaRochelle, Olivier; Petit, Arnaud; Rohrlich, Pierre; Ferrand, Christophe; Van Den Neste, Eric; Poirel, Hélène A.; Lamy, Thierry; Ouachée-Chardin, Marie; Mansat-De Mas, Véronique; Corre, Jill; Récher, Christian; Plat, Geneviève; Bachelerie, Françoise; Donadieu, Jean

2013-01-01

Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reported GATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. PMID:23223431

Enumerating bone marrow blasts from nonerythroid cellularity improves outcome prediction in myelodysplastic syndromes and permits a better definition of the intermediate risk category of the Revised International Prognostic Scoring System (IPSS-R).

PubMed

Calvo, Xavier; Arenillas, Leonor; Luño, Elisa; Senent, Leonor; Arnan, Montserrat; Ramos, Fernando; Pedro, Carme; Tormo, Mar; Montoro, Julia; Díez-Campelo, María; Blanco, María Laura; Arrizabalaga, Beatriz; Xicoy, Blanca; Bonanad, Santiago; Jerez, Andrés; Nomdedeu, Meritxell; Ferrer, Ana; Sanz, Guillermo F; Florensa, Lourdes

2017-07-01

The Revised International Prognostic Scoring System (IPSS-R) has been recognized as the score with the best outcome prediction capability in MDS, but this brought new concerns about the accurate prognostication of patients classified into the intermediate risk category. The correct enumeration of blasts is essential in prognostication of MDS. Recent data evidenced that considering blasts from nonerythroid cellularity (NECs) improves outcome prediction in the context of IPSS and WHO classification. We assessed the percentage of blasts from total nucleated cells (TNCs) and NECs in 3924 MDS patients from the GESMD, 498 of whom were MDS with erythroid predominance (MDS-E). We assessed if calculating IPSS-R by enumerating blasts from NECs improves prognostication of MDS. Twenty-four percent of patients classified into the intermediate category were reclassified into higher-risk categories and showed shorter overall survival (OS) and time to AML evolution than those who remained into the intermediate one. Likewise, a better distribution of patients was observed, since lower-risk patients showed longer survivals than previously whereas higher-risk ones maintained the outcome expected in this poor prognostic group (median OS < 20 months). Furthermore, our approach was particularly useful for detecting patients at risk of dying with AML. Regarding MDS-E, 51% patients classified into the intermediate category were reclassified into higher-risk ones and showed shorter OS and time to AML. In this subgroup of MDS, IPSS-R was capable of splitting our series in five groups with significant differences in OS only when blasts were assessed from NECs. In conclusion, our easy-applicable approach improves prognostic assessment of MDS patients. © 2017 Wiley Periodicals, Inc.

Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS.

PubMed

Mawad, Raya; Becker, Pamela S; Hendrie, Paul; Scott, Bart; Wood, Brent L; Dean, Carol; Sandhu, Vicky; Deeg, Hans Joachim; Walter, Roland; Wang, Lixia; Myint, Han; Singer, Jack W; Estey, Elihu; Pagel, John M

2016-01-01

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Thirty-four patients ≥60 years old (median age 70 years; range, 60-83) were randomized to receive tosedostat (120 mg on days 1-21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m2 /d) or decitabine (20 mg/m2 /d) every 35 d. Twenty-nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS-refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3-internal tandem duplication mutations. Median follow-up was 11.2 months (range, 0.5-22.3), and median survival was 11.5 months (95% confidence interval, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3-4 non-haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials. © 2015 John Wiley & Sons Ltd.

Acute Myeloid Leukemia with MYC Rearrangement and JAK2 V617F Mutation

PubMed Central

Ohanian, Maro; Bueso-Ramos, Carlos; Ok, Chi Young; Lin, Pei; Patel, Keyur; Alattar, Mona Lisa; Khoury, Joseph D.; Rozovski, Uri; Estrov, Zeev; Huh, Yang O.; Cortes, Jorge; Abruzzo, Lynne V.

2016-01-01

Little is known about MYC dysregulation in myeloid malignancies, and we can find no published studies that have evaluated MYC protein expression in primary cases of myelodysplastic syndromes (MDS) or acute myeloid leukemias (AML). We describe the clinical, morphologic, immunophenotypic, cytogenetic, and molecular genetic findings in two MDS/AML cases that contained both MYC rearrangement and JAK2-V617F mutation. We demonstrate MYC protein expression by immunohistochemistry in both patients. PMID:26382622

High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia.

PubMed

Pasquet, Marlène; Bellanné-Chantelot, Christine; Tavitian, Suzanne; Prade, Naïs; Beaupain, Blandine; Larochelle, Olivier; Petit, Arnaud; Rohrlich, Pierre; Ferrand, Christophe; Van Den Neste, Eric; Poirel, Hélène A; Lamy, Thierry; Ouachée-Chardin, Marie; Mansat-De Mas, Véronique; Corre, Jill; Récher, Christian; Plat, Geneviève; Bachelerie, Françoise; Donadieu, Jean; Delabesse, Eric

2013-01-31

Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. Mutations of key transcription factor in myeloid malignancies.

Allo-SCT for  Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Française de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC).

PubMed

Cahu, X; Chevallier, P; Clavert, A; Suarez, F; Michallet, M; Vincent, L; Vigouroux, S; Blaise, D; Mariette, C; Bilger, K; Robin, M; Yakoub-Agha, I; Peffault de Latour, R; Mohty, M

2014-06-01

Progression of Philadelphia-negative myeloproliferative (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) to acute myeloid leukemia (AML) is an adverse event in the course of the disease. Although allogeneic hematopoietic SCT (allo-SCT) is considered as the only curative therapy, few data exist on the outcome of patients with Philadelphia-negative MPN or MDS/MPN in blast phase who received an allo-SCT. Sixty patients were included in this retrospective study. AML was secondary to an MPN in 43 cases, whereas AML evolved from an MDS/MPN in 17 cases. Patients received allo-SCT in CR or advanced disease in 26 cases and 34 cases, respectively. With a median follow-up of 31 months (range, 25-44), OS and leukemia-free survival (LFS) were, respectively, 18% and 9% at 3 years. CR at transplant was associated with an improved LFS in univariate and multivariate analysis. The 3-year LFS was 18% for patients undergoing allo-SCT in CR versus 3% in advanced disease (P=0.008). Absence of thrombosis and an intermediate or favorable AML karyotype were associated with an improved outcome for patients who received allo-SCT in CR. New strategies are needed to improve the outcome of patients with MPN-MDS/MPN in blast phase.

Invasive fungal infections in AML/MDS patients treated with azacitidine: a risk worth considering antifungal prophylaxis?

PubMed

Pomares, Helena; Arnan, Montserrat; Sánchez-Ortega, Isabel; Sureda, Anna; Duarte, Rafael F

2016-08-01

The aim of this study is to analyse the risk of invasive fungal infection (IFI) and the need for antifungal prophylaxis in patients with acute myeloid leukaemia and myelodysplastic syndromes (AML/MDS) treated with azacitidine. We retrospectively analysed the incidence of IFI according to EORTC-MSG criteria in 121 consecutive AML/MDS patients receiving 948 azacitidine courses (median 5, range 1-43) between June 2007 and June 2015. Four cases of IFI (two possible, one probable aspergillosis and one proven candidemia) occurred in this series. The incidence rate of proven/probable IFI was 0.21% per treatment cycle and 1.6% per patient treated for the whole series, and 0.73% per treatment cycle and 4.1% per patient treated in those with severe neutropenia. Two patients died from IFI, leading to an IFI-attributable mortality rate of 1.65% per patient and 0.21% per treatment cycle. The numbers needed to treat with prophylaxis to prevent one case of IFI are 238 azacitidine cycles or 30 patients throughout their whole treatment course, and 137 azacitidine cycles or 24 patients among those with severe neutropenia. AML/MDS patients treated with azacitidine, including those with severe prolonged neutropenia, have a very low risk of IFI which does not justify the use of antifungal prophylaxis. © 2016 Blackwell Verlag GmbH.

Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

PubMed Central

DiNardo, Courtney D.; Garcia-Manero, Guillermo; Pierce, Sherry; Nazha, Aziz; Bueso-Ramos, Carlos; Jabbour, Elias; Ravandi, Farhad; Cortes, Jorge; Kantarjian, Hagop

2017-01-01

Acute myeloid leukemia (AML) is defined as ≥20% myeloblasts, representing a change from original guidelines where ≤30% blasts were considered as myelodysplastic syndromes (MDS), and 20–29% blasts classified as refractory anemia with excess blasts in transformation (RAEB-T). Whether the diagnostic bone marrow blast percentage has current value with regards to patient prognostication or identification of optimal treatment strategies is unclear. We retrospectively studied 1652 treatment-naïve adults with MDS or AML and ≥10% blasts from January 2000 to April 2014. Patients with 20–29% blasts were more similar to MDS patients in terms of advanced age, increased frequency of poor-risk cytogenetics, lower WBC count, and less frequent NPM1 and FLT3-ITD mutations. Median overall survival of MDS and RAEB-T were similar, 16.0 and 16.0 months, compared to 13.5 months for AML with ≥30% blasts (P =0.045). Multivariate analysis showed inferior survival with increased age (HR 1.81 age 60–69, HR 2.68 age ≥70, P < 0.0005); poor-risk cytogenetics (HR 2.25, P < 0.0005); therapy-related disease (HR 1.44, P < 0.0005); and markers of proliferative disease including WBC ≥25 × 109/L (HR 1.35, P = 0.0003), elevated LDH count (HR 1.24, P =0.0015), and peripheral blasts (HR 1.25, P =0.004). Among younger patients (≤60 years), intensive AML-type therapy resulted in similar outcomes regardless of blast percentage, suggesting this to be optimal therapy in this context. Among older patients (≥70 years), patients with 20–29% blasts had similar outcomes to patients with <20% blasts, and better than those with ≥30% blasts. In addition, among older patients, epigenetic therapy provided at least equivalent outcome to intensive chemotherapy. PMID:26799610

Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

PubMed

DiNardo, Courtney D; Garcia-Manero, Guillermo; Pierce, Sherry; Nazha, Aziz; Bueso-Ramos, Carlos; Jabbour, Elias; Ravandi, Farhad; Cortes, Jorge; Kantarjian, Hagop

2016-02-01

Acute myeloid leukemia (AML) is defined as ≥20% myeloblasts, representing a change from original guidelines where ≤30% blasts were considered as myelodysplastic syndromes (MDS), and 20-29% blasts classified as refractory anemia with excess blasts in transformation (RAEB-T). Whether the diagnostic bone marrow blast percentage has current value with regards to patient prognostication or identification of optimal treatment strategies is unclear. We retrospectively studied 1652 treatment-naïve adults with MDS or AML and ≥10% blasts from January 2000 to April 2014. Patients with 20-29% blasts were more similar to MDS patients in terms of advanced age, increased frequency of poor-risk cytogenetics, lower WBC count, and less frequent NPM1 and FLT3-ITD mutations. Median overall survival of MDS and RAEB-T were similar, 16.0 and 16.0 months, compared to 13.5 months for AML with ≥30% blasts (P = 0.045). Multivariate analysis showed inferior survival with increased age (HR 1.81 age 60-69, HR 2.68 age ≥70, P < 0.0005); poor-risk cytogenetics (HR 2.25, P < 0.0005); therapy-related disease (HR 1.44, P < 0.0005); and markers of proliferative disease including WBC ≥25 × 10(9) /L (HR 1.35, P = 0.0003), elevated LDH count (HR 1.24, P = 0.0015), and peripheral blasts (HR 1.25, P = 0.004). Among younger patients (≤60 years), intensive AML-type therapy resulted in similar outcomes regardless of blast percentage, suggesting this to be optimal therapy in this context. Among older patients (≥70 years), patients with 20-29% blasts had similar outcomes to patients with <20% blasts, and better than those with ≥30% blasts. In addition, among older patients, epigenetic therapy provided at least equivalent outcome to intensive chemotherapy. © 2015 Wiley Periodicals, Inc.

Adult Acute Erythroleukemia: An Analysis of 108 patients treated at a single institution

PubMed Central

Santos, Fabio; Faderl, Stefan; Garcia-Manero, Guillermo; Koller, Charles; Beran, Miloslav; O'Brien, Susan; Pierce, Sherry; Freireich, Emil; Huang, Xuelin; Borthakur, Gautam; Bueso-Ramos, Carlos; de Lima, Marcos; Keating, Michael; Cortes, Jorge; Kantarjian, Hagop; Ravandi, Farhad

2014-01-01

Acute erythroleukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML); it is considered to have a poor prognosis. From January 1st, 1980 to May 21st, 2008, 108 patients with newly diagnosed AML-M6 were seen at the University of Texas – M.D. Anderson Cancer Center (UT-MDACC). Half (50%) had a history of myelodysplatic syndrome (MDS), compared to 41% in our control group (patients with other AML subtypes) (p=0.05). Poor risk cytogenetics was more common in patients with AML-M6 (69% versus 46%, p<0.001). Complete remission rates were 63% for patients with AML-M6, comparing to 58% for the control group (p = 0.285). Median disease free survival (DFS) for patients with AML-M6 was 31 weeks, versus 49 weeks for the control group (p = 0.004). Median overall survival (OS) of patients with AML-M6 was 33 weeks, compared to 42 weeks for the control group (p = 0.13). On multivariate analysis for DFS and OS, AML-M6 was not an independent risk factor. Acute erythroleukemia is commonly associated with a previous diagnosis of MDS and poor risk karyotype. The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well know AML prognostic factors. PMID:19741728

Mutations of E3 Ubiquitin Ligase Cbl Family Members Constitute a Novel Common Pathogenic Lesion in Myeloid Malignancies

PubMed Central

Makishima, Hideki; Cazzolli, Heather; Szpurka, Hadrian; Dunbar, Andrew; Tiu, Ramon; Huh, Jungwon; Muramatsu, Hideki; O'Keefe, Christine; Hsi, Eric; Paquette, Ronald L.; Kojima, Seiji; List, Alan F.; Sekeres, Mikkael A.; McDevitt, Michael A.; Maciejewski, Jaroslaw P.

2009-01-01

Purpose Acquired somatic uniparental disomy (UPD) is commonly observed in myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or secondary acute myelogenous leukemia (sAML) and may point toward genes harboring mutations. Recurrent UPD11q led to identification of homozygous mutations in c-Cbl, an E3 ubiquitin ligase involved in attenuation of proliferative signals transduced by activated receptor tyrosine kinases. We examined the role and frequency of Cbl gene family mutations in MPN and related conditions. Methods We applied high-density SNP-A karyotyping to identify loss of heterozygosity of 11q in 442 patients with MDS, MDS/MPN, MPN, sAML evolved from these conditions, and primary AML. We sequenced c-Cbl, Cbl-b, and Cbl-c in patients with or without corresponding UPD or deletions and correlated mutational status with clinical features and outcomes. Results We identified c-Cbl mutations in 5% and 9% of patients with chronic myelomonocytic leukemia (CMML) and sAML, and also in CML blast crisis and juvenile myelomonocytic leukemia (JMML). Most mutations were homozygous and affected c-Cbl; mutations in Cbl-b were also found in patients with similar clinical features. Patients with Cbl family mutations showed poor prognosis, with a median survival of 5 months. Pathomorphologic features included monocytosis, monocytoid blasts, aberrant expression of phosphoSTAT5, and c-kit overexpression. Serial studies showed acquisition of c-Cbl mutations during malignant evolution. Conclusion Mutations in the Cbl family RING finger domain or linker sequence constitute important pathogenic lesions associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, suggesting that impairment of degradation of activated tyrosine kinases constitutes an important cancer mechanism. PMID:19901108

Fanconi anemia and the development of leukemia.

PubMed

Alter, Blanche P

2014-01-01

Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision. Published by Elsevier Ltd.

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

PubMed Central

Moudra, Alena; Hubackova, Sona; Machalova, Veronika; Vancurova, Marketa; Bartek, Jiri; Reinis, Milan; Hodny, Zdenek; Jonasova, Anna

2016-01-01

ABSTRACT Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammation-related changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosis in vitro. To provide insights into in vivo effects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement with in vitro experiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC. PMID:27853634

Gene-Specific Demethylation as Targeted Therapy in MDS

DTIC Science & Technology

2017-07-01

SUPPLEMENTARY NOTES 14. ABSTRACT Myelodysplastic Syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and...clonal hematopoietic disorders characterized by bone marrow failure and risk of progression to Acute Myeloid Leukemia (AML) in approximately 30 percent

Epigenetic regulation in myelodysplastic syndromes: implications for therapy.

PubMed

Vigna, Ernesto; Recchia, Anna Grazia; Madeo, Antonio; Gentile, Massimo; Bossio, Sabrina; Mazzone, Carla; Lucia, Eugenio; Morabito, Lucio; Gigliotti, Vincenzo; Stefano, Laura De; Caruso, Nadia; Servillo, Pasquale; Franzese, Stefania; Fimognari, Filippo; Bisconte, Maria Grazia; Gentile, Carlo; Morabito, Fortunato

2011-04-01

Myelodysplastic syndromes (MDS), characterized by ineffective hematopoiesis and dysplasia in one or more lineages, produce life-threatening cytopenias and progress to acute myeloid leukemia (AML). Growing evidence suggests that targeting epigenetic mechanisms improves MDS/AML pathophysiology. This review provides an understanding of studies investigating novel agents published up to January 2011 aimed at normalizing and monitoring the epigenetic profile of the MDS cancer cell. The authors discuss how non-intensive epigenetic therapy can 're-programme' gene expression patterns of abnormal hematopoiesis in MDS. Recently FDA-approved DNA-methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine or decitabine, represent frontline nonablative treatments, while combinations with histone deacetylase inhibitors show promising synergism in preclinical and Phase I/II trials in tumor suppressor gene re-expression and overall survival. Additional epigenetic mechanisms including non-encoding transcripts with inhibitory posttranscriptional regulatory functions, such as microRNAs, though not fully understood, present novel molecular and clinical implications in these disorders. Alongside current single-agent epigenetic regimens, combination therapies represent potentially effective options for intermediate-2 and high-risk MDS. Methylation profiles and gene mutation predictors provide promising areas of development for monitoring MDS disease progression and outcome, while targeting microRNA dysregulation represents an important therapeutic goal.

KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study.

PubMed

Swords, Ronan T; Greenberg, Peter L; Wei, Andrew H; Durrant, Simon; Advani, Anjali S; Hertzberg, Mark S; Jonas, Brian A; Lewis, Ian D; Rivera, Gabriel; Gratzinger, Dita; Fan, Alice C; Felsher, Dean W; Cortes, Jorge E; Watts, Justin M; Yarranton, Geoff T; Walling, Jackie M; Lancet, Jeffrey E

2016-11-01

EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion. Copyright © 2016 Elsevier Ltd. All rights reserved.

Increased expression of HERG K+ channels contributes to myelodysplastic syndrome progression and displays correlation with prognosis stratification.

PubMed

Lu, Li; Du, Wen; Liu, Wei; Guo, Dongmei; He, Xiaoqi; Li, Huiyu

2016-12-01

Human ether-a-go-go-related gene (HERG) K + channels are shown to be aberrantly expressed in a variety of cancer cells where they play roles in contributing to cancer progression. Myelodysplastic syndromes (MDS) are a group of clinical heterogeneous disorders characterized by bone marrow failure and dysplasia of blood cells. However, the involvement of HERG K + channels in MDS development is poorly understood. The expression of HERG K + channels in untreated MDS, acute myeloid leukemia (AML) patients and the control group was detected by flow cytometry. The roles of HERG K + channels in regulation of SKM-1 cell proliferation, apoptosis, and cell cycle were determined by CCK-8 assay and flow cytometry, respectively. We found that expression of HERG K + channels in MDS patients was significantly higher than controls and was lower than AML. Percentage of HERG K + channels on CD34+CD38- cells gradually increased from controls to high-grade MDS subtypes. And HERG K + channel levels showed an ascending tendency from low-risk to high-risk MDS group. In addition, the CCK-8 assay, apoptosis and cell cycle analysis were performed and showed that blockage of HERG K + channels decreased the proliferation of MDS cells but rarely had effects on cell apoptosis and cell cycle distribution. Our study demonstrated that HERG K + channels might be a potential tumor marker of MDS. These channels were likely to contribute to MDS progression and were helpful for predicting prognosis of MDS. Inhibition of HERG K + channels might be a novel therapeutic measure for MDS.

Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia.

PubMed

Yoshimi, Ayami; Strahm, Brigitte; Baumann, Irith; Furlan, Ingrid; Schwarz, Stephan; Teigler-Schlegel, Andrea; Walther, Joachim-Ulrich; Schlegelberger, Brigitte; Göhring, Gudrun; Nöllke, Peter; Führer, Monika; Niemeyer, Charlotte M

2014-03-01

Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Concise review: preleukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells.

PubMed

Pandolfi, Ashley; Barreyro, Laura; Steidl, Ulrich

2013-02-01

Recent experimental evidence has shown that acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) arise from transformed immature hematopoietic cells following the accumulation of multiple stepwise genetic and epigenetic changes in hematopoietic stem cells and committed progenitors. The series of transforming events initially gives rise to preleukemic stem cells (pre-LSC), preceding the formation of fully transformed leukemia stem cells (LSC). Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in AML and MDS. The therapeutic elimination of all LSC, as well as pre-LSC, which provide a silent reservoir for the re-formation of LSC, will be essential for achieving lasting cures. Conventional sequencing and next-generation genome sequencing have allowed us to describe many of the recurrent mutations in the bulk cell populations in AML and MDS, and recent work has also focused on identifying the initial molecular changes contributing to leukemogenesis. Here we review recent and ongoing advances in understanding the roles of pre-LSC, and the aberrations that lead to pre-LSC formation and subsequent LSC transformation.

Dendritic cells (DCs) can be successfully generated from leukemic blasts in individual patients with AML or MDS: an evaluation of different methods.

PubMed

Kremser, Andreas; Dressig, Julia; Grabrucker, Christine; Liepert, Anja; Kroell, Tanja; Scholl, Nina; Schmid, Christoph; Tischer, Johanna; Kufner, Stefanie; Salih, Helmut; Kolb, Hans Jochem; Schmetzer, Helga

2010-01-01

Myeloid-leukemic cells (AML, MDS, CML) can be differentiated to leukemia-derived dendritic cell [DC (DCleu)] potentially presenting the whole leukemic antigen repertoire without knowledge of distinct leukemia antigens and are regarded as promising candidates for a vaccination strategy. We studied the capability of 6 serum-free DC culture methods, chosen according to different mechanisms, to induce DC differentiation in 137 cases of AML and 52 cases of MDS. DC-stimulating substances were cytokines ("standard-medium", "MCM-Mimic", "cytokine-method"), bacterial lysates ("Picibanil"), double-stranded RNA ["Poly (I:C)"] or a cytokine bypass method ("Ca-ionophore"). The quality/quantity of DC generated was estimated by flow cytometry studying (co) expressions of "DC"antigens, costimulatory, maturation, and blast-antigens. Comparing these methods on average 15% to 32% DC, depending on methods used, could be obtained from blast-containing mononuclear cells (MNC) in AML/MDS cases with a DC viability of more than 60%. In all, 39% to 64% of these DC were mature; 31% to 52% of leukemic blasts could be converted to DCleu and DCleu-proportions in the suspension were 2% to 70% (13%). Average results of all culture methods tested were comparable, however not every given case of AML could be differentiated to DC with 1 selected method. However performing a pre-analysis with 3 DC-generating methods (MCM-Mimic, Picibanil, Ca-ionophore) we could generate DC in any given case. Functional analyses provided proof, that DC primed T cells to antileukemia-directed cytotoxic cells, although an anti-leukemic reaction was not achieved in every case. In summary our data show that a successful, quantitative DC/DCleu generation is possible with the best of 3 previously tested methods in any given case. Reasons for different functional behaviors of DC-primed T cells must be evaluated to design a practicable DC-based vaccination strategy.

Arsenic disulfide induced apoptosis and concurrently promoted erythroid differentiation in cytokine-dependent myelodysplastic syndrome-progressed leukemia cell line F-36p with complex karyotype including monosomy 7.

PubMed

Hu, Xiao-mei; Tanaka, Sachiko; Onda, Kenji; Yuan, Bo; Toyoda, Hiroo; Ma, Rou; Liu, Feng; Hirano, Toshihiko

2014-05-01

Acute myeloid leukemia progressed from myelodysplastic syndrome (MDS/AML) is generally incurable with poor prognosis for complex karyotype including monosomy 7 (-7). Qinghuang Powder (, QHP), which includes Qing Dai (Indigo naturalis) and Xiong Huang (realgar) in the formula, is effective in treating MDS or MDS/AML even with the unfavorable karyotype, and its therapeutic efficacy could be enhanced by increasing the Xiong huang content in the formula, while Xiong huang contains > 90% arsenic disulfide (As2S2). F-36p cell line was established from a MDS/AML patient with complex karyotype including -7, and was in cytokine-dependent. The present study was to investigate the effects of As2S2 on F-36p cells. Cell proliferation was measured by an 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis was identified by Annexin V-staining. Cell viability was determined by a propidium iodide (PI) exclusion. Erythroid differentiation was evaluated by the expression of cell surface antigen CD235a (GpA). After treatment with As2S2 at concentrations of 0.5 to 16 μmol/L for 72 h, As2S2 inhibited the proliferation of F-36p cells. The 50% inhibitory concentrations (IC50) of As2S2 against the proliferation of F-36p cells was 6 μmol/L. The apoptotic cells significantly increased in a dose-dependent mannar (P<0.05). The cell viabilities were significantly inhibited by As2S2 dose-dependent in a dose-dependent manner (P<0.05). Significant increases of CD235a-positive cells were concurrently observed (P<0.05) also in a dose-dependent manner. As2S2 could inhibit proliferation and viability, induce apoptosis, and concurrently promote erythroid differentiation dose-dependently in F-36p cells. As2S2 can inhibit proliferation and viability, induce apoptosis, and concurrently promote erythroid differentiation in cytokine-dependent MDS-progressed human leukemia cell line F-36p with complex karyotype including -7. The data suggest that QHP and/or As2S2 could be a potential candidate in the treatment of MDS or MDS/AML even with unfavorable cytogenetics.

Efficacy and safety of deferasirox estimated by serum ferritin and labile plasma iron levels in patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia with transfusional iron overload.

PubMed

Kim, Il-Hwan; Moon, Joon-Ho; Lim, Sung-Nam; Sohn, Sang-Kyun; Kim, Hoon-Gu; Lee, Gyeong-Won; Kim, Yang-Soo; Lee, Ho-Sup; Kwon, Ki-Young; Kim, Sung-Hyun; Park, Kyung-Tae; Chung, Joo-Seop; Lee, Won-Sik; Lee, Sang-Min; Hyun, Myung-Soo; Kim, Hawk; Ryoo, Hun-Mo; Bae, Sung-Hwa; Joo, Young-Don

2015-07-01

Patients receiving red blood cell (RBC) transfusions are at risk of iron overload, which can cause significant organ damage and is an important cause of morbidity and mortality. This study was an open-label, single-arm, prospective clinical study to evaluate the efficacy and safety of deferasirox (DFX) in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). Patients with serum ferritin levels of at least 1000 ng/mL and ongoing transfusion requirements were enrolled. DFX was administered for up to 1 year. A total of 100 patients were enrolled. Serum ferritin levels decreased significantly following treatment (from 2000 to 1650 ng/mL, p = 0.004). The median absolute reduction in serum ferritin levels was -65 ng/mL in AA (p = 0.037), -647 ng/mL in lower-risk MDS (MDS-LR; p = 0.007), and -552 ng/mL in higher-risk MDS (MDS-HR)/AML (p = 0.482). Mean labile plasma iron (LPI) levels decreased from 0.24 μmol/L at baseline to 0.03 μmol/L at 1 year in all patients (p = 0.036). The mean LPI reduction in each group was -0.17 μmol/L in AA, -0.21 μmol/L in MDS-LR, and -0.30 μmol/L in MDS-HR/AML. Gastrointestinal disorders were commonly observed among groups (16.0%). DFX was temporarily skipped for adverse events in seven patients (7.0%) and was permanently discontinued in 11 patients (11.0%). DFX reduced serum ferritin and LPI levels in patients with transfusional iron overload. Despite the relatively high percentage of gastrointestinal side effects, DFX was tolerable in all subgroups. © 2015 AABB.

Myelodysplastic Syndrome with concomitant t(5;21)(q15;q22) and del(5)(q13q33): case report and review of literature

PubMed Central

Weckbaugh, Brandon; Sirridge, Christopher; Woodroof, Janet; Persons, Diane

2016-01-01

Chromosomal abnormalities lead to the development of hematologic malignancies such as Myelodysplastic Syndrome (MDS). Known chromosomal changes causing MDS include deletion of the long arm of chromosome 5, runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1), and very rarely fusion genes involving RUNX1 at t(5;21)(q15;q22). We present a case of a 71-year-old female with MDS, refractory anemia with excess blasts, type 1, with a combination of two cytogenetic abnormalities, specifically a concomitant translocation between chromosomes 5q15 and 21q22 and deletion of chromosome 5q13q33. Fluorescence in-situ hybridization (FISH) using a probe for RUNX1 (AML1), localized to 21q22, showed three FISH signals for RUNX1, consistent with rearrangement of RUNX1. Therapy was started with Lenalidomide leading to normal blood counts. Most significantly, repeat cytogenetics revealed normal karyotype and resolution of deletion on the long arm of chromosome 5 and a t(5;21). FISH negative for deletion 5q. The results altogether meet criteria for a complete cytogenetic remission (CR). We report a new case of t(5;21)(q15;q22) involving the RUNX1 gene and del(5)(q13q33) in a MDS patient, a combination of chromosomal abnormalities heretofore not reported in the literature. RUNX1 rearrangement is usually associated with an adverse prognosis in AML and MDS. Deletions of 5q are typically associated with poor prognosis in AML, however it is usually associated with a favorable prognosis in MDS. Our patient responded very well to Lenalidomide therapy with achievement of CR. Lenalidomide is approved for treatment of anemia in low and intermediate risk MDS with del (5q), however based on a search of literature it seems that RUNX1 mutations are also more prominent in patients who have responded to Lenalidomide therapy. MDS is a genomically unstable disease. Hence, it is conceivable that our patient started with a 5q minus syndrome and then acquired the second hit RUNX1 translocation leading to an accelerated phase of myeloid neoplasm or refractory anemia with excess blasts, type 1. Hence, the temporal relationship between acquisition of del 5q and RUNX1 rearrangement may have influenced the clinical outcome and possibly response to therapy. PMID:27358895

Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms

PubMed Central

Jankowska, Anna M.; Szpurka, Hadrian; Tiu, Ramon V.; Makishima, Hideki; Afable, Manuel; Huh, Jungwon; O'Keefe, Christine L.; Ganetzky, Rebecca; McDevitt, Michael A.

2009-01-01

Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number–neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders. PMID:19372255

Vaccination with autologous myeloblasts admixed with GM-K562 cells in patients with advanced MDS or AML after allogeneic HSCT

PubMed Central

Kim, Haesook T.; Bavli, Natalie; Mihm, Martin; Pozdnyakova, Olga; Piesche, Matthias; Daley, Heather; Reynolds, Carol; Souders, Nicholas C.; Cutler, Corey; Koreth, John; Alyea, Edwin P.; Antin, Joseph H.; Ritz, Jerome; Dranoff, Glenn; Soiffer, Robert J.

2017-01-01

We report a clinical trial testing vaccination of autologous myeloblasts admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells after allogeneic hematopoietic stem cell transplantation (HSCT). Patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with ≥5% marrow blasts underwent myeloblast collection before HSCT. At approximately day +30, 6 vaccines composed of irradiated autologous myeloblasts mixed with GM-K562 were administered. Tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was not tapered until vaccine completion (∼day 100). Thirty-three patients with AML (25) and MDS (8) enrolled, 16 (48%) had ≥5% marrow blasts at transplantation. The most common vaccine toxicity was injection site reactions. One patient developed severe eosinophilia and died of eosinophilic myocarditis. With a median follow-up of 67 months, cumulative incidence of grade 2-4 acute and chronic GVHD were 24% and 33%, respectively. Relapse and nonrelapse mortality were 48% and 9%, respectively. Progression-free survival (PFS) and overall survival (OS) at 5 years were 39% and 39%. Vaccinated patients who were transplanted with active disease (≥5% marrow blasts) had similar OS and PFS at 5 years compared with vaccinated patients transplanted with <5% marrow blasts (OS, 44% vs 35%, respectively, P = .81; PFS, 44% vs 35%, respectively, P = .34). Postvaccination antibody responses to angiopoietin-2 was associated with superior OS (hazard ratio [HR], 0.43; P = .031) and PFS (HR, 0.5; P = .036). Patients transplanted with active disease had more frequent angiopoeitin-2 antibody responses (62.5% vs 20%, P = .029) than those transplanted in remission. GM-K562/leukemia cell vaccination induces biologic activity, even in patients transplanted with active MDS/AML. This study is registered at www.clinicaltrials.gov as #NCT 00809250. PMID:29296875

Therapeutic Antibodies for Myeloid Neoplasms—Current Developments and Future Directions

PubMed Central

Schürch, Christian M.

2018-01-01

Therapeutic monoclonal antibodies (mAbs) such as antibody–drug conjugates, ligand–receptor antagonists, immune checkpoint inhibitors and bispecific T cell engagers have shown impressive efficacy in the treatment of multiple human cancers. Numerous therapeutic mAbs that have been developed for myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are currently investigated in clinical trials. Because AML and MDS originate from malignantly transformed hematopoietic stem/progenitor cells—the so-called leukemic stem cells (LSCs) that are highly resistant to most standard drugs—these malignancies frequently relapse and have a high disease-specific mortality. Therefore, combining standard chemotherapy with antileukemic mAbs that specifically target malignant blasts and particularly LSCs or utilizing mAbs that reinforce antileukemic host immunity holds great promise for improving patient outcomes. This review provides an overview of therapeutic mAbs for AML and MDS. Antibody targets, the molecular mechanisms of action, the efficacy in preclinical leukemia models, and the results of clinical trials are discussed. New developments and future studies of therapeutic mAbs in myeloid neoplasms will advance our understanding of the immunobiology of these diseases and enhance current therapeutic strategies. PMID:29868474

A systematic review of patient reported outcomes in phase II or III clinical trials of myelodysplastic syndromes and acute myeloid leukemia.

PubMed

Bryant, Ashley Leak; Drier, Sarah W; Lee, Sejin; Bennett, Antonia V

2018-06-07

The purpose of this systematic literature review was to identify clinical trials of MDS and AML that included patient-reported outcome (PRO) instruments, and to summarize the symptom and other health related quality of life (HRQOL) concepts most frequently assessed and the PRO instruments that were used. Sixteen manuscripts describing 14 distinct trials met all criteria (i.e., phase 2 or 3 clinical trial for MDS or AML which included PRO assessment) and were published between 1996-2017. In trials evaluating anemia, PRO scores showed significant improvement in relevant domains (e.g. fatigue, function) among patients identified as responders. In trials evaluating the impact of anti-cancer therapies, improvements the baseline to end of treatment were observed in physical functioning and HRQOL, however the rates of missing data in many of the trials was high or unreported. PRO instruments have the ability to capture changes over time in patients' function and well-being, and PRO instruments and guidance documents are available to support the assessment of HRQOL in AML/MDS clinical trials. Copyright © 2018. Published by Elsevier Ltd.

Detection of NPM/MLF1 fusion in t(3;5)-positive acute myeloid leukemia and myelodysplasia.

PubMed

Arber, Daniel A; Chang, Karen L; Lyda, Mark H; Bedell, Victoria; Spielberger, Ricardo; Slovak, Marilyn L

2003-08-01

Balanced translocations are rare in myelodysplasia (MDS) and acute myeloid leukemia (AML) with multilineage dysplasia; however, the t(3;5)(q25;q35) and insertion variant occur in a subset of patients. To evaluate the possible genes involved in this translocation, we studied 6 cases with a t(3;5) by fluorescence in situ hybridization with probes directed against the nucleophosmin (NPM), EVI1, and Ribophorin genes, as well as a newly developed myeloid leukemia factor 1 (MLF1) BAC clone. The histologic spectrum of the cases was variable, ranging from refractory cytopenia with multilineage dysplasia to AML with multilineage dysplasia in the World Health Organization classification. An NPM/MLF1 fusion was identified in 5 of 6 cases, whereas the EVI1 and Ribophorin genes were not involved in any of the cases. The NPM/MLF1-positive cases were predominantly young adult males (median age, 33 years) who responded well to hematopoietic stem cell transplantation. These findings suggest that an NPM/MLF1 fusion is the primary molecular abnormality in t(3;5) MDS and AML with multilineage dysplasia, and also that cases with NPM/MLF1 may be clinically distinct from other MDS-associated disease.

Accelerate Genomic Aging in Congenital Neutropenia

DTIC Science & Technology

2015-08-01

for the markedly increased risk of transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital...Hematopoietic stem cells Granulocyte colony-stimulating factor Granulocyte colony-stimulating factor receptor Acute myeloid leukemia Myelodysplastic... myeloid leukemia (AML) is perhaps the major clinical concern in patients with severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS

New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge

PubMed Central

Schanz, Julie; Tüchler, Heinz; Solé, Francesc; Mallo, Mar; Luño, Elisa; Cervera, José; Granada, Isabel; Hildebrandt, Barbara; Slovak, Marilyn L.; Ohyashiki, Kazuma; Steidl, Christian; Fonatsch, Christa; Pfeilstöcker, Michael; Nösslinger, Thomas; Valent, Peter; Giagounidis, Aristoteles; Aul, Carlo; Lübbert, Michael; Stauder, Reinhard; Krieger, Otto; Garcia-Manero, Guillermo; Faderl, Stefan; Pierce, Sherry; Le Beau, Michelle M.; Bennett, John M.; Greenberg, Peter; Germing, Ulrich; Haase, Detlef

2012-01-01

Purpose The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. Patients and Methods Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. Results In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. Conclusion In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories. PMID:22331955

A phase 2 trial of high dose lenalidomide in patients with relapsed/refractory higher-risk myelodysplastic syndromes and acute myeloid leukaemia with trilineage dysplasia.

PubMed

Zeidan, Amer M; Smith, B Douglas; Carraway, Hetty E; Gojo, Ivana; DeZern, Amy; Gore, Steven D

2017-01-01

Limited therapies exist for patients with refractory and relapsed (RR) higher-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukaemia with trilineage dysplasia (AML-TD). High dose (HD) lenalidomide (50 mg) has activity as frontline therapy in elderly AML but there is limited data in the RR setting. This phase II trial included patients with RR HR-MDS or AML-TD at 2 doses of lenalidomide (15 or 50 mg) on days 1-28 of 42-day cycles. The primary endpoint was response rate using the 2006 International Working Group criteria. Overall survival (OS) was estimated by Kaplan-Meier methods. Of 27 patients enrolled, 59% had HR-MDS and 31% AML-TD. No patient had isolated del5q; 41% had poor-risk karyotype. Of 9 patients treated at 15 mg, 56% completed ≥2 cycles with no responses. Of 18 patients treated at 50 mg, 39% completed ≥2 cycles and 11% responded but all experienced grade 3/4 neutropenic fever/infection. The 60-day mortality rate was 30%. Median OS was 114 days with 19% surviving ≥1 year. The study was terminated due to lack of robust clinical activity. In conclusion, lenalidomide at 15 mg is ineffective in RR myeloid malignancies. Continous high dosing schedules are poorly tolerated and minimally active. Further evaluation should be considered in upfront intensive chemotherapy-ineligible patients. © 2016 John Wiley & Sons Ltd.

Constitutional t(5;7)(q11;p15) rearranged to acquire monosomy 7q and trisomy 1q in a patient with myelodysplastic syndrome transforming to acute myelocytic leukemia.

PubMed

Ganly, Peter; McDonald, Margaret; Spearing, Ruth; Morris, Christine M

2004-03-01

We report the case of a 61-year-old woman who presented with a myelodysplastic syndrome (MDS) and a t(5;7)(q11.2;p15) in her bone marrow cells. Subsequent analysis of phytohemagglutinin-stimulated peripheral blood lymphocytes and cultured skin fibroblasts showed that the translocation was constitutional. Disruption of chromosome bands 5q11.2 and 7p15 has been described recurrently in MDS and acute myelocytic leukemia (AML) and, although the age of onset was not earlier than usual, it is nonetheless possible that genes interrupted by this translocation may been a predisposing factor for her condition. With progression to AML, a further rearrangement of the constitutional der(7)t(5;7) occurred, involving chromosome arm 1q. Fluorescence in situ hybridization (FISH) with whole-chromosome paints showed that the result of the second rearrangement, a t(1;7)(q32.1;q32), was observed, leading to trisomy of the segment 1q32.1 approximately qter and monosomy of the segment 7q32.1 approximately qter. The acquired imbalances, particularly loss of 7q, are commonly associated with MDS/AML and a poor prognosis; however, this patient remained in remission after treatment for more than two years before AML relapse, perhaps because the affected regions fall outside of the critical regions of imbalance.

Myelodysplastic Syndrome and Benzene Exposure Among Petroleum Workers: An International Pooled Analysis

PubMed Central

2012-01-01

Background Benzene at high concentrations is known to cause acute myeloid leukemia (AML), but its relationship with other lymphohematopoietic (LH) cancers remains uncertain, particularly at low concentrations. In this pooled analysis, we examined the risk of five LH cancers relative to lower levels of benzene exposure in petroleum workers. Methods We updated three nested case–control studies from Australia, Canada, and the United Kingdom with new incident LH cancers among petroleum distribution workers through December 31, 2006, and pooled 370 potential case subjects and 1587 matched LH cancer-free control subjects. Quantitative benzene exposure in parts per million (ppm) was blindly reconstructed using historical monitoring data, and exposure certainty was scored as high, medium, or low. Two hematopathologists assigned diagnoses and scored the certainty of diagnosis as high, medium, or low. Dose–response relationships were examined for five LH cancers, including the three most common leukemia cell-types (AML, chronic myeloid leukemia [CML], and chronic lymphoid leukemia [CLL]) and two myeloid tumors (myelodysplastic syndrome [MDS] and myeloproliferative disease [MPD]). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, controlling for age, sex, and time period. Results Cumulative benzene exposure showed a monotonic dose–response relationship with MDS (highest vs lowest tertile, >2.93 vs ≤0.348 ppm-years, OR = 4.33, 95% CI = 1.31 to 14.3). For peak benezene exposures (>3 ppm), the risk of MDS was increased in high and medium certainty diagnoses (peak exposure vs no peak exposure, OR = 6.32, 95% CI = 1.32 to 30.2) and in workers having the highest exposure certainty (peak exposure vs no peak exposure, OR = 5.74, 95% CI = 1.05 to 31.2). There was little evidence of dose–response relationships for AML, CLL, CML, or MPD. Conclusions Relatively low-level exposure to benzene experienced by petroleum distribution workers was associated with an increased risk of MDS, but not AML, suggesting that MDS may be the more relevant health risk for lower exposures. PMID:23111193

Multicenter validation study of a transplantation-specific cytogenetics grouping scheme for patients with myelodysplastic syndromes.

PubMed

Armand, P; Deeg, H J; Kim, H T; Lee, H; Armistead, P; de Lima, M; Gupta, V; Soiffer, R J

2010-05-01

Cytogenetics is an important prognostic factor for patients with myelodysplastic syndromes (MDS). However, existing cytogenetics grouping schemes are based on patients treated with supportive care, and may not be optimal for patients undergoing allo-SCT. We proposed earlier an SCT-specific cytogenetics grouping scheme for patients with MDS and AML arising from MDS, based on an analysis of patients transplanted at the Dana-Farber Cancer Institute/Brigham and Women's Hospital. Under this scheme, abnormalities of chromosome 7 and complex karyotype are considered adverse risk, whereas all others are considered standard risk. In this retrospective study, we validated this scheme on an independent multicenter cohort of 546 patients. Adverse cytogenetics was the strongest prognostic factor for outcome in this cohort. The 4-year relapse-free survival and OS were 42 and 46%, respectively, in the standard-risk group, vs 21 and 23% in the adverse group (P<0.0001 for both comparisons). This grouping scheme retained its prognostic significance irrespective of patient age, disease type, earlier leukemogenic therapy and conditioning intensity. Therapy-related disease was not associated with increased mortality in this cohort, after taking cytogenetics into account. We propose that this SCT-specific cytogenetics grouping scheme be used for patients with MDS or AML arising from MDS who are considering or undergoing SCT.

Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers

PubMed Central

Rushton, L; Schnatter, A R; Tang, G; Glass, D C

2014-01-01

Background: High benzene exposure causes acute myeloid leukaemia (AML). Three petroleum case–control studies identified 60 cases (241 matched controls) for AML and 80 cases (345 matched controls) for chronic lymphoid leukaemia (CLL). Methods: Cases were classified and scored regarding uncertainty by two haematologists using available diagnostic information. Blinded quantitative benzene exposure assessment used work histories and exposure measurements adjusted for era-specific circumstances. Statistical analyses included conditional logistic regression and penalised smoothing splines. Results: Benzene exposures were much lower than previous studies. Categorical analyses showed increased ORs for AML with several exposure metrics, although patterns were unclear; neither continuous exposure metrics nor spline analyses gave increased risks. ORs were highest in terminal workers, particularly for Tanker Drivers. No relationship was found between benzene exposure and risk of CLL, although the Australian study showed increased risks in refinery workers. Conclusion: Overall, this study does not persuasively demonstrate a risk between benzene and AML. A previously reported strong relationship between myelodysplastic syndrome (MDS) (potentially previously reported as AML) at our study's low benzene levels suggests that MDS may be the more relevant health risk for lower exposure. Higher CLL risks in refinery workers may be due to more diverse exposures than benzene alone. PMID:24357793

Combined venetoclax and alvocidib in acute myeloid leukemia.

PubMed

Bogenberger, James; Whatcott, Clifford; Hansen, Nanna; Delman, Devora; Shi, Chang-Xin; Kim, Wontak; Haws, Hillary; Soh, Katherine; Lee, Ye Sol; Peterson, Peter; Siddiqui-Jain, Adam; Weitman, Steven; Stewart, Keith; Bearss, David; Mesa, Ruben; Warner, Steven; Tibes, Raoul

2017-12-05

More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro , ex vivo and in vivo . Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.

Combined venetoclax and alvocidib in acute myeloid leukemia

PubMed Central

Bogenberger, James; Whatcott, Clifford; Hansen, Nanna; Delman, Devora; Shi, Chang-Xin; Kim, Wontak; Haws, Hillary; Soh, Katherine; Lee, Ye Sol; Peterson, Peter; Siddiqui-Jain, Adam; Weitman, Steven; Stewart, Keith; Bearss, David; Mesa, Ruben; Warner, Steven; Tibes, Raoul

2017-01-01

More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25–50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo. Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS. PMID:29291023

Myelodysplastic syndromes: more prevalent than we know.

PubMed

Sandhu, Satinderpal K; Sekeres, Mikkael A

2008-11-01

Myelodysplastic syndromes (MDS), a hematopoietic disorder for which formal tracking began as recently as 2001, is rapidly gaining recognition as a cause of anemia. The incidence of MDS increases with age and is considered the most common hematologic cancer in the elderly. The disease can follow an indolent course or rapidly progress to acute myelogenous leukemia (AML). Comorbidities and functional issues make this disease challenging to diagnose and treat in geriatric patients. This article reviews the epidemiology, classification, and treatment options for MDS.

Second malignancies after multiple myeloma: from 1960s to 2010s

PubMed Central

Thomas, Anish; Mailankody, Sham; Korde, Neha; Kristinsson, Sigurdur Y.; Turesson, Ingemar

2012-01-01

Based on small numbers, recent reports from 3 randomized trials have consistently demonstrated more hematologic malignancies in patients treated with lenalidomide as maintenance (vs placebo). This fact has prompted concern and highlighted the association between multiple myeloma and second malignancies. Furthermore, an excess of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after multiple myeloma has been known for over 4 decades. Most prior studies have been restricted because of small numbers of patients, inadequate follow-up, and limitations of ascertainment of second malignancies. Although the underlying biologic mechanisms of AML/MDS after multiple myeloma are unknown, treatment-related factors are presumed to be responsible. Recently, an excess risk of AML/MDS was found among 5652 patients with IgG/IgA (but not IgM) monoclonal gammopathy of undetermined significance, supporting a role for disease-related factors. Furthermore, there is evidence to suggest that polymorphisms in germline genes may contribute to a person's susceptibility to subsequent cancers, whereas the potential influence of environmental and behavioral factors remains poorly understood. This review discusses current knowledge regarding second malignancies after multiple myeloma and gives future directions for efforts designed to characterize underlying biologic mechanisms, with the goal to maximize survival and minimize the risk for second malignancies for individual patients. PMID:22310913

Evaluation and Management of Patients with Isolated Neutropenia

PubMed Central

Newburger, Peter E.; Dale, David C.

2013-01-01

Neutropenia, defined as an absolute neutrophil count below 1.5 × 109/L, encompasses a wide range of diagnoses, from normal variants to life-threatening acquired and congenital disorders. This review addresses the diagnosis and management of isolated neutropenia, not multiple cytopenias due to splenomegaly, bone marrow replacement, or myelosuppression by chemotherapy or radiation. Laboratory evaluation generally includes repeat complete blood counts with differentials and bone marrow examination with cytogenetics. Neutrophil antibody testing may be useful, but only in the context of clinical and bone marrow findings. The discovery of genes responsible for congenital neutropenias now permits genetic diagnosis in many cases. Management of severe chronic neutropenia includes common-sense precautions to avoid infection; aggressive treatment of bacterial or fungal infections; and administration of granulocyte colony-stimulating factor (G-CSF). Patients with severe congenital neutropenia, particularly those who respond poorly to G-CSF, have a risk of eventually developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and require monitoring for this complication, which can also occur without G-CSF therapy. Patients with cyclic, idiopathic and autoimmune neutropenia have virtually no risk of evolving to MDS or AML. Hematopoietic stem cell transplantation is a curative therapy for congenital neutropenia with MDS/AML or with cytogenetic abnormalities indicating impending conversion. PMID:23953336

Second Malignant Neoplasms After Treatment of Childhood Acute Lymphoblastic Leukemia

PubMed Central

Schmiegelow, Kjeld; Levinsen, Mette Frandsen; Attarbaschi, Andishe; Baruchel, Andre; Devidas, Meenakshi; Escherich, Gabriele; Gibson, Brenda; Heydrich, Christiane; Horibe, Keizo; Ishida, Yasushi; Liang, Der-Cherng; Locatelli, Franco; Michel, Gérard; Pieters, Rob; Piette, Caroline; Pui, Ching-Hon; Raimondi, Susana; Silverman, Lewis; Stanulla, Martin; Stark, Batia; Winick, Naomi; Valsecchi, Maria Grazia

2013-01-01

Purpose Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. Patients and Methods We analyzed data on risk factors and outcomes of 642 children with SMNs occurring after treatment for ALL from 18 collaborative study groups between 1980 and 2007. Results Acute myeloid leukemia (AML; n = 186), myelodysplastic syndrome (MDS; n = 69), and nonmeningioma brain tumor (n = 116) were the most common types of SMNs and had the poorest outcome (5-year survival rate, 18.1% ± 2.9%, 31.1% ± 6.2%, and 18.3% ± 3.8%, respectively). Five-year survival estimates for AML were 11.2% ± 2.9% for 125 patients diagnosed before 2000 and 34.1% ± 6.3% for 61 patients diagnosed after 2000 (P < .001); 5-year survival estimates for MDS were 17.1% ± 6.4% (n = 36) and 48.2% ± 10.6% (n = 33; P = .005). Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation. Five-year survival rates were above 90% for patients with meningioma, Hodgkin lymphoma, thyroid carcinoma, basal cell carcinoma, and parotid gland tumor, and 68.5% ± 6.4% for those with non-Hodgkin lymphoma. Eighty-nine percent of patients with brain tumors had received cranial irradiation. Solid tumors were associated with cyclophosphamide exposure, and myeloid malignancy was associated with topoisomerase II inhibitors and starting doses of methotrexate of at least 25 mg/m2 per week and mercaptopurine of at least 75 mg/m2 per day. Myeloid malignancies with monosomy 7/5q− were associated with high hyperdiploid ALL karyotypes, whereas 11q23/MLL-rearranged AML or MDS was associated with ALL harboring translocations of t(9;22), t(4;11), t(1;19), and t(12;21) (P = .03). Conclusion SMNs, except for brain tumors, AML, and MDS, have outcomes similar to their primary counterparts. PMID:23690411

Novel Therapeutic Approaches Targeting MDSC in Myelodysplastic Syndrome

DTIC Science & Technology

2016-09-01

hematopoiesis and a propensity for progression to acute myeloid leukemia (AML). MDS are senescence-dependent myeloid malignancies with a rising prevalence owing... myeloid -derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells, which play a critical role in MDS pathogenesis. A key...cell death of myeloid progenitors. MDSC-mediated suppressive activity is stimulated by the danger-associated molecular pattern (DAMP) heterodimer

A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03).

PubMed

Cooper, Todd M; Sison, Edward Allan Racela; Baker, Sharyn D; Li, Lie; Ahmed, Amina; Trippett, Tanya; Gore, Lia; Macy, Margaret E; Narendran, Aru; August, Keith; Absalon, Michael J; Boklan, Jessica; Pollard, Jessica; Magoon, Daniel; Brown, Patrick A

2017-08-01

Plerixafor, a reversible CXCR4 antagonist, inhibits interactions between leukemic blasts and the bone marrow stromal microenvironment and may enhance chemosensitivity. A phase 1 trial of plerixafor in combination with intensive chemotherapy in children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) was performed to determine a tolerable and biologically active dose. Plerixafor was administered daily for 5 days at four dose levels (6, 9, 12, and 15 mg/m 2 /dose) followed 4 hr later by high-dose cytarabine (every 12 hr) and etoposide (daily). Nineteen patients (13 with AML, 5 with ALL, 1 with MDS) were treated. The most common grade 3 or greater nonhematologic toxicities attributable to plerixafor were febrile neutropenia and hypokalemia. There were no dose-limiting toxicities (DLTs). Plerixafor exposure increased with increasing dose levels and clearance was similar on days 1 and 5. Eighteen patients were evaluable for response. Two patients achieved complete remission (CR) and one patient achieved CR with incomplete hematologic recovery (CRi): all three had AML. No responses were seen in patients with ALL or MDS. Plerixafor mobilized leukemic blasts into the peripheral blood in 14 of 16 evaluable patients (median 3.4-fold increase), and the degree of mobilization correlated with surface CXCR4 expression. Plerixafor, in combination with high-dose cytarabine and etoposide, was well tolerated in children and young adults with relapsed/refractory acute leukemias and MDS. While biologic responses were observed, clinical responses in this heavily pretreated cohort were modest. © 2017 Wiley Periodicals, Inc.

Unrelated cord blood transplantation in adults with myelodysplasia or secondary acute myeloblastic leukemia: a survey on behalf of Eurocord and CLWP of EBMT.

PubMed

Robin, M; Sanz, G F; Ionescu, I; Rio, B; Sirvent, A; Renaud, M; Carreras, E; Milpied, N; Mohty, M; Beguin, Y; Bordigoni, P; de Witte, T; Picardi, A; Purtill, D; Gluckman, E; Kroger, N; Rocha, V

2011-01-01

The aim of our study was to evaluate, through the Eurocord and European Group for Blood and Marrow Transplantation (EBMT) registries, outcomes and risk factors for outcomes in adult patients who underwent single or double unrelated cord blood transplantation (UCBT) for myelodysplastic syndrome (MDS) or secondary acute myeloblastic leukemia (sAML). A total of 180 adults with MDS (n=39) or sAML (n=69) were analyzed. Risk factors for outcomes were analyzed using the Fine and Gray method and the Cox model. Median age was 43 (18-72) years. In all, 77 patients (71%) received a single UCBT. Myeloablative conditioning regimen (MAC) was given to 57 (53%) patients. Median numbers of nucleated and CD34(+) cells at freezing were 3.6 × 10(7) and 1.1 × 10(5) kg. At 60 days, cumulative incidence of neutrophil recovery was 78±4% and was independently associated with the number of CD34(+) cells per kg (>1.1 × 10(5); P=0.005) and advanced disease status (blasts <5% at time of UCBT, P=0.016). A 2-year non-relapse mortality (NRM) was significantly higher after MAC (62 vs 34%; P=0.009). A 2-year disease-free-survival (DFS) and overall survival (OS) were 30 and 34%, respectively. In multivariate analysis, patients with high-risk disease (blasts >5% and International Prognostic scoring system (IPSS) intermediate-2 or high in MDS) had significant poorer DFS (hazard ratio (HR): 1.76; P=0.047). In spite of high NRM, these data indicate that UCBT is an acceptable alternative option to treat adults with high-risk MDS or sAML, without a suitable human leukocyte antigen (HLA)-matched donor.

Azacitidine in the 'real-world': an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada.

PubMed

Mozessohn, Lee; Cheung, Matthew C; Fallahpour, Saber; Gill, Tripat; Maloul, Asmaa; Zhang, Liying; Lau, Olivia; Buckstein, Rena

2018-06-01

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher-risk disease treated with azacitidine (AZA) in the 'real-world' remains largely unknown. We evaluated 1101 consecutive higher-risk MDS patients (International Prognostic Scoring System intermediate-2/high) and low-blast count acute myeloid leukaemia (AML; 21-30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5-2-2. Overall, median number of cycles was 6 (range 1-67) and 8 (range 6-14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7-12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6-19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML. © 2018 John Wiley & Sons Ltd.

A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia.

PubMed

Burnett, A K; Russell, N H; Hills, R K; Kell, J; Nielsen, O J; Dennis, M; Cahalin, P; Pocock, C; Ali, S; Burns, S; Freeman, S; Milligan, D; Clark, R E

2017-02-01

The study was designed to compare clofarabine plus daunorubicin vs daunorubicin/ara-C in older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Eight hundred and six untreated patients in the UK NCRI AML16 trial with AML/high-risk MDS (median age, 67 years; range 56-84) and normal serum creatinine were randomised to two courses of induction chemotherapy with either daunorubicin/ara-C (DA) or daunorubicin/clofarabine (DClo). Patients were also included in additional randomisations; ± one dose of gemtuzumab ozogamicin in course 1; 2v3 courses and ± azacitidine maintenance. The primary end point was overall survival. The overall response rate was 69% (complete remission (CR) 60%; CRi 9%), with no difference between DA (71%) and DClo (66%). There was no difference in 30-/60-day mortality or toxicity: significantly more supportive care was required in the DA arm even though platelet and neutrophil recovery was significantly slower with DClo. There were no differences in cumulative incidence of relapse (74% vs 68%; hazard ratio (HR) 0.93 (0.77-1.14), P=0.5); survival from relapse (7% vs 9%; HR 0.96 (0.77-1.19), P=0.7); relapse-free (31% vs 32%; HR 1.02 (0.83-1.24), P=0.9) or overall survival (23% vs 22%; HR 1.08 (0.93-1.26), P=0.3). Clofarabine 20 mg/m 2 given for 5 days with daunorubicin is not superior to ara-C+daunorubicin as induction for older patients with AML/high-risk MDS.

Continuous sequential infusion of fludarabine and cytarabine for elderly patients with acute myeloid leukaemia secondary to a previously diagnosed myelodysplastic syndrome.

PubMed

Ferrara, Felicetto; Palmieri, Salvatore; Izzo, Tiziana; Criscuolo, Clelia; Riccardi, Cira

2010-12-01

Acute myeloid leukaemia (AML) secondary to myelodysplastic syndrome (MDS) is characterized by poor prognosis, namely in older patients. The combination of fludarabine (F) with cytarabine (ARA-C) ± G-CSF was proven as effective in patients with poor risk AML. The efficacy and toxicity of a regimen including F + ARA-C as sequential continuous infusion (CI-FLA) in 64 untreated patients aged >60 years, in which AML arose after a previous MDS, was investigated. Median age was 67 years (61-81). In patients achieving CR, an additional course, followed by G-CSF to mobilize CD34+ cells and subsequent autologous stem cell transplantation (ASCT) were programmed. Overall, 43 patients (67%) achieved complete remission (CR). There were 10 induction deaths (16%), while 11 patients (17%) were refractory to induction treatment. Thirty-four patients (79% of remitters) were eligible for the consolidation and 30 were monitorized for the mobilization of CD34+ cells, collection being successful in 20 of them (67%). Median number of CD34+ cells/kg collected was 6.8 × 10E6. Thirteen patients (20% of the whole population) received ASCT. Median disease free survival (DFS) and overall survival (OS) were 10 and 9 months, respectively. Survival at 5 years is projected to 15%. The only parameter significantly related to either DFS duration or OS duration was unfavourable cytogenetics, which did significantly influence also CR achievement. CI-FLA is effective in elderly patients with AML secondary to previously diagnosed MDS. Best results are achievable in the subgroup of patients with diploid karyotype. Copyright © 2010 John Wiley & Sons, Ltd.

A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia

PubMed Central

Burnett, A K; Russell, N H; Hills, R K; Kell, J; Nielsen, O J; Dennis, M; Cahalin, P; Pocock, C; Ali, S; Burns, S; Freeman, S; Milligan, D; Clark, R E

2017-01-01

The study was designed to compare clofarabine plus daunorubicin vs daunorubicin/ara-C in older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Eight hundred and six untreated patients in the UK NCRI AML16 trial with AML/high-risk MDS (median age, 67 years; range 56–84) and normal serum creatinine were randomised to two courses of induction chemotherapy with either daunorubicin/ara-C (DA) or daunorubicin/clofarabine (DClo). Patients were also included in additional randomisations; ± one dose of gemtuzumab ozogamicin in course 1; 2v3 courses and ± azacitidine maintenance. The primary end point was overall survival. The overall response rate was 69% (complete remission (CR) 60% CRi 9%), with no difference between DA (71%) and DClo (66%). There was no difference in 30-/60-day mortality or toxicity: significantly more supportive care was required in the DA arm even though platelet and neutrophil recovery was significantly slower with DClo. There were no differences in cumulative incidence of relapse (74% vs 68% hazard ratio (HR) 0.93 (0.77–1.14), P=0.5); survival from relapse (7% vs 9% HR 0.96 (0.77–1.19), P=0.7); relapse-free (31% vs 32% HR 1.02 (0.83–1.24), P=0.9) or overall survival (23% vs 22% HR 1.08 (0.93–1.26), P=0.3). Clofarabine 20 mg/m2 given for 5 days with daunorubicin is not superior to ara-C+daunorubicin as induction for older patients with AML/high-risk MDS. PMID:27624670

c-Src activation through a TrkA and c-Src interaction is essential for cell proliferation and hematological malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Min Soo; Kim, Gyoung Mi; Choi, Yun-Jeong

2013-11-15

Highlights: •TrkA was mainly present in other types of leukemia including AML. •TrkA enhances the survival of leukemia by activation of PI3K/Akt pathway. •TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1. •TrkA acted as a key regulator of leukemogenesis and survival through c-Src activation. -- Abstract: Although the kinase receptor TrkA may play an important role in acute myeloid leukemia (AML), its involvement in other types of leukemia has not been reported. Furthermore, how it contributes to leukemogenesis is unknown. Here, we describe a molecular network that is important for TrkA function in leukemogenesis. We found that TrkAmore » is frequently overexpressed in other types of leukemia such as acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) including AML. In addition, TrkA was overexpressed in patients with MDS or secondary AML evolving from MDS. TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1, and enhanced survival and proliferation of leukemia, which was correlated with activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway. Moreover, endogenous TrkA associated with c-Src complexes was detected in leukemia. Suppression of c-Src activation by TrkA resulted in markedly decreased expression of PLK-1 and Twist-1 via suppressed activation of Akt/mTOR cascades. These data suggest that TrkA plays a key role in leukemogenesis and reveal an unexpected physiological role for TrkA in the pathogenesis of leukemia. These data have important implications for understanding various hematological malignancies.« less

Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

ClinicalTrials.gov

2018-06-01

Leukemia, Acute; Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL); Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL)

Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies

ClinicalTrials.gov

2009-01-28

Leukemia, Acute Lymphocytic (ALL); Leukemia, Myeloid, Acute(AML); Leukemia, Myeloid, Chronic(CML); Juvenile Myelomonocytic Leukemia(JMML); Hemoglobinuria, Paroxysmal Nocturnal (PNH); Lymphoma, Non-Hodgkin (NHL); Myelodysplastic Syndrome (MDS)

Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis—Masters of Survival and Clonality?

PubMed Central

Pleyer, Lisa; Valent, Peter; Greil, Richard

2016-01-01

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the “reprogramming” of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs. PMID:27355944

Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis-Masters of Survival and Clonality?

PubMed

Pleyer, Lisa; Valent, Peter; Greil, Richard

2016-06-27

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the "reprogramming" of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs.

Nonmyeloablative Allo SCT for the Treatment of Hematologic Disorders

ClinicalTrials.gov

2017-04-05

AML; ALL; CML Chronic Phase, Accelerated Phase, or Blast Crisis; CLL; MDS; RELAPSED NON-HODGKIN'S OR HODGKIN'S LYMPHOMA; APLASTIC ANEMIA; MULTIPLE MYELOMA; MYELOPROLIFERATIVE DISORDER (P Vera, CMML, ET)

CD34+ (Malignant) Stem Cell Selection for Patients Receiving Allogenic Stem Cell Transplant

ClinicalTrials.gov

2017-07-13

Chronic Myeloid Leukemia (CML); Acute Myelogenous Leukemia (AML); Myelodysplastic Syndrome (MDS); Juvenile Myelomonocytic Leukemia (JMML); Acute Lymphoblastic Leukemia (ALL); Lymphoma (Hodgkin's and Non-Hodgkin's)

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia.

PubMed

Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur; Yuan, Han; Ho, Tzu-Chieh; Wang, Tiansu; Vora, Shailee; Solovyov, Alexander; Husser, Chrystel; Olszewska, Malgorzata; Teruya-Feldstein, Julie; Perumal, Deepak; Klimek, Virginia M; Spyridonidis, Alexandros; Rampal, Raajit K; Silverman, Lewis; Reddy, E Premkumar; Papaemmanuil, Elli; Parekh, Samir; Greenbaum, Benjamin D; Leslie, Christina S; Kharas, Michael G; Papapetrou, Eirini P

2017-03-02

Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide

ClinicalTrials.gov

2018-04-18

Myelodysplastic Syndrome (MDS); Chronic Lymphocytic Leukemia (CLL); Chemotherapy-sensitive Lymphoma; Acute Lymphoblastic Leukemia (ALL)/T Lymphoblastic Lymphoma; Acute Myelogenous Leukemia (AML); Acute Biphenotypic Leukemia (ABL); Acute Undifferentiated Leukemia (AUL)

Phase 1 Study of Terameprocol (EM-1421) in Patients With Leukemia

ClinicalTrials.gov

2016-02-20

Leukemias; Acute Myeloid Leukemia (AML); Acute Lymphocytic Leukemia (ALL); Adult T Cell Leukemia (ATL); Chronic Myeloid Leukemia (CML-BP); Chronic Lymphocytic Leukemia (CLL); Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML)

Allogeneic hematopoietic cell transplantation after conditioning with I-131-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pagel, John M.; Gooley, T. A.; Rajendran, Joseph G.

2009-12-24

We conducted a study to estimate the maximum tolerated dose (MTD) of I-131-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the bloodmore » by day 28 after the transplantation. The MTD of I-131-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.« less

Risk of myeloid neoplasms after solid organ transplantation

PubMed Central

Morton, Lindsay M.; Gibson, Todd M.; Clarke, Christina A.; Lynch, Charles F.; Anderson, Lesley A.; Pfeiffer, Ruth; Landgren, Ola; Weisenburger, Dennis D.; Engels, Eric A.

2014-01-01

Solid organ transplant recipients have elevated cancer risks, due in part to pharmacologic immunosuppression. However, little is known about risks for hematologic malignancies of myeloid origin. We linked the US Scientific Registry of Transplant Recipients with 15 population-based cancer registries to ascertain cancer occurrence among 207,859 solid organ transplants (1987–2009). Solid organ transplant recipients had significantly elevated risk for myeloid neoplasms, with standardized incidence ratios (SIRs) of 4.6 (95% confidence interval 3.8–5.6; N=101) for myelodysplastic syndromes (MDS), 2.7 (2.2–3.2; N=125) for acute myeloid leukemia (AML), 2.3 (1.6–3.2; N=36) for chronic myeloid leukemia, and 7.2 (5.4–9.3; N=57) for polycythemia vera. SIRs were highest among younger individuals and varied by time since transplantation and organ type (Poisson regression P<0.05 for all comparisons). Azathioprine for initial maintenance immunosuppression increased risk for MDS (P=0.0002) and AML (2–5 years after transplantation, P=0.0163). Overall survival following AML/MDS among transplant recipients was inferior to that of similar patients reported to US cancer registries (log-rank P<0.0001). Our novel finding of increased risks for specific myeloid neoplasms after solid organ transplantation supports a role for immune dysfunction in myeloid neoplasm etiology. The increased risks and inferior survival should heighten clinician awareness of myeloid neoplasms during follow-up of transplant recipients. PMID:24727673

Enhancing Natural Killer Cell Mediated Targeting and Responses to Myeloid Leukemias

DTIC Science & Technology

2017-10-01

Syndromes , AML – Acute Myeloid Leukemia, BiKE – Bi-specific Killer Engager, TriKE – Tri-specific Killer E 16. SECURITY CLASSIFICATION OF: 17...Natural Killer CML – Chronic Myeloid Leukemia MDS – Myelodysplastic Syndromes AML – Acute Myeloid Leukemia BiKE – Bi-specific Killer Engager TriKE...incidence of myeloid malignancies is increased due to exposure to ionizing radiation , chemicals, and other agents during deployment. Although

Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q).

PubMed

Fenaux, Pierre; Giagounidis, Aristoteles; Selleslag, Dominik; Beyne-Rauzy, Odile; Mittelman, Moshe; Muus, Petra; Nimer, Stephen D; Hellström-Lindberg, Eva; Powell, Bayard L; Guerci-Bresler, Agnes; Sekeres, Mikkael A; Deeg, H Joachim; Del Cañizo, Consuelo; Greenberg, Peter L; Shammo, Jamile M; Skikne, Barry; Yu, Xujie; List, Alan F

2017-06-26

Particularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed. We assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials. A total of 33.9, 34.3, and 31.8% patients were aged <65 years, ≥65 to <75 years, and ≥75 years, respectively. Age <65 years was associated with less favorable International Prognostic Scoring System (IPSS) risk and additional cytopenias at baseline versus older age groups, significantly lower cytogenetic response rates (p = 0.022 vs. ≥65 to <75 years; p = 0.047 vs. ≥75 years), and higher rates of acute myeloid leukemia (AML) progression (Gray's test, p = 0.013). Lenalidomide was equally well tolerated across age groups, producing consistently high rates of red blood cell transfusion independence ≥26 weeks. Baseline disease characteristics and AML progression appear to be more severe in younger lower-risk MDS patients with del(5q), whereas older age does not seem to compromise the response to lenalidomide. ClinicalTrials.gov NCT00065156 and NCT00179621.

[Myelodysplastic syndromes].

PubMed

Thol, F; Heuser, M; Ganser, A

2015-04-01

Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of diseases originating in hematopoietic stem cells and is characterized by inefficient hematopoiesis and dysplastic changes in the bone marrow. In peripheral blood patients show anemia (mostly macrocytic), frequently accompanied by neutropenia and thrombocytopenia. Thus, clinically the patients suffer from fatigue (anemia), increased bleeding (thrombocytopenia) and infectious complications (neutropenia). Approximately one quarter of MDS patients develop acute myeloid leukemia (AML) in the course of the disease, which is characterized by a 20 % or more increase of blasts in the bone marrow. The estimated overall survival as well as the risk for AML transformation can be calculated with the international prognostic scoring system (IPSS) as well as the revised IPSS score (IPSS-R). Novel sequencing methods (e.g. next generation sequencing) allow the detection of recurrent gene mutations in MDS patients. Genes of the splicing machinery as well as genes involved in epigenetic regulation (e.g. ASXL1 and TET2) are most frequently mutated in MDS. Therapy is selected based on the patient risk profile (IPSS). Allogeneic stem cell transplantation is a curative approach for high risk patients (i.e. IPSS int-2 and higher) with a good performance status and a biological age below 70 years. Otherwise, high risk patients are treated with demethylating agents (e.g. decitabine and azacitidine). Low risk patients (IPSS low and int-1) mainly receive supportive therapy including iron chelation. An exceptional position is presented by MDS with an isolated 5q deletion as it can be treated with lenalidomide with good success. Enrolling patients in clinical trials is strongly recommended to improve the prospects of this disease.

Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies

ClinicalTrials.gov

2018-05-09

Leukemia, Acute Lymphocytic (ALL); Leukemia, Myeloid, Acute(AML); Leukemia, Myeloid, Chronic(CML); Juvenile Myelomonocytic Leukemia (JMML); Hemoglobinuria, Paroxysmal Nocturnal (PNH); Hodgkin Lymphoma; Lymphoma, Non-Hodgkin (NHL); Myelodysplastic Syndrome (MDS)

Haploid Allogeneic Transplant Using the CliniMACS System

ClinicalTrials.gov

2015-02-26

Acute Myelogenous Leukemia (AML) - Relapsed, Primary Refractory Disease or Poor Risk Factors; Chronic Myelogenous Leukemia (CML) - Accelerated or Second Chronic Phase; Myelodysplastic Syndrome (MDS) - High and Intermediate Risk; Non-Hodgkin's Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL) - Refractory

Late effect of atomic bomb radiation on myeloid disorders: leukemia and myelodysplastic syndromes.

PubMed

Tsushima, Hideki; Iwanaga, Masako; Miyazaki, Yasushi

2012-03-01

Leukemia was the first malignancy linked to radiation exposure in atomic bomb survivors. Clear evidence of the dose-dependent excess risk of three major types of leukemia (acute lymphocytic leukemia, acute myeloid leukemia [AML], and chronic myeloid leukemia) was found, especially in people exposed at young ages. Such leukemia risks were at their highest in the late 1950s, and declined gradually thereafter over the past 50 years. Findings from recent risk analyses, however, suggest the persistence of AML risk even after 1990, and evidence of increased risk of myelodysplastic syndromes (MDS) due to atomic bomb radiation has recently been shown. High-risk MDS and forms involving complex chromosomal aberrations were found to be much more frequent in people exposed to higher radiation doses. These lines of epidemiological evidence suggest that the risk of radiation-induced hematological malignancies has persisted for six decades since the initial exposure.

Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation.

PubMed

Bousquet, Marina; Quelen, Cathy; Rosati, Roberto; Mansat-De Mas, Véronique; La Starza, Roberta; Bastard, Christian; Lippert, Eric; Talmant, Pascaline; Lafage-Pochitaloff, Marina; Leroux, Dominique; Gervais, Carine; Viguié, Franck; Lai, Jean-Luc; Terre, Christine; Beverlo, Berna; Sambani, Costantina; Hagemeijer, Anne; Marynen, Peter; Delsol, Georges; Dastugue, Nicole; Mecucci, Cristina; Brousset, Pierre

2008-10-27

Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34(+) cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.

Outcome of acute myeloid leukemia and high-risk myelodysplastic syndrome according to health insurance status.

PubMed

Al-Ameri, Ali; Anand, Ankit; Abdelfatah, Mohamed; Kanaan, Zeyad; Hammonds, Tracy; Haller, Nairmeen; Cherry, Mohamad

2014-12-01

Age, cytogenetic status, and molecular features are the most important prognostic factors in acute myeloid leukemia (AML). This study aimed to analyze the outcomes of patients with AML or high-risk myelodysplastic syndrome (MDS) according to insurance status. A retrospective chart review was performed, covering all patients with AML and high-risk MDS evaluated and treated at Akron General Medical Center between 2002 and 2012. A Cox regression model was analyzed to account for survival over time, adjusted for insurance type, while controlling for patient age at diagnosis and patient risk of mortality. A total of 130 adult patients (age ≥ 18 years) were identified. Insurance information was available for 97 patients enrolled in the study; 3 were excluded because of self-pay status. Cox regression analysis with insurance type as the predictor found that overall survival declines over time and that the rate of decline may be influenced by insurance type (χ(2)(2) = 6.4; P = .044). The likelihood of survival in patients with Medicaid or Medicare without supplemental insurance was .552 (95% CI, .338-.903; P = .018) times the likelihood in patients who had Medicare with supplemental insurance. To explain the difference, variables of age, gender, and risk of mortality were added to the model. Age and risk of mortality were found to be significant predictors of survival. The addition of insurance type to the model did not significantly contribute (χ(2)(3) = 3.83; P = .147). No significant difference in overall survival was observed when patients with AML or high-risk MDS were analyzed according to their health insurance status. The overall survival was low in this study compared with the national average. Early referral to a specialized center or possible clinical trial enrollment may be a good alternative to improve outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A.

PubMed

Oben, Karine Z; Alhakeem, Sara S; McKenna, Mary K; Brandon, Jason A; Mani, Rajeswaran; Noothi, Sunil K; Jinpeng, Liu; Akunuru, Shailaja; Dhar, Sanjit K; Singh, Inder P; Liang, Ying; Wang, Chi; Abdel-Latif, Ahmed; Stills, Harold F; St Clair, Daret K; Geiger, Hartmut; Muthusamy, Natarajan; Tohyama, Kaoru; Gupta, Ramesh C; Bondada, Subbarao

2017-09-29

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS.

Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A

PubMed Central

Oben, Karine Z.; Alhakeem, Sara S.; McKenna, Mary K.; Brandon, Jason A.; Mani, Rajeswaran; Noothi, Sunil K.; Jinpeng, Liu; Akunuru, Shailaja; Dhar, Sanjit K.; Singh, Inder P.; Liang, Ying; Wang, Chi; Abdel-Latif, Ahmed; Stills Jr, Harold F.; St. Clair, Daret K.; Geiger, Hartmut; Muthusamy, Natarajan; Tohyama, Kaoru; Gupta, Ramesh C.; Bondada, Subbarao

2017-01-01

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS. PMID:29100399

A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.

PubMed

Sugino, N; Kawahara, M; Tatsumi, G; Kanai, A; Matsui, H; Yamamoto, R; Nagai, Y; Fujii, S; Shimazu, Y; Hishizawa, M; Inaba, T; Andoh, A; Suzuki, T; Takaori-Kondo, A

2017-11-01

Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.

RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.

PubMed

Estécio, Marcos R H; Maddipoti, Sirisha; Bueso-Ramos, Carlos; DiNardo, Courtney D; Yang, Hui; Wei, Yue; Kondo, Kimie; Fang, Zhihong; Stevenson, William; Chang, Kun-Sang; Pierce, Sherry A; Bohannan, Zachary; Borthakur, Gautam; Kantarjian, Hagop; Garcia-Manero, Guillermo

2015-05-01

Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias. © 2015 John Wiley & Sons Ltd.

Conditioning with Treosulfan and Fludarabine Followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

PubMed Central

Nemecek, Eneida R.; Guthrie, Katherine A.; Sorror, Mohamed L.; Wood, Brent L.; Doney, Kristine C.; Hilger, Ralf A.; Scott, Bart L.; Kovacsovics, Tibor J.; Maziarz, Richard T.; Woolfrey, Ann E.; Bedalov, Antonio; Sanders, Jean E.; Pagel, John M.; Sickle, Eileen J.; Witherspoon, Robert; Flowers, Mary E.; Appelbaum, Frederick R.; Deeg, H. Joachim

2010-01-01

In this prospective study 60 patients of median age 46 (range 5–60) years, with acute myeloid leukemia (AML; n=44), acute lymphoblastic leukemia (ALL; n=3), or myelodysplastic syndrome (MDS; n=13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine combination. Most patients were considered at high risk for relapse or non-relapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m2/day (n=5) or 14 g/m2/day (n=55) on days -6 to -4, and fludarabine (30 mg/m2/day) on days -6 to -2, followed by infusion of marrow (n=7) or peripheral blood stem cells (n=53) from HLA-identical siblings (n=30) or unrelated donors (n=30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival for all patients was 58% and 88% for patients without high risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/fludarabine regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/fludarabine to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients. PMID:20685259

Federal Logistics Information System (FLIS). Volume 18. Automated Mailing Labels System (AMLS) FLIS Procedures Manual

DTIC Science & Technology

1993-07-01

LPLPW3t TIME XXXX\\ LISI ADDRESSES AND DISIRIBUTION FOR XX XXXXXXXXXXXXXXXXXX\\ LSER ID XXX P %G[ ZZ.zz9 AA MLG MAILING ADDRESS ZIP CODE PI C x XNXX XX...4100.39-M Volume Is APPENDIX C AMLS INFORMATIONAL MESSAGES Corrective Action: Press the F6 ( COM MIT) function key to add the Distribution information

Clonal hematopoiesis in acquired aplastic anemia.

PubMed

Ogawa, Seishi

2016-07-21

Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1 Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA. © 2016 by The American Society of Hematology.

Clonal hematopoiesis in acquired aplastic anemia

PubMed Central

2016-01-01

Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA. PMID:27121470

Economic evaluation of posaconazole versus fluconazole or itraconazole in the prevention of invasive fungal infection in high-risk neutropenic patients in Sweden.

PubMed

Lundberg, Johan; Höglund, Martin; Björkholm, Magnus; Åkerborg, Örjan

2014-07-01

In patients undergoing induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), posaconazole has been proven more effective in the prevention of invasive fungal infection (IFI) than fluconazole or itraconazole (standard azoles) The current analysis seeks to estimate the cost effectiveness of prophylactic posaconazole compared with standard azoles in AML or MDS patients with severe chemotherapy-induced neutropenia in Sweden. A decision-analytic model was used to estimate life expectancy, costs, and quality-adjusted life-years (QALYs). Efficacy data were derived from a phase III clinical trial. Life expectancy and quality of life data were collected from the literature. A modified Delphi method was used to gather expert opinion on resource use for an IFI. Unit costs were captured from hospital and pharmacy pricelists. A probabilistic sensitivity analysis (PSA) was used to investigate the impact of uncertainty in the model parameters on the cost-effectiveness results. The estimated mean direct cost per patient with posaconazole prophylaxis was 46,893 Swedish kronor (SEK) (€5,387) and SEK50,017 (€5,746) with standard azoles. Prophylaxis with posaconazole resulted in 0.075 QALYs gained compared with standard azoles. At a cost-effectiveness threshold of SEK500,000/QALY the PSA demonstrated a more than 95 % probability that posaconazole is cost effective versus standard azoles for the prevention of IFI in high-risk neutropenic patients in Sweden. Given the assumptions, methods, and data used, posaconazole is expected to be cost effective compared with standard azoles when used as antifungal prophylaxis in AML or MDS patients with chemotherapy-induced prolonged neutropenia in Sweden.

[Phase II study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate) on hematological malignancies].

PubMed

Tatsumi, N; Yamada, K; Ohshima, T; Nakamura, T; Ohno, R; Masaoka, T; Kimura, I; Kimura, K

1990-12-01

Phase II study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate), a derivative of cytosine arabinoside, on hematological malignancies was conducted by multi-institutional cooperative group. YNK01 was administered orally at dose of 100-300 mg/body/day for more than 2 weeks. The number of registered and evaluated patients were 211 and 156, respectively. Of 23 patients with acute myelogeneous leukemia (AML), 2 complete response (CR), one partial response (PR) were observed (CR + PR: 13.0%). Hypoplastic leukemia (1/4: 25%), acute unclassified leukemia (1/1: 100%). Of 45 patients with MDS, 2CRs, 6 good response (GR) and 5PRs were observed (CR + PR: 28.9%). AML developing after a prior history of MDS (5/17: 29.4%), CML-BC (2/9: 22.2%). Of 19 patients with CML, 9 achieved CR, 3 achieved PR (63.2%). Of 11 patients with polycythemia vera, 4 achieved CR, 5 achieved PR (81.8%). Of 6 patients with essential thrombocytosis, 2 achieved CR, one achieved PR (50%). The major adverse effects included gastrointestinal toxicities such as nausea, vomiting, anorexia, diarrhea, and elevation of GOT and GPT which were tolerable and reversible. This study indicates that YNK01 is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL.

Expression of lung resistance protein and correlation with other drug resistance proteins and outcome in myelodysplastic syndromes.

PubMed

Lepelley, P; Poulain, S; Grardel, N; Preudhomme, C; Cosson, A; Fenaux, P

1998-05-01

The major vault lung resistance protein LRP is a cytoplasmic protein involved in drug resistance, especially in acute myeloid leukemia. We looked for LRP overexpression, using immunocytochemistry with LRP 56 monoclonal antibody, on marrow slides from 41 cases of myelodysplastic syndromes (MDS). LRP overexpression (LRP+) was defined by expression of LRP 56 in at least 20% of marrow blasts. LRP overexpression was seen in 19 (46%) cases. Concordant results between LRP overexpression and P-glycoprotein (PGP) expression were seen in 66% of the cases (p = 0.03), and discordant results (LRP+ and PGP-, or LRP- and PGP+) in 33% of the cases. No correlation was seen between LRP overexpression and FAB type, karyotype, CD34, p53 expression and bcl2 overexpression in blasts. Furthermore, in the 18 cases treated with anthracycline-AraC intensive chemotherapy and the 7 cases treated with low dose AraC, the response rate was not significantly different in LRP+ and LRP- patients. Survival was also similar in LRP+ and LRP- patients. In conclusion, LRP overexpression is probably more frequent in MDS than in de novo AML and, as in AML, is only partially correlated with PGP expression. In our experience, however, LRP was not a prognostic factor for response to chemotherapy and survival in MDS.

Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome.

PubMed

Maslak, P; Chanel, S; Camacho, L H; Soignet, S; Pandolfi, P P; Guernah, I; Warrell, R; Nimer, S

2006-02-01

Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.

Donor cell-derived leukemia after cord blood transplantation and a review of the literature: differences between cord blood and BM as the transplant source.

PubMed

Shiozaki, H; Yoshinaga, K; Kondo, T; Imai, Y; Shiseki, M; Mori, N; Teramura, M; Motoji, T

2014-01-01

Donor cell-derived leukemia (DCL) is a rare complication of SCT. Here, we present a case of DCL following cord blood transplantation (CBT) and review the clinical features of previously reported DCL. To our knowledge, this is the first report comparing clinical characteristics of DCL from the standpoint of the transplant source, with umbilical cord blood and BM. AML and myelodysplastic syndrome (MDS) were recognized more frequently in DCL after CBT, whereas the incidence of AML and ALL was similar after BMT. The median duration between the occurrence of DCL following CBT and BMT was 14.5 and 36 months, respectively. DCL occurred in a significantly shorter period after CBT than after BMT. Abnormal karyotypes involving chromosome 7 were observed in 52.4% of CBT recipients and 17.3% of BMT recipients; this was a statistically significant difference. Particularly, the frequency of monosomy 7 was significantly higher in DCL after CBT than after BMT. The types of abnormal karyotypes in DCL following BMT were similar to those characteristically observed in adult de novo AML and MDS. DCL patients generally have a poor prognosis in both groups. SCT is the best treatment for curing DCL. DCL appears to have different clinical features according to the transplant source.

Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage.

PubMed

Souza, Liliana R; Silva, Erica; Calloway, Elissa; Kucuk, Omer; Rossi, Michael; McLemore, Morgan L

2014-05-01

Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSF-induced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation.

Therapy-related Myeloid Leukemia

PubMed Central

Godley, Lucy A.; Larson, Richard A.

2008-01-01

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are thought to be the direct consequence of mutational events induced by chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities, given for a pre-existing condition. The outcomes for these patients have been poor historically compared to people who develop de novo AML. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-AML. Survival varies according to cytogenetic risk group in t-AML patients, with better outcomes being observed in those with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. A deeper understanding of the factors that predispose patients to the development of therapy-related myeloid leukemia would help clinicians monitor patients more carefully after treatment for a primary condition. Ultimately, this knowledge could influence initial treatment strategies with the goal of decreasing the incidence of this serious complication. PMID:18692692

Spectral karyotyping (SKY) in hematological neoplasia

NASA Astrophysics Data System (ADS)

Preiss, Birgitte S.; Pedersen, Rikke K.; Kerndrup, Gitte B.

2001-07-01

From November 1, 1997 till November 1, 2000 we have investigated 204 cases of acute myeloid leukemia (AML) (nequals95), acute lymphatic leukemia (ALL) (nequals40), myelodysplastic syndrome (MDS) (nequals11), chronic myeloid leukemia (CML) (nequals9), chronic lymphatic leukemia (CLL) (nequals4) and non-Hodgkin lymphoma (NHL) (nequals45) cytogenetically, using G-band analysis and spectral karyotyping (SKY). By SKY we were able to detect the abnormal clones in all cases but 9. In the G-band preparations these cases showed very few abnormal mitoses. The SKY either extended or confirmed the G-band findings in 94% of those with an abnormal karyotype. Cryptic translocations (translocations not suspected from the G-band karyotype) were found in 71 cases (26 AML, 9 ALL, 5 MDS, 2 CLL and 29 NHL). We find SKY a powerful adjuvant diagnostic tool that does not compromise one of the advantages of karyotyping techniques, the analysis of the entire genome which, in contrast to molecular biological techniques, still leave the possibility to get mroe answers than questions posed.

Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies.

PubMed

Maples, Kathryn T; Sabo, Roy T; McCarty, John M; Toor, Amir A; Hawks, Kelly G

2018-04-04

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time.

Myeloid cell differentiation arrest by miR-125b-1 in myelodysplasic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation

PubMed Central

Bousquet, Marina; Quelen, Cathy; Rosati, Roberto; Mansat-De Mas, Véronique; La Starza, Roberta; Bastard, Christian; Lippert, Eric; Talmant, Pascaline; Lafage-Pochitaloff, Marina; Leroux, Dominique; Gervais, Carine; Viguié, Franck; Lai, Jean-Luc; Terre, Christine; Beverlo, Berna; Sambani, Costantina; Hagemeijer, Anne; Marynen, Peter; Delsol, Georges; Dastugue, Nicole; Mecucci, Cristina; Brousset, Pierre

2008-01-01

Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34+ cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity. PMID:18936236

Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions

PubMed Central

Valent, Peter; Orazi, Attilio; Steensma, David P.; Ebert, Benjamin L.; Haase, Detlef; Malcovati, Luca; van de Loosdrecht, Arjan A.; Haferlach, Torsten; Westers, Theresia M.; Wells, Denise A.; Giagounidis, Aristoteles; Loken, Michael; Orfao, Alberto; Lübbert, Michael; Ganser, Arnold; Hofmann, Wolf-Karsten; Ogata, Kiyoyuki; Schanz, Julie; Béné, Marie C.; Hoermann, Gregor; Sperr, Wolfgang R.; Sotlar, Karl; Bettelheim, Peter; Stauder, Reinhard; Pfeilstöcker, Michael; Horny, Hans-Peter; Germing, Ulrich; Greenberg, Peter; Bennett, John M.

2017-01-01

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, dysplasia, and a variable clinical course with about 30% risk to transform to secondary acute myeloid leukemia (AML). In the past 15 years, diagnostic evaluations, prognostication, and treatment of MDS have improved substantially. However, with the discovery of molecular markers and advent of novel targeted therapies, new challenges have emerged in the complex field of MDS. For example, MDS-related molecular lesions may be detectable in healthy individuals and increase in prevalence with age. Other patients exhibit persistent cytopenia of unknown etiology without dysplasia. Although these conditions are potential pre-phases of MDS they may also transform into other bone marrow neoplasms. Recently identified molecular, cytogenetic, and flow-based parameters may add in the delineation and prognostication of these conditions. However, no generally accepted integrated classification and no related criteria are as yet available. In an attempt to address this challenge, an international consensus group discussed these issues in a working conference in July 2016. The outcomes of this conference are summarized in the present article which includes criteria and a proposal for the classification of pre-MDS conditions as well as updated minimal diagnostic criteria of MDS. Moreover, we propose diagnostic standards to delineate between ´normal´, pre-MDS, and MDS. These standards and criteria should facilitate diagnostic and prognostic evaluations in clinical studies as well as in clinical practice. PMID:29088721

Resource Utilization and Safety of Outpatient Management Following Intensive Induction or Salvage Chemotherapy for Acute Myeloid Leukemia or Myelodysplastic Syndrome: A Nonrandomized Clinical Comparative Analysis.

PubMed

Vaughn, Jennifer E; Othus, Megan; Powell, Morgan A; Gardner, Kelda M; Rizzuto, Donelle L; Hendrie, Paul C; Becker, Pamela S; Pottinger, Paul S; Estey, Elihu H; Walter, Roland B

2015-11-01

Adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) typically remain hospitalized after induction or salvage chemotherapy until blood cell count recovery, with resulting prolonged inpatient stays being a primary driver of health care costs. Pilot studies suggest that outpatient management following chemotherapy might be safe and could reduce costs for these patients. To compare safety, resource utilization, infections, and costs between adults discharged early following AML or MDS induction or salvage chemotherapy and inpatient controls. Nonrandomized, phase 2, single-center study conducted at the University of Washington Medical Center. Over a 43-month period (January 1, 2011, through July 31, 2014), 178 adults receiving intensive AML or MDS chemotherapy were enrolled. After completion of chemotherapy, 107 patients met predesignated medical and logistical criteria for early discharge, while 29 met medical criteria only and served as inpatient controls. Early-discharge patients were released from the hospital at the completion of chemotherapy, and supportive care was provided in the outpatient setting until blood cell count recovery (median, 21 days; range, 2-45 days). Controls received inpatient supportive care (median, 16 days; range, 3-42 days). We analyzed differences in early mortality, resource utilization including intensive care unit (ICU) days, transfusions per study day, and use of intravenous (IV) antibiotics per study day), numbers of infections, and total and inpatient charges per study day among early-discharge patients vs controls. Four of the 107 early-discharge patients and none of the 29 control patients died within 30 days of enrollment (P=.58). Nine early-discharge patients (8%) but no controls required ICU-level care (P=.20). No differences were noted in the median daily number of transfused red blood cell units (0.27 vs 0.29; P=.55) or number of transfused platelet units (0.26 vs 0.29; P=.31). Early-discharge patients had more positive blood cultures (37 [35%] vs 4 [14%]; P=.04) but required fewer IV antibiotic days per study day (0.48 vs 0.71; P=.01). Overall, daily charges among early-discharge patients were significantly lower than for inpatients (median, $3840 vs $5852; P<.001) despite increased charges per inpatient day when readmitted (median, $7405 vs $5852; P<.001). Early discharge following intensive AML or MDS chemotherapy can reduce costs and use of IV antibiotics, but attention should be paid to complications that may occur in the outpatient setting.

Acute leukaemia and myelodysplastic syndromes with chromosomal rearrangement involving 11q23 locus, but not MLL gene.

PubMed

Zuo, Wenli; Wang, Sa A; DiNardo, Courtney; Yabe, Mariko; Li, Shaoying; Medeiros, L Jeffrey; Tang, Guilin

2017-03-01

Chromosome 11q23 translocations, resulting in MLL (KMT2A ) rearrangement, have been well characterised in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). However, little is known of haematopoietic neoplasms associated with 11q23 translocation but without MLL rearrangement (11q23+/ MLL -). The aim of this study is to characterise such cases with 11q23+/ MLL -. We retrospectively searched our database for cases with haematopoietic malignancies with 11q23+/ MLL -. We identified nine patients, two with AML, two with B-lymphoblastic leukaemia (B-ALL); two with T-lymphoblastic leukaemia (T-ALL), two with myelodysplastic syndrome (MDS) and one with chronic myelomonocytic leukaemia (CMML). The translocations included t(X;11)(p11.2;q23), t(2;11)(p21;q23), t(6;11)(q27;q23), t(8;9;11)(q13;q13;q23), t(11;11)(p15;q23), t(11;14)(q23;q24) and t(11;15)(q23;q14). Five of six patients with acute leukaemia had received chemotherapy and detection of 11q23 translocation occurred at time of disease relapse. Both patients with MDS and the patient with CMML had 11q23 translocation detected at time of initial diagnosis, all three patients progressed to AML after >1 year on hypomethylating agent therapy. All patients received risk-adapted therapies, including stem cell transplant in five patients. At the last follow-up, eight patients died with a median overall survival of 14 months. 11q23+/ MLL - occurs rarely, involving different partner chromosomes and showing clinical and pathological features and disease subtypes different from those cases with MLL rearrangement. 11q23+/ MLL - appears to be associated with clonal evolution/disease progression in acute leukaemia, a high risk for AML progression in MDS/CMML and a high incidence of disease relapse. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Optimizing therapy for iron overload in the myelodysplastic syndromes: recent developments.

PubMed

Leitch, Heather A

2011-01-22

The myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of progression to acute myeloid leukaemia (AML). Most MDS patients eventually require transfusion of red blood cells for anaemia, placing them at risk of transfusional iron overload. In β-thalassaemia major, transfusional iron overload leads to organ dysfunction and death; however, with iron chelation therapy, organ function is improved, and survival improved to near normal and correlated with the degree of compliance with chelation. In lower-risk MDS, several nonrandomized studies suggest an adverse effect of iron overload on survival and that lowering iron with chelation may minimize this impact. Emerging data indicate that chelation may improve organ function, particularly hepatic function, and a minority of patients may have improvement in cell counts and decreased transfusion requirements. While guidelines for MDS generally recommend chelation in selected lower-risk patients, data from nonrandomized trials suggest iron overload may impact adversely on the outcome of higher-risk MDS and stem cell transplantation (SCT). This effect may be due to increased transplant-related mortality, infection and AML progression, and preliminary data suggest that lowering iron may be beneficial in this patient group. Other areas of active and future investigation include optimizing the monitoring of iron overload using imaging such as T2* MRI and measures of labile iron and oxidative stress; correlating new methods of measuring iron to clinical outcomes; clarifying the contribution of different cellular and extracellular iron pools to iron toxicity; optimizing chelation by using agents that access the appropriate iron pools to minimize the relevant clinical consequences in individual patients; and incorporating measures of quality of life and co-morbidities into clinical trials of chelation in MDS. It should be noted that chelation is costly and potentially toxic, and in MDS should be initiated after weighing potential risks and benefits for each patient until more definitive data are available. In this review, data on the impact of iron overload in MDS and SCT are discussed; for example, several noncontrolled studies show inferior survival in patients with iron overload in these clinical settings, including an increase in transplant-related mortality and infection risk. Possible mechanisms of iron toxicity include oxidative stress, which can damage cellular components, and the documented impact of lowering iron on organ function with measures such as iron chelation therapy includes an improvement in elevated liver transaminases. Lowering iron also appears to improve survival in both lower-risk MDS and SCT in nonrandomized studies. Selected aspects of iron metabolism, transport, storage and distribution that may be amenable to future intervention and improved removal of iron from important cellular sites are discussed, as are attempts to quantify quality of life and the importance of co-morbidities in measures to treat MDS, including chelation therapy.

Bone Marrow and Kidney Transplant for Patients With Chronic Kidney Disease and Blood Disorders

ClinicalTrials.gov

2017-03-21

Chronic Kidney Disease; Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Chronic Myelogenous Leukemia (CML); Chronic Lymphocytic Leukemia (CLL); Non-Hodgkin's Lymphoma (NHL); Hodgkin Disease; Multiple Myeloma; Myelodysplastic Syndrome (MDS); Aplastic Anemia; AL Amyloidosis; Diamond Blackfan Anemia; Myelofibrosis; Myeloproliferative Disease; Sickle Cell Anemia; Autoimmune Diseases; Thalassemia

Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

ClinicalTrials.gov

2018-01-03

Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myeloid Sarcoma; Chronic Myeloid Leukemia (CML); Juvenile Myelomonocytic Leukemia (JMML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL)

Repetitious appearance and disappearance of different kinds of clonal cytogenetic abnormalities after allogeneic bone marrow transplantation.

PubMed

Lin, Y W; Hamahata, K; Watanabe, K; Adachi, S; Akiyama, Y; Kubota, M; Nakahata, T

2001-07-01

We report a childhood case that showed the repeated appearance and disappearance of various kinds of cytogenetic abnormalities (CA) for 5.5 years after allogeneic bone marrow transplantation (BMT). The patient underwent allogeneic BMT from an HLA-matched unrelated donor during the second complete remission of acute lymphoblastic leukemia. The conditioning regimen for BMT consisted of etoposide, cyclophosphamide, anti-human thymocyte immunoglobulin, and total body irradiation. There were no leukemic relapses or secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) since the BMT. The CA occurred from residual recipient cells, which were damaged by chemotherapy or radiation prior to BMT. Although previous studies about post-BMT CA had reported the continuous emergence of identical clones, the present case showed the appearance of one different type of clone after another. Although the appearance of different types of CA may mean that these clones did not obtain any growth advantages, it may be a sign of genomic instability, which is probably a risk factor for the development of secondary AML/MDS.

Second cancers in patients with Chronic Lymphocytic Leukemia who received frontline FCR therapy – Distribution and clinical outcomes

PubMed Central

Benjamini, Ohad; Jain, Preetesh; Trinh, Long; Qiao, Wei; Strom, Sara S.; Lerner, Susan; Wang, Xuemei; Burger, Jan; Ferrajoli, Alessandra; Kantarjian, Hagop; O’Brien, Susan; Wierda, William; Estrov, Zeev; Keating, Michael

2015-01-01

Patients with Chronic Lymphocytic Leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving Fludarabine, Cyclophosphamide, and Rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety three patients (40%) had other cancers before and 66 patients (28%) after FCR. The rates of t-AML/MDS (5.1%) and Richter’s transformation (RT) (9%) were high while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT and as speculated the survival of affected patients is shorter. PMID:25308294

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey.

PubMed

Beguin, Y; Selleslag, D; Meers, S; Graux, C; Bries, G; Deeren, D; Vrelust, I; Ravoet, C; Theunissen, K; Voelter, V; Potier, H; Trullemans, F; Noens, L; Mineur, P

2015-02-01

We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. The median age of patients was 74·7 (range: 43·9-87·8) years; 69·4% had MDS, 26·5% had primary or secondary AML, and 4·1% had CMML. Treatment-related TEAEs, grade 3-4 TEAEs, and TESAEs were reported in 67·3%, 28·6%, and 18·4% of patients, respectively. During 1YOP, patients received a median of 7 (1-12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n = 29), 41·4% had CR, PR, or HI, 41·4% had SD, and 17·2% had TF. Among AML patients (n = 9), 44·4% had CR or PR, 33·3% had SD, and 22·2% had TF. TI was observed in 14/32 (43·8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326-555) days; 1-year OS estimate was 0·571 (0·422-0·696). Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy.

Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy.

PubMed

Mattiuzzi, Gloria N; Kantarjian, Hagop; Faderl, Stefan; Lim, JoAnn; Kontoyiannis, Dimitrios; Thomas, Deborah; Wierda, William; Raad, Isaam; Garcia-Manero, Guillermo; Zhou, Xian; Ferrajoli, Alexandra; Bekele, Nebiyou; Estey, Elihu

2004-02-01

The optimal antifungal prophylactic regimen for patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing induction chemotherapy has yet to be identified. A prospective historical control study evaluated the efficacy and safety of amphotericin B lipid complex (ABLC) in this patient population. Newly diagnosed patients with AML or high-risk MDS who were undergoing induction chemotherapy received prophylactic ABLC 2.5 mg/kg intravenously 3 times weekly. This treatment group was compared with a historical control group that had similar baseline characteristics and received prophylactic liposomal amphotericin B (L-AmB) 3 mg/kg 3 times weekly. The primary endpoint was the incidence of documented or suspected fungal infections during and up to 4 weeks after cessation of prophylaxis. Reported adverse events were used to assess tolerability. The overall efficacy of antifungal prophylaxis was similar in patients who received ABLC and patients who received L-AmB (P=0.95). Among 131 ABLC-treated patients and 70 L-AmB-treated patients who were assessed for efficacy and safety, 49% of patients in each group completed therapy without developing a documented or suspected fungal infection. Documented fungal infections occurred in 5% of ABLC-treated patients and in 4% of L-AmB-treated patients. Alternative antifungal strategies were required because of persistent fever or pneumonia of unknown pathogen in 28% and 32% of ABLC-treated and L-AmB-treated patients, respectively. Grade 3 and 4 adverse events, therapy discontinuations due to adverse events, and survival rates also were similar between treatment groups. ABLC and L-AmB appeared to have similar efficacy and were tolerated well as antifungal prophylaxis in patients with AML and high-risk MDS who were undergoing induction chemotherapy. Copyright 2003 American Cancer Society.

Wilms' Tumor 1 Gene Expression Using a Standardized European LeukemiaNet-Certified Assay Compared to Other Methods for Detection of Minimal Residual Disease in Myelodysplastic Syndrome and Acute Myelogenous Leukemia after Allogeneic Blood Stem Cell Transplantation.

PubMed

Rautenberg, Christina; Pechtel, Sabrina; Hildebrandt, Barbara; Betz, Beate; Dienst, Ariane; Nachtkamp, Kathrin; Kondakci, Mustafa; Geyh, Stefanie; Wieczorek, Dagmar; Haas, Rainer; Germing, Ulrich; Kobbe, Guido; Schroeder, Thomas

2018-05-16

Overexpression of the Wilms' tumor 1 (WT1) gene is informative in many patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) and is measurable in peripheral blood (PB). Despite these advantages, WT1 has not broadly been established as a marker for minimal residual disease (MRD) monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to limited patient numbers, differing sample sources, and nonstandardized in-house methods. To estimate the value of WT1 as an MRD marker, we serially quantified PB WT1 expression using a standardized European LeukemiaNet-certified assay in 59 patients with AML and MDS after allo-HSCT. We compared its performance with routine methods such as chimerism, XY-fluorescence in situ hybridization (FISH), disease-specific cytogenetic, and molecular analyses, which were accessible in 100%, 34%, 68%, and 37%, respectively. Twenty-four patients (41%) relapsed within a median of 126 days after allo-HSCT, and 20 of them showed at least 1 elevated WT1 value above the validated cutoff. The other 35 patients (59%) remained in complete remission, and only 1 patient had a transient increase in WT1 expression. This reflects a sensitivity of 83% and a specificity of 97% for WT1 and appears to be favorable compared with the sensitivities and specificities observed for chimerism (33% and 91%), XY-FISH (67% and 73%), cytogenetic (33% and 77%), and molecular (78% and 85%) analyses. Further supporting its predictive impact, elevated WT1 expression prompted an earlier BM biopsy and consecutively the diagnosis of relapse in 62% of patients. The results of this real-life experience imply that PB WT1 expression is measurable by a standardized assay and predicts imminent relapse after allo-HSCT with high sensitivity and specificity in most patients with AML and MDS. Copyright © 2018. Published by Elsevier Inc.

Digging deep into “dirty” drugs – modulation of the methylation machinery

PubMed Central

Pleyer, Lisa; Greil, Richard

2015-01-01

Abstract DNA methylation and histone modification are epigenetic mechanisms that result in altered gene expression and cellular phenotype. The exact role of methylation in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remains unclear. However, aberrations (e.g. loss-/gain-of-function or up-/down-regulation) in components of epigenetic transcriptional regulation in general, and of the methylation machinery in particular, have been implicated in the pathogenesis of these diseases. In addition, many of these components have been identified as therapeutic targets for patients with MDS/AML, and are also being assessed as potential biomarkers of response or resistance to hypomethylating agents (HMAs). The HMAs 5-azacitidine (AZA) and 2′-deoxy-5-azacitidine (decitabine, DAC) inhibit DNA methylation and have shown significant clinical benefits in patients with myeloid malignancies. Despite being viewed as mechanistically similar drugs, AZA and DAC have differing mechanisms of action. DAC is incorporated 100% into DNA, whereas AZA is incorporated into RNA (80–90%) as well as DNA (10–20%). As such, both drugs inhibit DNA methyltransferases (DNMTs; dependently or independently of DNA replication) resulting in the re-expression of tumor-suppressor genes; however, AZA also has an impact on mRNA and protein metabolism via its inhibition of ribonucleotide reductase, resulting in apoptosis. Herein, we first give an overview of transcriptional regulation, including DNA methylation, post-translational histone-tail modifications, the role of micro-RNA and long-range epigenetic gene silencing. We place special emphasis on epigenetic transcriptional regulation and discuss the implication of various components in the pathogenesis of MDS/AML, their potential as therapeutic targets, and their therapeutic modulation by HMAs and other substances (if known). The main focus of this review is laid on dissecting the rapidly evolving knowledge of AZA and DAC with a special focus on their differing mechanisms of action, and the effect of HMAs on transcriptional regulation. PMID:25566693

A Safety and Tolerability Study of CDX-301 With or Without Plerixafor for Stem Cell Mobilization in Matched Related Allogeneic Donor/Recipient Sibling Transplant Pairs

ClinicalTrials.gov

2017-04-06

For Donors; Related Donors Giving Peripheral Blood Stem Cells (PBSC) to a Sibling; For Recipients; Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS); Chronic Myelogenous Leukemia (CML); Non-Hodgkins Lymphoma (NHL); Hodgkins Disease (HD); Chronic Lymphocytic Leukemia (CLL)

Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts

PubMed Central

Kode, Aruna; Manavalan, John S.; Mosialou, Ioanna; Bhagat, Govind; Rathinam, Chozha V.; Luo, Na; Khiabanian, Hossein; Lee, Albert; Vundavalli, Murty; Friedman, Richard; Brum, Andrea; Park, David; Galili, Naomi; Mukherjee, Siddhartha; Teruya-Feldstein, Julie; Raza, Azra; Rabadan, Raul; Berman, Ellin; Kousteni, Stavroula

2014-01-01

Summary Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML. PMID:24429522

A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia.

PubMed

Gröschel, Stefan; Sanders, Mathijs A; Hoogenboezem, Remco; de Wit, Elzo; Bouwman, Britta A M; Erpelinck, Claudia; van der Velden, Vincent H J; Havermans, Marije; Avellino, Roberto; van Lom, Kirsten; Rombouts, Elwin J; van Duin, Mark; Döhner, Konstanze; Beverloo, H Berna; Bradner, James E; Döhner, Hartmut; Löwenberg, Bob; Valk, Peter J M; Bindels, Eric M J; de Laat, Wouter; Delwel, Ruud

2014-04-10

Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET inhibition. Our data show that structural rearrangements involving the chromosomal repositioning of a single enhancer can cause deregulation of two unrelated distal genes, with cancer as the outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

A 54-Year-Old Woman with Donor Cell Origin of Multiple Myeloma after Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of CML

PubMed Central

Maestas, Erika; Jain, Shikha; Stiff, Patrick

2016-01-01

Chronic myeloid leukemia is a myeloproliferative disorder that may be treated with hematopoietic stem cell transplantation (HSCT). While posttransplantation relapse of disease resulting from a failure to eradicate the patient's original leukemia could occur, patients may also rarely develop a secondary malignancy or myelodysplastic syndrome (MDS) of donor origin termed donor cell leukemia (DCL). Cases of donor-derived acute myeloid leukemia (AML) or MDS after HSCT or solid tumor transplantation have been published. However, very few cases of donor-derived multiple myeloma (MM) exist. We describe a patient who developed a donor-derived MM following allogeneic HSCT from a sibling donor. PMID:26989529

Nature of frequent deletions in CEBPA.

PubMed

Fuchs, Ota; Kostecka, Arnost; Provaznikova, Dana; Krasna, Blazena; Brezinova, Jana; Filkukova, Jitka; Kotlin, Roman; Kouba, Michal; Kobylka, Petr; Neuwirtova, Radana; Jonasova, Anna; Caniga, Miroslav; Schwarz, Jiri; Markova, Jana; Maaloufova, Jacqueline; Sponerova, Dana; Novakova, Ludmila; Cermak, Jaroslav

2009-01-01

C/EBPalpha (CCAAT/enhancer binding protein alpha) belongs to the family of leucine zipper transcription factors and is necessary for transcriptional control of granulocyte, adipocyte and hepatocyte differentiation, glucose metabolism and lung development. C/EBPalpha is encoded by an intronless gene. CEBPA mutations cause a myeloid differentiation block and were detected in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma and non-Hodgkin's lymphoma (NHL) patients. In this study we identified in 41 individuals from 824 screened individuals (290 AML patients, 382 MDS patients, 56 NHL patients and 96 healthy individuals) a single class of 23 deletions in CEBPA gene which involved a direct repeat of at least 2 bp. These mutations are characterised by the loss of one of two same repeats at the ends of deleted sequence. Three most frequent repeats included in these deletions in CEBPA gene are CGCGAG (493-498_865-870), GCCAAGCAGC (508-517_907-916) and GG (486-487_885-886), all according to GenBank accession no. NM_004364.2. A mechanism for deletion formation between two repetitive sequences can be recombination events in the repair process. Double-stranded cut in DNA can initiate these recombination events of adjacent DNA sequences.

Fanconi anemia.

PubMed

Soulier, Jean

2011-01-01

Fanconi anemia (FA) is the most frequent inherited cause of BM failure (BMF). Fifteen FANC genes have been identified to date, the most prevalent being FANCA, FANCC, FANCG, and FANCD2. In addition to classical presentations with progressive BMF during childhood and a positive chromosome breakage test in the blood, atypical clinical and/or biological situations can be seen in which a FA diagnosis has to be confirmed or eliminated. For this, a range of biological tools have been developed, including analysis of skin fibroblasts. FA patients experience a strong selective pressure in the BM that predisposes to clonal evolution and to the emergence in their teens or young adulthood of myelodysplasia syndrome (MDS) and/or acute myeloid leukemia (AML) with a specific pattern of somatic chromosomal lesions. The cellular mechanisms underlying (1) the hematopoietic defect which leads to progressive BMF and (2) somatic clonal evolutions in this background, are still largely elusive. Elucidation of these mechanisms at the molecular and cellular levels should be useful to understand the physiopathology of the disease and to adapt the follow-up and treatment of FA patients. This may also ultimately benefit older, non-FA patients with aplastic anemia, MDS/AML for whom FA represents a model genetic condition.

Distribution of chromosome breakpoints in benzene-exposed and unexposed AML patients.

PubMed

Kerzic, Patrick J; Irons, Richard D

2017-10-01

Results of laboratory studies and investigations of occupationally exposed healthy individuals have been used to develop a mode of action for benzene-induced leukemia that mirrors disease following treatment with chemotherapeutic agents. Recently we have described series of AML and MDS cases with benzene exposure history, and have provided cytogenetic, molecular, and pathologic evidence that these cases differ significantly in many features from therapy-related disease. Here we have extended this work, and describe chromosome breakpoints across 441 identifiable regions, in terms of gains or losses, in 710 AML cases collected during the Shanghai Health Study, which include 75 with a history of benzene exposure. Using FISH and cytogenetic analysis, we developed prevalence information and risk ratios for benzene exposure across all regions with a lesion in at least one exposed and unexposed case. These results indicate that AML following benzene exposure mirrors de novo disease, and supports a mechanism for development of hematopoietic disease that bears no resemblance to therapy-related disease. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Myeloid malignancies in the real-world: Occurrence, progression and survival in the UK's population-based Haematological Malignancy Research Network 2004-15.

PubMed

Roman, Eve; Smith, Alex; Appleton, Simon; Crouch, Simon; Kelly, Richard; Kinsey, Sally; Cargo, Catherine; Patmore, Russell

2016-06-01

Population-based information on cancer incidence, prevalence and outcome are required to inform clinical practice and research; but contemporary data are lacking for many myeloid malignancy subtypes. Set within a socio-demographically representative UK population of ∼4 million, myeloid malignancy data (N=5231 diagnoses) are from an established patient cohort. Information on incidence, survival (relative & overall), transformation/progression, and prevalence is presented for >20 subtypes. The median diagnostic age was 72.4years (InterQuartile Range 61.6-80.2), but there was considerable subtype heterogeneity, particularly among the acute myeloid leukaemias (AML) where medians ranged from 20.3 (IQR 13.9-43.8) for AML 11q23 through to 73.7 (IQR 57.3-79.1) for AML with no recurrent genetic changes. Five-year Relative Survival (RS) estimates varied hugely; from <5% for aggressive entities like therapy-related AML (2.6%, 95% Confidence Interval 0.4-9.0) to >85% for indolent/treatable conditions like chronic myeloid leukaemia (89.8%, 95% CI 84.0-93.6). With a couple of notable exceptions, males experienced higher rates and worse survival than females: the age-standardized incidence rates of several conditions was 2-4 higher in males than females, and the 5-year RS for all subtypes combined was 48.8% (95% CI 46.5-51.2) and 60.4% (95% CI 57.7-62.9) for males and females respectively. During follow-up (potential minimum 2 years and maximum 11years) myelodysplastic syndrome (MDS) progression to AML ranged from 25% for refractory anaemia with excess blasts through to 5% for refractory anaemia with ring sideroblasts: the median interval between MDS and AML diagnosis was 9.0 months (IQR 4.8-17.4months). The marked incidence and outcome variations seen by subtype, sex and age, confirm the requirement for "real-world" longitudinal data to inform aetiological hypotheses, healthcare planning, and future monitoring of therapeutic change. Several challenges for routine cancer registration were identified, including the need to link more effectively to diagnostic and clinical data sources, and to review policies on the recording of progressions and transformations. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A Population-Based Study on Myelodysplastic Syndromes in the Lazio Region (Italy), Medical Miscoding and 11-Year Mortality Follow-Up: the Gruppo Romano-Laziale Mielodisplasie Experience of Retrospective Multicentric Registry.

PubMed

Mayer, Flavia; Faglioni, Laura; Agabiti, Nera; Fenu, Susanna; Buccisano, Francesco; Latagliata, Roberto; Ricci, Roberto; Spiriti, Maria Antonietta Aloe; Tatarelli, Caterina; Breccia, Massimo; Cimino, Giuseppe; Fianchi, Luana; Criscuolo, Marianna; Gumenyuk, Svitlana; Mancini, Stefano; Maurillo, Luca; Nobile, Carolina; Niscola, Pasquale; Piccioni, Anna Lina; Tafuri, Agostino; Trapè, Giulio; Andriani, Alessandro; De Fabritiis, Paolo; Voso, Maria Teresa; Davoli, Marina; Zini, Gina

2017-01-01

Data on Myelodysplastic Syndromes (MDS) are difficult to collect by cancer registries because of the lack of reporting and the use of different classifications of the disease. In the Lazio Region, data from patients with a confirmed diagnosis of MDS, treated by a hematology center, have been collected since 2002 by the Gruppo Romano-Laziale Mielodisplasie (GROM-L) registry, the second MDS registry existing in Italy. This study aimed at evaluating MDS medical miscoding during hospitalizations, and patients' survival. For these purposes, we selected 644 MDS patients enrolled in the GROM-L registry. This cohort was linked with two regional health information systems: the Hospital Information System (HIS) and the Mortality Information System (MIS) in the 2002-2012 period. Of the 442 patients who were hospitalized at least once during the study period, 92% had up to 12 hospitalizations. 28.5% of patients had no hospitalization episodes scored like MDS, code 238.7 of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM). The rate of death during a median follow-up of 46 months (range 0.9-130) was 45.5%. Acute myeloid leukemia (AML) was the first cause of mortality, interestingly a relevant portion of deaths is due to cerebro-cardiovascular events and second tumors. This study highlights that MDS diagnosis and treatment, which require considerable healthcare resources, tend to be under-documented in the HIS archive. Thus we need to improve the HIS to better identify information on MDS hospitalizations and outcome. Moreover, we underline the importance of comorbidity in MDS patients' survival.

Characteristics and outcome of myelodysplastic syndromes (MDS) with isolated 20q deletion: a report on 62 cases.

PubMed

Braun, Thorsten; de Botton, Stéphane; Taksin, Anne-Laure; Park, Sophie; Beyne-Rauzy, Odile; Coiteux, Valérie; Sapena, Rosa; Lazareth, Anne; Leroux, Geneviève; Guenda, Khaled; Cassinat, Bruno; Fontenay, Michaela; Vey, Norbert; Guerci, Agnès; Dreyfus, François; Bordessoule, Dominique; Stamatoullas, Aspasia; Castaigne, Sylvie; Terré, Christine; Eclache, Virginie; Fenaux, Pierre; Adès, Lionel

2011-07-01

Isolated 20q deletion is common in MDS and considered of good prognosis, but no large series have been reported. We compared characteristics of 62 MDS patients with isolated del 20q, 36 patients with del 20q and other cytogenetic abnormalities, and 1335 MDS patients without del20q. Significant differences between MDS with isolated del 20q and patients without del 20q were lower platelet count (mean 144 vs. 196 G/l, p=0.005), lower marrow blast count (mean 3.9% vs. 5.6%, p=0.0008), and higher reticulocyte count (mean 72.5 vs. 51.7 G/l, p=0.04). Ten (16%) patients with isolated del 20q had Hb>12 g/dl and platelets <100 G/l, compared to 7.3% of patients without del 20q (p=0.025). Review of marrow slides of those 10 patients showed that could be readily identified as MDS prior to cytogenetics. Fourteen percent of patients with isolated del 20q progressed to AML compared to 11% with one and 24% with several additional abnormalities. Median survival was 54 months in patients with isolated del 20q, not reached and 12 months for del 20q with one and several additional abnormalities, respectively (p=0.035) confirming the favorable prognosis of del 20q without complex abnormalities. Copyright © 2011 Elsevier Ltd. All rights reserved.

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group.

PubMed

Lübbert, Michael; Suciu, Stefan; Hagemeijer, Anne; Rüter, Björn; Platzbecker, Uwe; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; Germing, Ulrich; Salih, Helmut R; Muus, Petra; Pflüger, Karl-Heinz; Schaefer, Hans-Eckart; Bogatyreva, Lioudmila; Aul, Carlo; de Witte, Theo; Ganser, Arnold; Becker, Heiko; Huls, Gerwin; van der Helm, Lieke; Vellenga, Edo; Baron, Frédéric; Marie, Jean-Pierre; Wijermans, Pierre W

2016-01-01

In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.

Synthetic Lethality as a Targeted Approach to Advanced Prostate Cancer

DTIC Science & Technology

2014-05-01

syndrome (MDS) [36-41]. Multiple Phase III trials of tipifarnib monotherapy in acute myeloid leukemia (AML) and in refractory advanced colorectal...cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome . Cancer 2011;117(6):1236-44 42. Harousseau JL...multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome . Blood 2007;109(10):4158

Autologous hematopoietic stem cell transplantation in lymphoma patients is associated with a decrease in the double strand break repair capacity of peripheral blood lymphocytes.

PubMed

Lacoste, Sandrine; Bhatia, Smita; Chen, Yanjun; Bhatia, Ravi; O'Connor, Timothy R

2017-01-01

Patients who undergo autologous hematopoietic stem cell transplantation (aHCT) for treatment of a relapsed or refractory lymphoma are at risk of developing therapy related- myelodysplasia/acute myeloid leukemia (t-MDS/AML). Part of the risk likely resides in inherent interindividual differences in their DNA repair capacity (DRC), which is thought to influence the effect chemotherapeutic treatments have on the patient's stem cells prior to aHCT. Measuring DRC involves identifying small differences in repair proficiency among individuals. Initially, we investigated the cell model in healthy individuals (primary lymphocytes and/or lymphoblastoid cell lines) that would be appropriate to measure genetically determined DRC using host-cell reactivation assays. We present evidence that interindividual differences in DRC double-strand break repair (by non-homologous end-joining [NHEJ] or single-strand annealing [SSA]) are better preserved in non-induced primary lymphocytes. In contrast, lymphocytes induced to proliferate are required to assay base excision (BER) or nucleotide excision repair (NER). We established that both NHEJ and SSA DRCs in lymphocytes of healthy individuals were inversely correlated with the age of the donor, indicating that DSB repair in lymphocytes is likely not a constant feature but rather something that decreases with age (~0.37% NHEJ DRC/year). To investigate the predictive value of pre-aHCT DRC on outcome in patients, we then applied the optimized assays to the analysis of primary lymphocytes from lymphoma patients and found that individuals who later developed t-MDS/AML (cases) were indistinguishable in their DRC from controls who never developed t-MDS/AML. However, when DRC was investigated shortly after aHCT in the same individuals (21.6 months later on average), aHCT patients (both cases and controls) showed a significant decrease in DSB repair measurements. The average decrease of 6.9% in NHEJ DRC observed among aHCT patients was much higher than the 0.65% predicted for such a short time frame, based on ageing results for healthy individuals.

Impact on acute myeloid leukemia relapse in granulocyte colony-stimulating factor application: a meta-analysis.

PubMed

Feng, Xiaoqin; Lan, He; Ruan, Yongsheng; Li, Chunfu

2018-03-08

This meta-analysis evaluated the impact of granulocyte colony-stimulating factor (G-CSF) added to chemotherapy on treatment outcomes including survival and disease recurrence in patients with acute myeloid leukemia (AML). Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 19 September 2016 using search terms. Studies that investigated patients with AML who underwent stem-cell transplantation were included. The overall analysis revealed a significant improvement in overall survival (OS) (P = .019) and disease-free survival (DFS) (P = .002) for patients receiving G-CSF with chemotherapy. Among patients without prior AML treatment, there was a significant improvement in DFS (P = .014) and reduction in incidence of relapse (P = .015) for those who received G-CSF. However, subgroup analyses found no significant difference between G-CSF (+) and G-CSF (-) treatments in rates of OS (P = .104) and complete remission (CR) (P = .572) for patients without prior AML treatment. Among patients with relapsed/refractory AML, there was no significant difference found between G-CSF (+) and G-CSF (-) groups for OS (P = .225), DFS (P = .209), and CR (P = .208). Treatment with chemotherapy plus G-CSF appears to provide better survival and treatment responses compared with chemotherapy alone, particularly for patients with previously untreated AML. AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; DFS, disease-free survival; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HR, hazard ratio; MDS, myelodysplastic syndrome; OR, odds ratio; OS, overall survival; RCTs, randomized control trials; RR, relative risk.

Meta-Analytical Online Repository of Gene Expression Profiles of MDS Stem Cells

DTIC Science & Technology

2015-12-01

Myelodysplastic syndrome , AML: Acute myeloid leukemia, ALL: Acute lymphoblastic leukemia Numbers in brackets are reference numbers. doi:10.1371/journal.pone...disorders such as acute leukemias and myelodysplastic syndromes would be distinguishable in our analysis. Unsupervised clustering showed that even though...al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes . Blood. 2000;96:2240–2245. [PubMed: 10979972] 17. Yoon SY, Li CY, Lloyd

A Multicenter Access and Distribution Protocol for Unlicensed Cryopreserved Cord Blood Units (CBUs)

ClinicalTrials.gov

2018-05-15

Hematologic Malignancies; Inherited Disorders of Metabolism; Inherited Abnormalities of Platelets; Histiocytic Disorders; Acute Myelogenous Leukemia (AML or ANLL); Acute Lymphoblastic Leukemia (ALL); Other Acute Leukemia; Chronic Myelogenous Leukemia (CML); Myelodysplastic (MDS) / Myeloproliferative (MPN) Diseases; Other Leukemia; Hodgkin Lymphoma; Non-hodgkin Lymphoma; Multiple Myeloma/ Plasma Cell Disorder (PCD); Inherited Abnormalities of Erythrocyte Differentiation or Function; Disorders of the Immune System; Automimmune Diseases; Severe Aplastic Anemia

Secondary Primary Malignancies in Multiple Myeloma: An Old Nemesis Revisited

PubMed Central

Yang, Jay; Terebelo, Howard R.; Zonder, Jeffrey A.

2012-01-01

The treatment of myeloma has undergone extraordinary improvements in the past half century. These advances have been accompanied by a concern for secondary primary malignancies (SPMs). It has been known for decades that extended therapy with alkylating chemotherapy agents, such as melphalan, carries an increased risk of therapy-related myelodysplastic syndrome and/or acute myeloid leukemia (t-MDS/AML), with a cumulative risk as high as 10–15%. High-dose chemotherapy with autologous stem cell support became widely accepted for myeloma in the 1990s. Despite the use of high doses of melphalan, the risk of t-MDS/AML with this procedure is estimated to be less than 5%, with much of this risk attributable to pretransplant therapy. Recently, lenalidomide has come under scrutiny for its possible association with SPMs. It is too soon to declare a causal relationship at this time, but there appears to be an increased number of SPMs in reports from several studies using lenalidomide maintenance. Current studies should be amended and future studies planned to better define the risk of SPMs and the risk factors and mechanisms for its development. Patients should be educated regarding this potential concern but the current use of lenalidomide should not generally be altered until further data are available. PMID:22851973

Secondary primary malignancies in multiple myeloma: an old NEMESIS revisited.

PubMed

Yang, Jay; Terebelo, Howard R; Zonder, Jeffrey A

2012-01-01

The treatment of myeloma has undergone extraordinary improvements in the past half century. These advances have been accompanied by a concern for secondary primary malignancies (SPMs). It has been known for decades that extended therapy with alkylating chemotherapy agents, such as melphalan, carries an increased risk of therapy-related myelodysplastic syndrome and/or acute myeloid leukemia (t-MDS/AML), with a cumulative risk as high as 10-15%. High-dose chemotherapy with autologous stem cell support became widely accepted for myeloma in the 1990s. Despite the use of high doses of melphalan, the risk of t-MDS/AML with this procedure is estimated to be less than 5%, with much of this risk attributable to pretransplant therapy. Recently, lenalidomide has come under scrutiny for its possible association with SPMs. It is too soon to declare a causal relationship at this time, but there appears to be an increased number of SPMs in reports from several studies using lenalidomide maintenance. Current studies should be amended and future studies planned to better define the risk of SPMs and the risk factors and mechanisms for its development. Patients should be educated regarding this potential concern but the current use of lenalidomide should not generally be altered until further data are available.

Causes of death in 2877 patients with myelodysplastic syndromes.

PubMed

Nachtkamp, Kathrin; Stark, Romina; Strupp, Corinna; Kündgen, Andrea; Giagounidis, Aristoteles; Aul, Carlo; Hildebrandt, Barbara; Haas, Rainer; Gattermann, Norbert; Germing, Ulrich

2016-05-01

Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Düsseldorf registry who have been followed up for a median time of 21 months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71 years. At the time of analysis, 2877 patients (75.9 %) had deceased. In 1212 cases (42.1 %), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4 %) succumbed directly disease-related (AML (46.6 %), infection (27.0 %), bleeding (9.8 %)), whereas 277 patients (16.6 %) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease.

High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21.

PubMed

Preudhomme, C; Warot-Loze, D; Roumier, C; Grardel-Duflos, N; Garand, R; Lai, J L; Dastugue, N; Macintyre, E; Denis, C; Bauters, F; Kerckaert, J P; Cosson, A; Fenaux, P

2000-10-15

The AML1 gene, situated in 21q22, is often rearranged in acute leukemias through t(8;21) translocation, t(12;21) translocation, or less often t(3;21) translocation. Recently, point mutations in the Runt domain of the AML1 gene have also been reported in leukemia patients. Observations for mutations of the Runt domain of the AML1 gene in bone marrow cells were made in 300 patients, including 131 with acute myeloid leukemia (AML), 94 with myelodysplastic syndrome (MDS), 28 with blast crisis chronic myeloid leukemia (CML), 3 with atypical CML, 41 with acute lymphoblastic leukemia (ALL), and 3 with essential thrombocythemia (ET). Forty-one of the patients had chromosome 21 abnormalities, including t(8;21) in 6 of the patients with AML, t(12;21) in 8 patients with ALL, acquired trisomy 21 in 17 patients, tetrasomy 21 in 7 patients, and constitutional trisomy 21 (Down syndrome) in 3 patients. A point mutation was found in 14 cases (4.7%), including 9 (22%) of the 41 patients with AML of the Mo type (MoAML) (none of them had detectable chromosome 21 rearrangement) and 5 (38%) of the 13 myeloid malignancies with acquired trisomy 21 (1 M1AML, 2 M2AML, 1 ET, and 1 atypical CML). In at least 8 of 9 mutated cases of MoAML, both AML alleles were mutated: 3 patients had different stop codon mutations of the 2 AML1 alleles, and 5 patients had the same missense or stop codon mutation in both AML1 alleles, which resulted in at least 3 of the patients having duplication of the mutated allele and deletion of the normal residual allele, as shown by FISH analysis and by comparing microsatellite analyses of several chromosome 21 markers on diagnosis and remission samples. In the remaining mutated cases, with acquired trisomy 21, a missense mutation of AML1, which involved 2 of the 3 copies of the AML1 gene, was found. Four of the 7 mutated cases could be reanalyzed in complete remission, and no AML1 mutation was found, showing that mutations were acquired in the leukemic clone. In conclusion, these findings confirm the possibility of mutations of the Runt domain of the AML1 gene in leukemias, mainly in MoAML and in myeloid malignancies with acquired trisomy 21. AML1 mutations, in MoAML, involved both alleles and probably lead to nonfunctional AML1 protein. As AML1 protein regulates the expression of the myeloperoxidase gene, the relationship between AML1 mutations and Mo phenotype in AML will have to be further explored. (Blood. 2000;96:2862-2869)

Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study.

PubMed

Voso, M T; Leone, G; Piciocchi, A; Fianchi, L; Santarone, S; Candoni, A; Criscuolo, M; Masciulli, A; Cerqui, E; Molteni, A; Finelli, C; Parma, M; Poloni, A; Carella, A M; Spina, F; Cortelezzi, A; Salvi, F; Alessandrino, E P; Rambaldi, A; Sica, S

2017-07-01

Allogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1-11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases. A HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients' comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively. Our study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be 'bridged' using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS. The trial has been registered with the EudraCT number 2010-019673-1. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.

PubMed

Swansbury, G J; Slater, R; Bain, B J; Moorman, A V; Secker-Walker, L M

1998-05-01

This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.

Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group.

PubMed

Wierzbowska, Agnieszka; Robak, Tadeusz; Pluta, Agnieszka; Wawrzyniak, Ewa; Cebula, Barbara; Hołowiecki, Jerzy; Kyrcz-Krzemień, Sławomira; Grosicki, Sebastian; Giebel, Sebastian; Skotnicki, Aleksander B; Piatkowska-Jakubas, Beata; Kuliczkowski, Kazimierz; Kiełbiński, Marek; Zawilska, Krystyna; Kłoczko, Janusz; Wrzesień-Kuś, Agata

2008-02-01

Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2-CdA) increase cytotoxic effect of Ara-C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi-center phase II study evaluating the efficacy and toxicity of CLAG-M salvage regimen in poor risk refractory/relapsed AML patients. The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C 2 g/m2, MIT 10 mg/m2, and granulocyte-colony stimulating factor. In the case of PR, a second CLAG-M was administered. Patients in CR received consolidation courses based on high doses of Ara-C and MIT with or without 2-CdA. One hundred and eighteen patients from 11 centers were registered; 78 primary resistant and 40 relapsed. Sixty-six patients (58%) achieved CR after one or two courses of CLAG-M, 49 (35%) were refractory, and 8 (7%) died early. WBC >10 g/L and age >34 yr were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of OS at 4 yr was 14% (95% CI 4-23%). OS was influenced by age, WBC >10 g/L and poor karyotype in both univariate and multivariate analyses. The probability of 4 yr DFS was 30% for all 66 patients in CR (95% CI 11-49%). Poor karyotype was the only factor associated with decreased probability of DFS. We conclude that CLAG-M is a well-tolerated and highly effective salvage regimen in poor risk refractory/relapsed AML.

miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target.

PubMed

Yamamoto, Haruna; Lu, Jun; Oba, Shigeyoshi; Kawamata, Toyotaka; Yoshimi, Akihide; Kurosaki, Natsumi; Yokoyama, Kazuaki; Matsushita, Hiromichi; Kurokawa, Mineo; Tojo, Arinobu; Ando, Kiyoshi; Morishita, Kazuhiro; Katagiri, Koko; Kotani, Ai

2016-01-12

The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor prognostic leukemia.

Study of Rpl22 in MDS and AML

DTIC Science & Technology

2014-10-01

Previously I had determined that Rpl22 functions as a haploinsufficient tumor suppressor in mouse T - cell lymphoma model by activating the NF B and...preclinical animal models of T cell malignancy as well as in the manipulation of development of primary hematopoietic stem cells in vitro and in vivo...allelic inactivation can accelerate the development of T - cell lymphoma in a mouse model where disease is driven by a MyrAkt2-transgene. Rpl22 inactivation

Study of Rpl22 in MDS and AML

DTIC Science & Technology

2015-10-01

T cell malignancy as well as in the manipulation of development of primary hematopoietic stem cells in vitro and in vivo, has enabled me to...lymphoblastic leukemia/ lymphoma ( T -ALL), and that loss of just one Rpl22 allele accelerates T - cell lymphomagenesis by activating NF-κB and inducing the stem ...3). Previously I have determined that Rpl22 functions as a haploinsufficient tumor suppressor in a mouse T - cell lymphoma model by activating NFκB

cDNA cloning, expression pattern, and chromosomal localization of Mlf1, murine homologue of a gene involved in myelodysplasia and acute myeloid leukemia.

PubMed

Hitzler, J K; Witte, D P; Jenkins, N A; Copeland, N G; Gilbert, D J; Naeve, C W; Look, A T; Morris, S W

1999-07-01

The NPM-MLF1 fusion protein is expressed in blasts from patients with myelodysplasia/acute myeloid leukemia (MDS/AML) containing the t(3;5) chromosomal rearrangement. Nucleophosmin (NPM), a previously characterized nucleolar phosphoprotein, contributes to two other fusion proteins found in lympho-hematopoietic malignancies, anaplastic large cell lymphoma (NPM-ALK) and acute promyelocytic leukemia (NPM-RARalpha). By contrast, the function of the carboxy-terminal fusion partner, myelodysplasia/myeloid leukemia factor 1 (MLF1), is unknown. To aid in understanding normal MLF1 function, we isolated the murine cDNA, determined the chromosomal localization of Mlf1, and defined its tissue expression by in situ hybridization. Mlf1 was highly similar to its human homologue (86% and 84% identical nucleotide and amino acid sequence, respectively) and mapped to the central region of chromosome 3, within a segment lacking known mouse mutations. Mlf1 tissue distribution was restricted during both development and postnatal life, with high levels present only in skeletal, cardiac, and selected smooth muscle, gonadal tissues, and rare epithelial tissues including the nasal mucosa and the ependyma/choroid plexus in the brain. Mlf1 transcripts were undetectable in the lympho-hematopoietic organs of both the embryonic and adult mouse, suggesting that NPM-MLF1 contributes to the genesis of MDS/AML in part by enforcing the ectopic overexpression of MLF1 within hematopoietic tissues.

Angiogenic cytokines are antibody targets during graft-versus-leukemia reactions

PubMed Central

Piesche, Matthias; Ho, Vincent T.; Kim, Haesook; Nakazaki, Yukoh; Nehil, Michael; Yaghi, Nasser; Kolodin, Dmitriy; Weiser, Jeremy; Altevogt, Peter; Kiefel, Helena; Alyea, Edwin P.; Antin, Joseph H.; Cutler, Corey; Koreth, John; Canning, Christine; Ritz, Jerome; Soiffer, Robert J.; Dranoff, Glenn

2014-01-01

Purpose The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed advanced myelodysplasia (MDS) and acute myeloid leukemia (AML) patients who received an autologous, granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT). Experimental Design A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were employed to characterize sera obtained longitudinally from 15 AML/MDS patients who were vaccinated early after allogeneic HSCT. Results A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival. Conclusions These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with NK cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias. PMID:25538258

Study of RpI22 in MDS and AML

DTIC Science & Technology

2016-12-01

developed significantly larger and markedly more vascularized thymic tumors than those observed in Rpl22þ/þ control mice. But, unlike Rpl22þ/þ or Rpl22þ...hypoxia (31). Alternatively, we did not observe obvious necrosis in the center of the large thymic tumors from Rpl22-deficent mice, suggesting Rpl22...Orthop Res 2004;22:1175–81. 32. Loeffler S, Fayard B, Weis J, Weissenberger J. Interleukin-6 induces tran- scriptional activation of vascular endothelial

A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591 in Patients With High-Risk Castrate, Biochemically Relapsed Prostate Cancer

DTIC Science & Technology

2016-09-01

sent to WCMC for submission to the FDA. 7.5 Secondary AML/MDS Myelodysplastic syndrome and acute myeloid leukemia has been reported in patients...K, Feldman EJ, Leonard JP. Therapy-related myelodysplastic syndrome and acute myeloid leukemia following initial treatment with chemotherapy plus...Knox SJ, Horning S, Press OW, Radford JA, Kroll SM, Capizzi RL. Assessment of treatment-related myelodysplastic syndromes and acute myeloid

Bendamustine and Idarubicin in Treating Older Patients With Previously Untreated AML or MDS

ClinicalTrials.gov

2017-07-20

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Untreated Adult Acute Myeloid Leukemia

Cytogenetic clonal evolution in myelodysplastic syndromes is associated with inferior prognosis.

PubMed

Neukirchen, Judith; Lauseker, Michael; Hildebrandt, Barbara; Nolting, Ann-Christin; Kaivers, Jennifer; Kobbe, Guido; Gattermann, Norbert; Haas, Rainer; Germing, Ulrich

2017-12-01

The karyotype of bone marrow cells at the time of diagnosis is a strong prognostic parameter for overall survival as well as acute myeloid leukemia (AML) progression in patients with myelodysplastic syndromes (MDS). However, to the authors' knowledge, few data exist regarding the prognostic impact of cytogenetic clonal evolution during the course of MDS. The authors evaluated follow-up karyotype analyses in 549 patients from the Dusseldorf MDS Registry. Clonal evolution was detectable in 24% of the entire cohort and in 18% of 294 patients receiving best supportive care. The authors noted a clear adverse effect of clonal evolution on the risk of leukemic transformation (hazard ratio, 2.233; P = .036) and overall survival (hazard ratio, 3.677; P<.001). The authors also analyzed the prognostic influence of subclones detectable at the time of diagnosis. Again, such a finding was associated with a significantly shorter overall survival and a higher 5-year-probability of acute myeloid leukemia progression (30% vs 22%). The results of the current study support the belief that follow-up karyotype analyses should be performed, especially in patients with lower-risk and intermediate-risk MDS, to identify those patients who are at higher risk of disease progression and therefore might benefit from earlier or more intensive treatment. Cancer 2017;123:4608-4616. © 2017 American Cancer Society. © 2017 American Cancer Society.

Proposal for refining the definition of dysgranulopoiesis in acute myeloid leukemia and myelodysplastic syndromes.

PubMed

Goasguen, Jean E; Bennett, John M; Bain, Barbara J; Brunning, Richard; Vallespi, Maria-Teresa; Tomonaga, Masao; Zini, Gina; Renault, Alain

2014-04-01

Studies of morphology of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) refer to the definitions produced by the French-American-British (FAB) group and by the World Health Organization expert group. To clarify some points regarding the dysgranulopoiesis that are still unclear we analyzed a series of 98 neutrophils from MDS patients with regard to granularity, nuclear segmentation, the appearance of the chromatin, the presence of giant neutrophils, and the presence of nuclear chromatin extensions. We found that cells with at least 2/3 reduction of the content of granules, Pelger-like neutrophils, dysplastic non-Pelger cells, neutrophils with abnormal clumping of the chromatin, and macropolycytes could be recognized as dysplastic and included in the 10% count recommended by these two classifications. In addition, we suggest that neutrophils with more than 4 nuclear projections could be recognized as a relevant dysplastic feature. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Hypoplastic acute promyelocytic leukemia with continuous hypocellular bone marrow after remission].

PubMed

Nakamura, Toshiki; Makiyama, Junya; Matsuura, Ayumi; Kurohama, Hirokazu; Kitanosono, Hideaki; Ito, Masahiro; Yoshida, Shinichiro; Miyazaki, Yasushi

2018-01-01

An 87-year old female presented with unsteady gait and occasional subcutaneous hematomas. Blood examination findings revealed pancytopenia and mild coagulopathy. Both the histopathological evaluation of bone marrow smears and bone marrow biopsy revealed a hypocellular bone marrow. However, APL cells were observed and PML-RARA fusion gene was detected. On the basis of these findings, the patient was diagnosed with hypoplastic acute promyelocytic leukemia. She received ATRA treatment and achieved complete remission (CR) 29 days from the commencement of therapy. After the first CR, she received two courses of ATO as a consolidation therapy. Following the latter treatments, she maintained CR, but a hypoplastic bone marrow was still observed. Hypoplastic AML is defined as AML with a low bone marrow cellularity. It is clinically important to distinguish it from aplastic anemia and hypoplastic MDS. It has been suggested that both cytogenetic and morphological diagnosis are imperative to the differential diagnosis of hypocellular bone marrow.

[Application of multiplex rt-PCR assay for screening rare or cryptic chromosome translocations in de novo patients with acute myeloid leukemia].

PubMed

Chen, Hai-Min; Yuan, Hai-Yang; Fan, Xing; He, Hai-Yan; Chen, Bing; Shi, Jing-Yi; Zhu, Yong-Mei

2010-10-01

This study was aimed to investigate the clinical feasibility of using multiplex PT-PCR assay for screening rare/cryptic chromosome translocations in patients with de novo acute myeloid leukemia. For 126 patients with de novo AML-M4/M5 without common chromosome translocations including t(15;17), t(8;21) and t(16;16), 3 parallel multiplex RT-PCR assays were set up to detect 6 mll-related gene rearrangements (mll/af10, mll/af17, mll/ell, mll/af9, mll/af6 and mll/enl) with low detection rate and 4 rare fusion genes (dek/can, tls/erg, aml1/mds (evi1) and npm/mlf1). The results showed that 11 patients with positive result from 126 patients were detected which involved in 5 molecular abnormalities. Among them, 10 cases were AML-M5 (16.67%), 1 cases AML-M4 (1.51%). The marker chromosomes were observed in 2 cases out of 11 cases through conventional karyotyping analysis, the karyotyping analysis in 1 case was not performed because this case had 1 mitotic figure only, no any cytogenetic aberrations were found in other 8 cases through R-band karyotyping analysis. It is concluded that multiplex RT-PCR designed in this study can quickly, effectively and accurately identify the rare/cryptic chromosome translocations and can be used in clinical detection.

Decreased invasive fungal disease but no impact on overall survival by posaconazole compared to fluconazole prophylaxis: a retrospective cohort study in patients receiving induction therapy for acute myeloid leukaemia/myelodysplastic syndromes.

PubMed

Dahlén, Torsten; Kalin, Mats; Cederlund, Kerstin; Nordlander, Anna; Björkholm, Magnus; Ljungman, Per; Blennow, Ola

2016-02-01

Posaconazole prophylaxis during induction chemotherapy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has been shown to significantly decrease the incidence of invasive fungal disease (IFD) and increase overall survival in a trial setting, but only small real-life studies have been published. This was a retrospective cohort study including consecutive patients with AML/MDS treated with intensive induction chemotherapy; 176 patients received fluconazole prophylaxis 2008-2011 and 107 patients received posaconazole prophylaxis 2011-2013. Only proven and probable IFD according to the revised EORTC/MSG criteria were included in the analysis. The two cohorts were well matched without significant differences in patient characteristics. At day 100, patients receiving posaconazole had a significantly lower incidence of total IFD (0.9% vs. 10.8%, P < 0.01), invasive aspergillosis (0% vs. 5.7%, P = 0.02) and invasive candidiasis (0% vs. 4.0%, P < 0.05). There was no significant difference in overall survival, neither at day 100 (87% in the posaconazole group vs. 85% in the fluconazole group) nor at end of follow-up (78% vs. 77%). Posaconazole prophylaxis decreased the incidence of IFD but did not improve short-term overall survival. Improved treatment efficacy of manifest IFD is likely to explain the lack of survival benefit. © 2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

Effect of Granulocyte Colony-Stimulating Factor-Combined Conditioning in Cord Blood Transplantation for Myelodysplastic Syndrome and Secondary Acute Myeloid Leukemia: A Retrospective Study in Japan.

PubMed

Konuma, Takaaki; Takahashi, Satoshi; Uchida, Naoyuki; Kuwatsuka, Yachiyo; Yamasaki, Satoshi; Aoki, Jun; Onishi, Yasushi; Aotsuka, Nobuyuki; Ohashi, Kazuteru; Mori, Takehiko; Masuko, Masayoshi; Nakamae, Hirohisa; Miyamura, Kouichi; Kato, Koji; Atsuta, Yoshiko; Kato, Seiko; Asano, Shigetaka; Takami, Akiyoshi; Miyazaki, Yasushi

2015-09-01

Granulocyte colony-stimulating factor (G-CSF) increases the susceptibility of dormant malignant or nonmalignant hematopoietic cells to cytarabine arabinoside (Ara-C) through the induction of cell cycle entry. Therefore, G-CSF-combined conditioning before allogeneic stem cell transplantation might positively contribute to decreased incidences of relapse and graft failure without having to increase the dose of cytotoxic drugs. We conducted a retrospective nationwide study of 336 adult patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML) after single-unit cord blood transplantation (CBT) who underwent 4 different kinds of conditioning regimens: total body irradiation (TBI) ≥ 8 Gy + Ara-C/G-CSF + cyclophosphamide (CY) (n = 65), TBI ≥ 8 Gy + Ara-C + CY (n = 119), TBI ≥ 8 Gy + other (n = 104), or TBI < 8 Gy or non-TBI (n = 48). The TBI ≥ 8 Gy + Ara-C/G-CSF + CY regimen showed significantly higher incidence of neutrophil engraftment (hazard ratio, 1.52; 95% confidence interval [CI], 1.10 to 2.08; P = .009) and lower overall mortality (hazard ratio, .46; 95% CI, .26 to .82; P = .008) rates compared with those without a G-CSF regimen. This retrospective study shows that the G-CSF-combined conditioning regimen provides better engraftment and survival results in CBT for adults with MDS and sAML. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Characteristics and Outcomes of Second Malignant Neoplasms after Childhood Cancer Treatment: Multi-Center Retrospective Survey.

PubMed

Koh, Kyung-Nam; Yoo, Keon Hee; Im, Ho Joon; Sung, Ki Woong; Koo, Hong Hoe; Kim, Hyo Sun; Han, Jung Woo; Yoon, Jong Hyung; Park, Hyeon Jin; Park, Byung-Kiu; Baek, Hee Jo; Kook, Hoon; Lee, Jun Ah; Lee, Jae Min; Lee, Kwang Chul; Kim, Soon Ki; Park, Meerim; Lee, Young-Ho; Lyu, Chuhl Joo; Seo, Jong Jin

2016-08-01

This retrospective study investigated the clinical characteristics and outcomes of second malignant neoplasms (SMNs) in survivors of childhood cancer from multiple institutions in Korea. A total of 102 patients from 11 institutions who developed SMN after childhood cancer treatment between 1998 and 2011 were retrospectively enrolled. The most common primary malignant neoplasms (PMNs) were central nervous system (CNS) tumors (n = 17), followed by acute lymphoblastic leukemia (n = 16), non-Hodgkin lymphoma (n = 13), and osteosarcoma (n = 12). The most common SMNs were therapy-related myeloid neoplasms (t-MNs; acute myeloid leukemia [AML], 29 cases; myelodysplastic syndrome [MDS], 12 cases), followed by thyroid carcinomas (n = 15) and CNS tumors (n = 10). The median latency period was 4.9 years (range, 0.5-18.5 years). Among 45 patients with solid tumors defined as an SMN, 15 (33%) developed the lesion in a field previously subjected to radiation. The 5-year overall survival (OS) rate of patients with an SMN was 45% with a median follow-up time of 8.6 years. Patients with AML, MDS, and CNS tumors exhibited the poorest outcomes with 5-year OS rates of 18%, 33%, and 32%, respectively, whereas those with second osteosarcoma showed comparable outcomes (64%) to patients with primary counterpart and those with second thyroid carcinoma had a 100% OS rate. Further therapeutic efforts are recommended to improve the survival outcomes in patients with SMNs, especially in cases with t-MNs and CNS tumors.

cDNA Cloning, Expression Pattern, and Chromosomal Localization of Mlf1, Murine Homologue of a Gene Involved in Myelodysplasia and Acute Myeloid Leukemia

PubMed Central

Hitzler, Johann K.; Witte, David P.; Jenkins, Nancy A.; Copeland, Neal G.; Gilbert, Debra J.; Naeve, Clayton W.; Look, A. Thomas; Morris, Stephan W.

1999-01-01

The NPM-MLF1 fusion protein is expressed in blasts from patients with myelodysplasia/acute myeloid leukemia (MDS/AML) containing the t(3;5) chromosomal rearrangement. Nucleophosmin (NPM), a previously characterized nucleolar phosphoprotein, contributes to two other fusion proteins found in lympho-hematopoietic malignancies, anaplastic large cell lymphoma (NPM-ALK) and acute promyelocytic leukemia (NPM-RARα). By contrast, the function of the carboxy-terminal fusion partner, myelodysplasia/myeloid leukemia factor 1 (MLF1), is unknown. To aid in understanding normal MLF1 function, we isolated the murine cDNA, determined the chromosomal localization of Mlf1, and defined its tissue expression by in situ hybridization. Mlf1 was highly similar to its human homologue (86% and 84% identical nucleotide and amino acid sequence, respectively) and mapped to the central region of chromosome 3, within a segment lacking known mouse mutations. Mlf1 tissue distribution was restricted during both development and postnatal life, with high levels present only in skeletal, cardiac, and selected smooth muscle, gonadal tissues, and rare epithelial tissues including the nasal mucosa and the ependyma/choroid plexus in the brain. Mlf1 transcripts were undetectable in the lympho-hematopoietic organs of both the embryonic and adult mouse, suggesting that NPM-MLF1 contributes to the genesis of MDS/AML in part by enforcing the ectopic overexpression of MLF1 within hematopoietic tissues. PMID:10393836

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

PubMed

Swords, Ronan T; Erba, Harry P; DeAngelo, Daniel J; Bixby, Dale L; Altman, Jessica K; Maris, Michael; Hua, Zhaowei; Blakemore, Stephen J; Faessel, Hélène; Sedarati, Farhad; Dezube, Bruce J; Giles, Francis J; Medeiros, Bruno C

2015-05-01

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. © 2015 John Wiley & Sons Ltd.

Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukeaemia (OPAL): a randomized open-label phase 2 study

PubMed Central

Cortes, Jorge; Feldman, Eric; Yee, Karen; Rizzieri, David; Advani, Anjali S.; Charman, Anthony; Spruyt, Richard; Toal, Martin; Kantarjian, Hagop

2017-01-01

Background Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase I/II study in elderly patients with relapsed/refractory acute myeloid leukaemia (RR AML). We present the results of a randomised phase II study comparing two dosing regimes of tosedostat. Methods Patients aged ≥60 years with AML with relapse after a first complete remission (CR) lasting up to 12 months, or no prior CR, were randomised to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. The primary endpoint was the proportion of patients who obtained a Complete Remission or Complete Remission with incomplete Platelet Recovery. The study was analysed on an intention to treat basis. The study was registered on clintrials.gov (NCT00780598) and the final study visit occurred in March 2011. Findings Seventy-three patients were treated with tosedostat. Seven patients (10%) achieved CR or a complete remission with incomplete platelet recovery (CRp): 2 of 38 (5%) in the 120 mg group and 5 of 35 (14%) in the 240 mg→120 mg group. The most common adverse events at grade 3 or worse were febrile neutropenia which occurred in 21/73 (29%) patients overall, 11/38 (29%) in the 120 mg group and 10/35 (29%) of the 240 mg→120 mg group, thrombocytopenia (16, 22%; 8, 21% and 8, 23%), fatigue (15, 21%; 7, 18% and 8, 23%), dyspnoea (12, 16%; 5, 13% and 7, 20%), pneumonia (10, 14%; 4, 11% and 6, 17%). There were 5 adverse events with an outcome of death, 3 in the 120 mg group and 2 in the 240 mg→120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation and left ventricular dysfunction. Interpretation Tosedostat, at either dose schedule, has efficacy in older patients with relapsed or refractory AML, particularly those with prior myelodysplastic syndromes (MDS) or prior hypomethylating agent therapy. Additional studies of tosedostat including combination with hypomethylating agents and low dose cytarabine in patients with high risk MDS and AML are ongoing and/or planned. Funding The OPAL study was funded by Chroma Therapeutics Ltd, Abingdon, UK. PMID:23453583

Somatic mutation dynamics in MDS patients treated with azacitidine indicate clonal selection in patients-responders

PubMed Central

Polgarova, Kamila; Vargova, Karina; Kulvait, Vojtech; Dusilkova, Nina; Minarik, Lubomir; Zemanova, Zuzana; Pesta, Michal; Jonasova, Anna; Stopka, Tomas

2017-01-01

Azacitidine (AZA) for higher risk MDS patients is a standard therapy with limited durability. To monitor mutation dynamics during AZA therapy we utilized massive parallel sequencing of 54 genes previously associated with MDS/AML pathogenesis. Serial sampling before and during AZA therapy of 38 patients (reaching median overall survival 24 months (Mo) with 60% clinical responses) identified 116 somatic pathogenic variants with allele frequency (VAF) exceeding 5%. High accuracy of data was achieved via duplicate libraries from myeloid cells and T-cell controls. We observed that nearly half of the variants were stable while other variants were highly dynamic. Patients with marked decrease of allelic burden upon AZA therapy achieved clinical responses. In contrast, early-progressing patients on AZA displayed minimal changes of the mutation pattern. We modeled the VAF dynamics on AZA and utilized a joint model for the overall survival and response duration. While the presence of certain variants associated with clinical outcomes, such as the mutations of CDKN2A were adverse predictors while KDM6A mutations yield lower risk of dying, the data also indicate that allelic burden volatility represents additional important prognostic variable. In addition, preceding 5q- syndrome represents strong positive predictor of longer overall survival and response duration in high risk MDS patients treated with AZA. In conclusion, variants dynamics detected via serial sampling represents another parameter to consider when evaluating AZA efficacy and predicting outcome. PMID:29340104

Clinical significance of repeat blood cultures during febrile neutropenia in adult acute myeloid leukaemia patients undergoing intensive chemotherapy.

PubMed

Kimura, Shun-Ichi; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Harada, Naonori; Ugai, Tomotaka; Kusuda, Machiko; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Nakasone, Hideki; Kako, Shinichi; Tanihara, Aki; Kanda, Yoshinobu

2017-10-01

We evaluated the clinical significance of repeat blood cultures in persistent and recurrent fever during neutropenia in adult acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients undergoing intensive chemotherapy. We retrospectively reviewed the chemotherapy cycles at our centre between January 2007 and December 2015. Blood cultures obtained within three days after initial febrile neutropenia (FN) were defined as initial blood cultures and those obtained on or after day 4 were defined as repeat blood cultures. Overall, 321 chemotherapy cycles in 89 patients were subjected to review. FN was identified in 276 (86.0%) chemotherapy cycles. In persistent FN (134 episodes), the causative pathogens were detected by repeat blood cultures in seven episodes (5.2%), including only three episodes (2.2%) of new infection. Shaking chills and high body temperature were identified as significant predictors for bloodstream infection (BSI). In recurrent FN (85 episodes), the causative pathogens were detected in seven episodes (8.2%), and all of these were new organisms. The frequency of detecting new pathogens by repeat blood cultures in recurrent FN (7/85) was higher than that in persistent FN (3/134) (p = .0491). A history of recent BSI was identified as a significant predictor for BSI in recurrent FN. The diagnostic yield of repeat blood cultures for persistent FN was low in intensive chemotherapy for AML and MDS. The frequency of repeat blood cultures for persistent FN could be reduced based on predictors. On the other hand, blood cultures were considered to be essential in cases with recurrent FN.

Clarifying the impact of polycomb complex component disruption in human cancers.

PubMed

Yamamoto, Yukiya; Abe, Akihiro; Emi, Nobuhiko

2014-04-01

The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR-like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479-84. ©2014 AACR.

Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein.

PubMed

Yoneda-Kato, N; Fukuhara, S; Kato, J

1999-06-24

The NPM-MLF1 chimeric protein is produced by the t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS) prior to progression into acute myeloid leukemia (AML). Here we report that K562 human leukemia cells ectopically expressing NPM-MLF1, but not those with wild-type MLF1, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3 mouse fibroblasts engineered to overexpress NPM-MLF1 grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of apoptotic induction confirmed that, neither NPM nor MLF1, but the NPM-MLF1 fusion protein was able to induce apoptosis. Analyses using a variety of deletion mutants of NPM-MLF1 revealed that induction of apoptosis required the N-terminal domain of MLF1 and the NPM domain containing nuclear localization signal and that removal of the NPM dimerization domain markedly impaired the ability to induce apoptosis. Co-expression of Bcl-2 rescued NIH3T3 fibroblasts from NPM-MLF1-mediated cell death without affecting the expression level or the subcellular localization of NPM-MLF1 and enabled cells to progress into S phase in low serum. These findings provide an NPM-MLF1-mediated novel mechanism of apoptotic induction and imply that NPM-MLFI in collaboration with anti-apoptotic oncoproteins may play an important role in multi-step progression from MDS to AML.

Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group.

PubMed

Takenaka, Katsuto; Nishida, Tetsuya; Asano-Mori, Yuki; Oshima, Kumi; Ohashi, Kazuteru; Mori, Takehiko; Kanamori, Heiwa; Miyamura, Koichi; Kato, Chiaki; Kobayashi, Naoki; Uchida, Naoyuki; Nakamae, Hirohisa; Ichinohe, Tatsuo; Morishima, Yasuo; Suzuki, Ritsuro; Yamaguchi, Takuhiro; Fukuda, Takahiro

2015-11-01

Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3 factors were significantly associated with a decreased risk of AML relapse and 1 factor with an increased risk of AML relapse: CMV reactivation (hazard ratio [HR], .77; 95% confidence interval [CI], .59 to .99), unrelated donor compared with related donor (HR, .59; 95% CI, .42 to .84), development of chronic GVHD (HR, .77; 95% CI, .60 to .99), and pretransplantation advanced disease status compared with standard disease status (HR, 1.99; 95% CI, 1.56 to 2.52). However, CMV reactivation was associated with increased nonrelapse mortality (HR, 1.60; 95% CI, 1.18 to 2.17) and overall mortality (HR, 1.37; 95% CI, 1.11 to 1.69). A beneficial effect of CMV reactivation on subsequent risk of relapse was observed in patients with AML but not in those with other hematological malignancies. However, this benefit was nullified by the increased nonrelapse mortality. The underlying mechanism is unclear; however, immunological activation against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options, including vaccination and adoptive T cell transfer, may be useful to take advantage of the efficacy of CMV reactivation with minimal increase in nonrelapse mortality. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC's 9th AML trial.

PubMed

Hoyle, C F; de Bastos, M; Wheatley, K; Sherrington, P D; Fischer, P J; Rees, J K; Gray, R; Hayhoe, F G

1989-05-01

The outcome of treatment with standard first line therapy of 66 patients with acute myeloid leukaemia (AML) secondary to preceding chemotherapy (Group 1), a myelodysplastic state (Group 2) or a myeloproliferative disorder (Group 3) was analysed in relation to the preceding disorder, the cytogenetic pattern where available, and the cytology and cytochemistry of blood and bone marrow. The complete remission (CR) rate for the secondary AMLs was 36% (24/66), with 24% (16/66) dying in the induction period and 39% (26/66) having resistant disease. The CR rate was 25% (5/20) for Group 1, 42% (15/36) for Group 2, and 40% (4/10) for Group 3. Even after allowance for the generally older age of the secondary AML patients, they still had a significantly poorer CR rate than the de novo AMLs (P = 0.0004). The lower CR rate was chiefly due to resistant disease. Despite this, overall survival was not significantly worse for the secondary AML patients (P = 0.15). For the 36% that achieved remission, remission duration appeared similar to that of de novo cases. Of 62 cases with adequate cytology, 38 (61%) had evidence of erythroid and/or megakaryocytic dysplasia with a CR rate of 32% (12/38). The CR rate of these multineage leukaemias was not significantly different from that of the 24 (39%) who showed granulocyte/monocyte precursor involvement only, 42% (10) of whom achieved CR. The presence of features of differentiation within blast cells such as Auer rods or sudanophilia (greater than 50% positive blasts) was associated with a higher remission rate 47% (18/38) than that of poorly differentiated cases 17% (3/18) (P = 0.04) and thus appeared to be a more important determinant of CR achievement than was lineage involvement. Cases with a normal karyotype had a 33% (7/21) CR rate, while those with chromosomal abnormalities had a 37% (9/24) CR rate. Only 12 of the 45 cases with adequate cytogenetic analysis showed deletions or monosomies involving chromosomes 5 or 7, and seven of these were in Group 1.

Patterns of hematological malignancies in Chernobyl clean-up workers (1996-2005).

PubMed

Gluzman, D; Imamura, N; Sklyarenko, L; Nadgornaya, V; Zavelevich, M; Machilo, V

2006-03-01

The question as to whether the incidence of leukemias and malignant lymphomas among the Chernobyl clean-up workers increased in 20 years after the catastrophe is still a point of much controversy. Precise diagnosis of the main forms of hematopoietic malignancies according to FAB classification and new WHO classification and comparison of these data with that in the general population will be helpful in estimating the relative contribution of the radiation factor to the overall incidence of such pathologies. The data on 218 consecutive cases of malignant diseases of hematopoietic and lymphoid tissues in Chernobyl clean-up workers diagnosed in 1996-2005 are given in comparison with the data of 2697 consecutive patients of general population of the same age group. The morphology and cytochemistry of bone marrow and peripheral blood cells were studied. Immunocytochemical techniques (APAAP, LSAB-AP) and the broad panel of monoclonal antibodies to lineage specific and differentiation antigens of leukocytes were employed for immunophenotyping leukemic cells. Various types of oncohematological diseases developing 10-20 years after Chernobyl accident were registered in a group of clean-up workers under study including myelodysplastic syndromes (MDS), acute leukemias (ALL and AML), chronic myelogenous leukemia (CML) and other chronic myeloproliferative diseases, chronic lymphocytic leukemia (B-CLL) and other chronic lymphoproliferative diseases of B and T cell origin. MDS percentage among patients of clean-up workers group tended to exceed MDS percentage in the group of patients representing the general population examined at the same period (4.58 vs. 3.70%). Among 34 AML cases, leukemia was preceded by MDS in seven patients. The relative contribution of CML to the total number of clean-up workers with leukemia was higher than the corresponding percentage value in general population examined at the same period (9.17 vs. 6.59%). B-CLL was a predominant form of hematopoietic malignancies in clean-up workers under study (25.68%). Nevertheless, B-CLL percentage in patients of clean-up workers group did not differ significantly from that in the patients of general population. The multiple myeloma percentage (7.79%) in the group of patients belonging to clean-up workers in our study turned out to be twice as much as in the patients of general population (4.0%). The verified diagnosis of tumors of hematopoietic and lymphoid tissue according to modern classification (EGIL, WHO) could be the prerequisite for further molecular genetic and analytical epidemiology study of leukemias that may be related to Chernobyl NPP accident consequences.

PubMed

Borges, D P; Santos, A W A; Magalhaes, S M M; Sidrim, J J; Rocha, M F G; Cordeiro, R A; Brilhante, R S N; Bandeira, S P; Valença Junior, J T; Pinheiro, R F

2018-06-01

Severely immunocompromised patients are at increased risk for uncommon infectious diseases with atypical presentations. Fusarium sp., has been reported in patients with hematological malignancies and prompt diagnosis is necessary due to high mortality. We report a myelodysplastic syndrome (MDS) patient who presented Fusarium solani infection associated with granulocytic sarcoma as an initial presentation of acute myeloid leukemia (AML) transformation. We performed histological examination, immunohistochemistry analysis, culture of the biopsy tissue and DNA sequencing to make a conclusive diagnosis of F. solani and granulocytic sarcoma, reinforcing the necessity of performing complete evaluation of skin lesions in immunocompromised patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Princeton VLSI Project: Semi-Annual Report.

DTIC Science & Technology

1982-11-01

already fully defined the new language and implementation is now under way o [7]. AMl differs from AU in two essential ways. First, it is based on...Our main thesis is that the VLSI design task can be profitably thought of as a progremmiW task, as opposed to a geometric editing task. We believe...S. Thesis , MIT, EECS Department, June, 1980. [4] Batali, J., Mayle, N., Shrobe, H., Sussman, G., Weise, D., "The DPL/Daedalus Design Environment

Genetic abnormalities in leukemia secondary to treatment in patients with Hodgkin's disease.

PubMed

Salas, Consuelo; Pérez-Vera, Patricia; Frías, Sara

2011-01-01

Hodgkin's disease has been treated mainly with two chemotherapy schedules, MOPP (nitrogen mustard, Oncovin, procarbazine and prednisone), which includes alkylating agents, and ABVD (adriamycin, bleomycin, vinblastine and dacarbazine), which includes topoisomerase II inhibitors, either with or without radiation therapy. Due to the types of agents used, patients with Hodgkin's disease often develop secondary leukemias. The alkylating agents included in the MOPP scheme were the first drugs associated with the development of therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML); both entities are the result of the clonal selection of cells with accumulated genomic lesions induced by antineoplastic therapy. In patients who developed t-MDS and t-AML, eight alternative routes with specific cytogenetic and molecular changes have been identified, and the routes are related to the type of therapy, alkylating agents or DNA topoisomerase II inhibitors. At the cytogenetic level, patients treated with alkylating agents show deletion 5q/monosomy 5 and deletion 7q/monosomy 7; in contrast, those who were treated with topoisomerase II inhibitors show 11q23 translocations involving the MLL gene. At the molecular level, there are two types of mutations: Class I, which alter the RAS-BRAF signal transduction pathways and increase cell proliferation; Class II, which disrupt genes that encode transcription factors and NPM1 that are involved in cell differentiation, and the inactivation of p53 tumor suppressor gene. Knowledge of the genetic alterations in these conditions is important for the classification, treatment and prognosis of patients as well as essential for increasing the knowledge of the biology of these diseases, which leads to identifying potential therapeutic targets.

[Development of Ph negative acute myeloid leukemia in a patient with minor-BCR/ABL positive chronic myeloid leukemia achieving a partial cytogenetic response during tyrosine kinase inhibitor treatment].

PubMed

Fujii, Soichiro; Miura, Ikuo; Tanaka, Hideo

2015-06-01

A 78-year-old male, who had CKD and chronic heart failure, was referred to our hospital for evaluation of leukocytosis. His bone marrow contained 12% blast cells and chromosome analysis showed the Ph chromosome as well as other changes. The patient was diagnosed with the accelerated-phase CML because FISH and RT-PCR disclosed BCR/ABL fusion signals and minor BCR/ABL, respectively. Imatinib was administered, but the CML was resistant to this treatment. We gave him nilotinib employing a reduced and intermittent administration protocol because of the progression of anemia and heart failure. The patient achieved PCyR in 8 months, but, 12 months later, his WBC count increased and 83% of the cells were blasts. Because the probable diagnosis was the blast crisis of CML, we switched from nilotinib to dasatinib. However, leukocytosis worsened and he died of pneumonia. It was later revealed that he had a normal karyotype and both FISH and RT-PCR analysis of BCR/ABL were negative. His final diagnosis was Ph negative AML developing from Ph positive CML in PCyR. Since there were no dysplastic changes indicative of MDS, it was assumed that the AML was not secondary leukemia caused by the tyrosine kinase inhibitor but, rather, de novo AML.

A Phase II Study Of The Farnesyltransferase Inhibitor ZANESTRA (R115777, NSC #702818, IND #58,359) In Complete Remission Following Induction And/Or Consolidation Chemotherapy In Adults With Poor-Risk Acute Myelogenous Leukemia (AML) And High-Risk Myelodysplasia (MDS)

ClinicalTrials.gov

2013-01-08

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Secondary Myelodysplastic Syndromes

Severe congenital neutropenia, a genetically heterogeneous disease group with an increased risk of AML/MDS

PubMed Central

Vandenberghe, Peter; Beel, Karolien

2011-01-01

Over the past decade, enormous progress has been made in the understanding of severe congenital neutropenia (SCN), by identification of several causal gene mutations: in ELANE, GFI1, HAX1, WAS and G3PC3. SCN is a preleukemic condition, independent of the genetic subtype. Acquired CSF3R mutations are specific for SCN and are strongly associated with malignant progression. In this review, we describe the known genetic subtypes of SCN, their molecular basis and clinical presentation and summarize the available evidence on CSF3R mutations and monosomy 7 in malignant conversion. PMID:22053285

Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells

PubMed Central

Srivastava, Pragya; Paluch, Benjamin E.; Matsuzaki, Junko; James, Smitha R.; Collamat-Lai, Golda; Karbach, Julia; Nemeth, Michael J.; Taverna, Pietro; Karpf, Adam R.; Griffiths, Elizabeth A.

2017-01-01

The mechanism of clinical action for the FDA approved hypomethylating drugs azacitidine and decitabine remains unresolved and in this context the potential immunomodulatory effect of these agents on leukemic cells is an area of active investigation. Induced expression of methylated Cancer Testis Antigen (CTA) genes has been demonstrated in leukemic cell lines following exposure to hypomethylating drugs in vitro. SGI-110 is a novel hypomethylating dinucleotide with prolonged in vivo exposure and clinical activity in patients with MDS and AML. We demonstrate that this agent, like decitabine, produces robust re-expression of the CTAs NY-ESO-1 and MAGE-A, both in vitro and in leukemia-bearing AML xenografts. Upregulation of these genes in vitro was sufficient to induce cytotoxicity by HLA-compatible CD8+ T-cells specific for NY-ESO-1, a well-recognized and immunogenic CTA. Additionally, exposure to SGI-110 enhances MHC class I and co-stimulatory molecule expression, potentially contributing to recognition of CTAs. SGI-110, like the parent compound decitabine, induces expression of CTAs and might modulate immune recognition of myeloid malignancy. PMID:25260825

Generation of physician-scientists manpower: a follow-up study of the first 294 graduates of the Harvard-MIT Program of Health Sciences and Technology.

PubMed

Abelmann, W H; Nave, B D; Wilkerson, L

1997-06-01

The MD program of the Harvard-MIT Division of Health Sciences and Technology was founded in 1970. One of its goals was the application of the academic resources of the two universities to the education of leaders in academic medicine and biomedical sciences. The first MD class was admitted in 1971. Prerequisites for admission are a strong background in quantitative sciences and demonstrated interest in research. Research and a thesis are obligatory. Enrollment in a PhD program is elective. Questionnaires were sent to 293 alumni who graduated from the MD program between 1975 and 1988, followed up by letters and telephone calls. By 1988, 296 students had graduated, 207 with an MD only, 89 with MD-PhD degrees. Follow-up by questionnaires of 293 living graduates (92%), plus indirect data on 11 others, revealed that 212 (75%) held faculty appointments in 64 medical schools. Overall, 73.5% of respondents were engaged in research: 68% of MDs and 86% of MD-PhDs. One hundred and four (38%) respondents spent more than 50% of their time on research: 54 (29%) of MDs and 50 (60%) of MD-PhDs. Seventy-five percent of respondents were active in teaching. Our experience indicates that both an MD-PhD program and a research-oriented MD program are effective in producing physician-scientists and leaders in academic medicine.

In-Silico Identification Of Micro-Loops In Myelodysplastic Syndromes

NASA Astrophysics Data System (ADS)

Beck, Dominik; Brandl, Miriam; Pham, Tuan D.; Chang, Chung-Che; Zhou, Xiaobo

2011-06-01

Micro-loops are regulatory network motifs that leverage transcriptional and posttranscriptional control to effectively regulate the transcriptome. In this paper a regulatory network for Myelodysplastic Syndromes (MDSs) was constructed from the literature and publicly available data sources. The network was filtered using data from deep-sequencing of small RNAs, exon and microarrays. Motif discovery showed that micro-loops might exist in MDS. We further used the identified micro-loops and performed basic network analysis to identify the known disease gene RUNX1/AML, as well as miRNA family hsa-mir-181. This suggested that the concept of micro-loops can be applied to enhance disease gene identification and biomarker discovery.

VLSI (Very Large Scale Integration) Design Tools, Reference Manual, Release 3.0.

DTIC Science & Technology

1985-08-01

generators/mult prior to running mult. The generated layout is output in directory 1ca in caesar cells with names of the form "caesarame*oca. Mut is a cft ...vlsa) spice(1.vlsi), User’s Guide to AML VLSI Dodgen Tools Reference Manual, UW/NW VLSI Consortium, University of Washington, (Christopher Terman, MIT...of the form ’caesarname..ca. Muls is a cft -based program and therefore also produces *.bd fiIls ’Caesaramew may not begin with the string mule. The

Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes.

PubMed

Svobodova, Karla; Zemanova, Zuzana; Lhotska, Halka; Novakova, Milena; Podskalska, Lucie; Belickova, Monika; Brezinova, Jana; Sarova, Iveta; Izakova, Silvia; Lizcova, Libuse; Berkova, Adela; Siskova, Magda; Jonasova, Anna; Cermak, Jaroslav; Michalova, Kyra

2016-03-01

Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation to acute myeloid leukemia and poor outcomes in patients. Copy number neutral loss of heterozygosity (CN-LOH, i.e., both copies of a chromosomal pair or their parts originate from one parent) might contribute to increased genomic instability in the bone-marrow cells of patients with MDS. The pathological potential of CN-LOH, which arises as a clonal aberration in a proportion of somatic cells, consists of tumor suppressor gene and oncogene homozygous mutations. The aim of our study was to evaluate the frequency of CN-LOH at 17p in bone-marrow cells of newly diagnosed MDS patients with complex chromosomal aberrations and to assess its correlation with mutations in the TP53 gene (17p13.1). CN-LOH was detected in 40 chromosomal regions in 21 (29%) of 72 patients analyzed. The changes in 27 of the 40 regions identified were sporadic. The most common finding was CN-LOH of the short arm of chromosome 17, which was detected in 13 (18%) of 72 patients. A mutational analysis confirmed the homozygous mutation of TP53 in all CN-LOH 17p patients, among which two frameshift mutations are not registered in the International Agency for Research on Cancer TP53 Database. CN-LOH 17p correlated with aggressive disease (median overall survival 4 months) and was strongly associated with a complex karyotype in the cohort studied, which might cause rapid disease progression in high-risk MDS. No other CN-LOH region previously recorded in MDS or AML patients (1p, 4q, 7q, 11q, 13q, 19q, 21q) was detected in our cohort of patients with complex karyotype examined at the diagnosis of MDS. The LOH region appeared to be balanced (i.e., with no DNA copy number change) when examined with conventional and molecular cytogenetic methods. Therefore, a microarray that detects single-nucleotide polymorphisms is an ideal method with which to identify and further characterize CN-LOH. Our data should specify the prognosis and should lead to the identification of potential targets for therapeutic interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Potential clinical applications of rhGM-CSF in acute myeloid leukemia based on its biologic activity and receptor interaction.

PubMed

Lanza, F; Rigolin, G M; Castagnari, B; Moretti, S; Castoldi, G

1997-01-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multilineage hemopoietic growth factor that stimulates proliferation, differentiation, and survival of progenitor cells, enhances the functional activities of mature myeloid effector cells, and plays a key role in host defense and the inflammatory process. Although the clinical use of rhGM-CSF in patients affected by lymphoid malignancies is widely accepted, its utility and safety in the management of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is still controversial. The three main schedules adopted for clinical application of GM-CSF in AML are as follows: A) post-chemotherapy, in order to shorten the duration of neutropenia and/or monocytopenia; B) prechemotherapy to recruit blast cells into active cell cycle phases, and to increase their sensitivity to cell cycle-dependent cytotoxic drugs; C) as a mobilizing agent to induce the release of progenitor cells from bone marrow into circulation (peripheral blood progenitor cell transplantation-PBPC). The objective of this paper is to analyze the potential clinical applications of rhGM-CSF in AML. The material examined in the present review includes several personal papers in this field and articles and abstracts published in journals covered by the Science Citation Index. Based on current knowledge, it may be argued that rhGM-CSF should be used only in a subset of AML patients at high risk of infection mortality, including elderly subjects, and/or in those AML patients who relapse or are resistant to induction treatment. However, the risk of stimulating the leukemic clone following GM-CSF therapy should be kept in mind when using this growth factor in the clinical setting, even though the great majority of the reported papers on this subject have shown that GM-CSF therapy does not affect relapse rates, frequency of remissions or patient life expectancy. It is likely that new data from controlled clinical trials will clarify the therapeutic role of GM-CSF in myeloid-derived malignancies, allowing the establishment of consensus guidelines for its use.

Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

PubMed

Mellinghoff, Sibylle C; Panse, Jens; Alakel, Nael; Behre, Gerhard; Buchheidt, Dieter; Christopeit, Maximilian; Hasenkamp, Justin; Kiehl, Michael; Koldehoff, Michael; Krause, Stefan W; Lehners, Nicola; von Lilienfeld-Toal, Marie; Löhnert, Annika Y; Maschmeyer, Georg; Teschner, Daniel; Ullmann, Andrew J; Penack, Olaf; Ruhnke, Markus; Mayer, Karin; Ostermann, Helmut; Wolf, Hans-H; Cornely, Oliver A

2018-02-01

Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.

An update to the cost-effectiveness of posaconazole vs fluconazole or itraconazole in the prevention of invasive fungal disease among neutropenic patients in the United States.

PubMed

Sung, Anita H; Marcella, Stephen W; Xie, Yang

2015-05-01

Posaconazole has shown superior clinical efficacy in the prevention of invasive fungal disease (IFD) among neutropenic patients as well as cost-effectiveness in the US healthcare setting vs fluconazole or itraconazole (FLU/ITRA) based on oral suspension formulations of each therapy. This study aims to provide an update on the cost-effectiveness of posaconazole in the current US healthcare setting to reflect bioequivalent tablet formulations of posaconazole and fluconazole, as well as changes in healthcare and drug costs. An existing model was used to assess the cost-effectiveness of posaconazole vs FLU/ITRA in the prevention of IFD among patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) and chemotherapy-induced neutropenia. Drug efficacy, mortality related to IFD, and death from other causes were estimated for tablet formulations using data from a randomized clinical trial of oral suspensions based on bioequivalence. IFD treatment costs were updated using the average inflation rate over 8 years (2006-2014) and drug costs were based on 2014 Analysource data. Trial data show a lower IFD probability over 100 days of follow-up with posaconazole compared to standard azole therapy (0.05 vs 0.11). The treatment duration on posaconazole is 29 days compared to 24 days for FLU and 29 days for ITRA. The average cost of prophylaxis is higher in the posaconazole group compared to FLU/ITRA ($4673 vs $353); however, the costs associated with treating the IFD are lower in the posaconazole group compared to FLU/ITRA ($2205 vs $5303). The incremental cost effectiveness ratio of IFD avoided for posaconazole is $18,898 vs FLU/ITRA. In the current healthcare cost environment where both drug costs and overall IFD treatment costs have increased since 2007, posaconazole tablets are a cost-effective alternative to fluconazole or itraconazole in the prevention of IFD among neutropenic patients with AML and MDS in the US.

Decitabine Followed by Idarubicin and Cytarabine in Treating Patients With Relapsed or Refractory AML and MDS

ClinicalTrials.gov

2017-02-14

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

Familial Investigations of Childhood Cancer Predisposition

ClinicalTrials.gov

2018-01-03

Acute Leukemia; Adenomatous Polyposis; Adrenocortical Carcinoma; AML; BAP1 Tumor Predisposition Syndrome; Carney Complex; Choroid Plexus Carcinoma; Constitutional Mismatch Repair Deficiency Syndrome; Diamond-Blackfan Anemia; DICER1 Syndrome; Dyskeratosis Congenita; Emberger Syndrome; Familial Acute Myeloid Leukemia; Familial Adenomatous Polyposis; Fanconi Anemia; Familial Cancer; Familial Wilms Tumor; Familial Neuroblastoma; GIST; Hereditary Breast and Ovarian Cancer; Hereditary Paraganglioma-Pheochromocytoma Syndrome; Hodgkin Lymphoma; Juvenile Polyposis; Li-Fraumeni Syndrome; Lynch Syndrome; MDS; Melanoma Syndrome; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Neuroblastoma; Neurofibromatosis Type 1; Neurofibromatosis Type II; Nevoid Basal Cell Carcinoma Syndrome; Non Hodgkin Lymphoma; Noonan Syndrome and Other Rasopathy; Overgrowth Syndromes; Pancreatic Cancer; Peutz-Jeghers Syndrome; Pheochromocytoma/Paraganglioma; PTEN Hamartoma Tumor Syndrome; Retinoblastoma; Rhabdoid Tumor Predisposition Syndrome; Rhabdomyosarcoma; Rothmund-Thomson Syndrome; Tuberous Sclerosis; Von Hippel-Lindau Disease

Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide

PubMed Central

2012-01-01

Background While lenalidomide (LEN) shows high efficacy in myelodysplastic syndromes (MDS) with del[5q], responses can be also seen in patients presenting without del[5q]. We hypothesized that improved detection of chromosomal abnormalities with new karyotyping tools may better predict response to LEN. Design and methods We have studied clinical, molecular and cytogenetic features of 42 patients with MDS, myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes and secondary acute myeloid leukemia (sAML) without del[5q] by metaphase cytogenetics (MC) who underwent therapy with LEN. Results Fluorescence in situ hybridization (FISH) or single nucleotide polymorphism array (SNP-A)-based karyotyping marginally increased the diagnostic yield over MC, detecting 2/42 (4.8%) additional cases with del[5q], one of whom were responded to LEN. Responses were more often observed in patients with a normal karyotype by MC (60% vs abnormal MC; 17%, p = .08) and those with gain of chromosome 8 material by either of all 3 karyotyping methods (83% vs all other chromosomal abnormalities; 44% p = .11). However, 5 out of those 6 patients received combined LEN/AZA therapy and it may also suggest those with gain of chromosome 8 material respond well to AZA. The addition of FISH or SNP-A did not improve the predictive value of normal cytogenetics by MC. Mutational analysis of TET2, UTX, CBL, EZH2, ASXL1, TP53, RAS, IDH1/2, and DNMT-3A was performed on 21 of 41 patients, and revealed 13 mutations in 11 patients, but did not show any molecular markers of responsiveness to LEN. Conclusions Normal karyotype and gain of chromosome 8 material was predictive of response to LEN in non-del[5q] patients with myeloid malignancies. PMID:22390313

[Immunosuppressive therapy using antithymocyte globulin and cyclosporin A with or without human granulocyte colony-stimulating factor in children with acquired severe aplastic anemia].

PubMed

Liu, Xiaoming; Zou, Yao; Wang, Shuchun; Zhang, Li; Yang, Wenyu; Zhang, Jiayuan; Liu, Fang; Liu, Tianfeng; Chen, Xiaojuan; Ruan, Min; Zhou, Jianfeng; Cai, Xiaojin; Qi, Benquan; Chang, Lixian; An, Wenbin; Guo, Ye; Chen, Yumei; Zhu, Xiaofan

2014-02-01

To compare the efficacy and safety of four different regimens for pediatric severe aplastic anemia (SAA) with immuno-suppressive therapy (IST) with or without combined human granulocyte colony-stimulating factor (G-CSF). The authors retrospectively analyzed 105 children with SAA treated with IST with or without G-CSF in the hospital from February 2000 to September 2010. Regimen A, without G-CSF in the whole treatment, was used to treat Group A patients, n = 27; Regimen B, G-CSF, was initiated in Group B, n = 24, before the IST until hematologic recovery; Regimen C, G-CSF, was used together with the IST for Group C patients, n = 24, until hematologic recovery; Regimen D,G-CSF was used for Group D, n = 30, after the end of IST until hematologic recovery. The response rate, relapse rate, mortality, infection rate, infection-related death rate, risk of evolving into MDS/AML, survival rate, factors affecting the time of event-free survival and so on. (1) The response (CR+PR) rates 4, 6, 12 and 24 months after IST of the whole series of 105 SAA children were 50.5% (7.6%+42.9%) , 60.0% (21.9%+38.1%) , 67.6% (38.1%+29.5%) and 69.5% (40.0%+29.5%) respectively. The 2-year survival rate was 90.5%; the follow-up of the patients for 13 years showed that the whole survival rate was 87.6%. (2) The differences of the response rates 4, 6, 12 and 24 months after IST of the 4 groups were not significant (P > 0.05). (3) No significant differences were found in the mortalities 4, 6, 12 and 24 months among the 4 groups (P > 0.05). (4) Of the 105 patients, 4 children had relapsed disease in the period of time from 6 to 24 months after IST. All the four patients belonged to the groups with G-CSF. (5) The use of G-CSF could not decrease the infection period before IST (day) (P = 0.273), and it had no impact on the infection rate after IST (P = 0.066). It did not reduce the rates of septicemia and infectious shock. And to the infection-related death rate no significant conclusion can be made. (6) Follow up of the patients for 13 years, showed that 2 had the evolution to MDS/AML in the 105 patients and the two children belonged to the groups with G-CSF. (7) Kaplan-meier curve analysis did not show any differences in the survival rates of the four groups. (8) Cox regression analysis showed that the use of G-CSF had no benefit to the patients' long term survival. While the age of diagnosis and the infection history before IST were significantly related to the patients' long term survival. The use of G-CSF did not contribute to the early response and could not reduce the infection rate, infection-related death rate and the patients' long term survival. There were no significant differences in the survival rates of the four groups. Attention should be paid to the risk of the evolution to MDS/AML.

Benign chronic neutropenia with abnormalities involving 16q22, affecting mother and daughter.

PubMed

Glasser, Lewis; Meloni-Ehrig, Aurelia; Joseph, Plakyil; Mendiola, Jennifer

2006-04-01

We report a case of familial, chronic, benign neutropenia in a 17-year-old female showing (1) the spontaneous expression of a heritable rare fragile site at 16q22 and (2) a deletion at the same region. The del(16)(q22), which most likely originated from the fragile site, was the main clonal abnormality detected in the patient's bone marrow cells, whereas a few cells with either del(16)(q22) or fra(16)(q22) were seen in the patient's peripheral blood. Interestingly, the del(16q) was also detected in the patient's uncultured cells, as demonstrated by FISH, excluding an in vitro origin of the del(16q) during culture. The bone marrow was hypocellular with decreased neutrophils and their precursors. Absolute neutrophil counts ranged from (0.62 to 1.24) x 10(9)/L with a median value of 1.02 x 10(9)/L. The patient had a more severe neutropenia than her mother, which correlated with the presence of more cells with del(16q) in the marrow. The patient's mother, who was also diagnosed with neutropenia, revealed only a few cells with the rare fra(16)(q22) in her peripheral blood cells, whereas her bone marrow showed cells with both fra(16)(q22) and del(16)(q22), although the del(16q) was present in only 2/20 cells. Some possible candidate genes contributing to the pathogenesis of the neutropenia are discussed. Chromosome abnormalities involving the 16q22 breakpoint have been observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this patient, the del(16)(q22) risk factor is unknown for subsequent development of MDS or AML. Another point to consider is the need to determine the origin of a chromosome abnormality, particularly when the clinical picture does not fit the chromosome findings. Although, the observation of a constitutional structural abnormality in a mosaic form is an extremely rare event, it is somewhat different in the case of a fragile site expression, which can, as in this case, be present in some cells and not in others. Copyright 2006 Wiley-Liss, Inc.

Distribution and features of hematological malignancies in Eastern Morocco: a retrospective multicenter study over 5 years.

PubMed

Elidrissi Errahhali, Mounia; Elidrissi Errahhali, Manal; Boulouiz, Redouane; Ouarzane, Meryem; Bellaoui, Mohammed

2016-02-25

Hematological malignancies (HM) are a public health problem. The pattern and distribution of diagnosed hematological cancers vary depending on age, sex, geography, and ethnicity suggesting the involvement of genetic and environmental factors for the development of these diseases. To our knowledge, there is no published report on HM in the case of Eastern Morocco. In this report we present for the first time the overall pattern of HM for this region. Retrospective descriptive study of patients diagnosed with HM between January 2008 and December 2012 in three centres in Eastern Morocco providing cancer diagnosis, treatment or palliative care services. The FAB (French-American-British) classification system has been taken into account in the analysis of myeloid and lymphoid neoplasms. In this study, a total of 660 cases of HM were registered between January 2008 and December 2012. Overall, 6075 cases of cancers all sites combined were registered during this study period, indicating that HM account for around 10.9 % (660/6075) of all cancers recorded. Among the 660 registered cases of HM, 53 % were males and 47 % were females, with a male to female ratio of 1.1. Thus, overall, men are slightly more affected with HM than women. By contrast, a female predominance was observed in the case of Hodgkin's lymphoma (HL), myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML) and the myelodysplastic syndrome (MDS). HM occur at a relatively young age, with an overall median age at diagnosis of 54 years. Non-Hodgkin's lymphoma (NHL) was the most common HM accounting for 29.7 % of all HM, followed by HL, MPN, multiple myelomas (MM), chronic lymphocytic leukemia (CLL), AML, MDS, acute lymphoblastic leukemia (ALL), and Waldenström macroglobulinemia (WM). The majority of HM cases have been observed among patients aged 60 years and over (40.4 % of HM). Among this age group, NHL was the most common HM. In adolescents, HL was the most frequent HM. This study provided for the first time the pattern and distribution of HM in Eastern Morocco. Our findings justify the need to establish a regional cancer registry as a first step in blood cancer control in Eastern Morocco.

cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP.

PubMed

Hanissian, Silva H; Akbar, Umar; Teng, Bin; Janjetovic, Zorica; Hoffmann, Anne; Hitzler, Johann K; Iscove, Norman; Hamre, Kristin; Du, Xiaoping; Tong, Yiai; Mukatira, Suraj; Robertson, Jon H; Morris, Stephan W

2004-04-29

Myelodysplasia/acute myeloid leukemia (MDS/AML) is characterized by a t(3;5)(q25.1;q34) chromosomal translocation that forms a fusion gene between nucleophosmin (NPM) and MDS/myeloid leukemia factor 1 (MLF1). We identified a novel protein, MLF1-interacting protein (MLF1IP), that specifically associates with MLF1 by yeast two-hybrid analysis and in pulldown assays, and colocalizes with it in both the nuclei and cytoplasm of cells. The MLF1IP gene locus is at chromosome 4q35.1 and is composed of 14 exons spanning 75.8 kb of genomic DNA. The MLF1IP cDNA encodes a 46-kDa protein that contains two bipartite and two classical nuclear localization signals, two nuclear receptor-binding motifs (LXXLL), two leucine zippers, two PEST residues and several potential phosphorylation sites. MLF1IP transcripts are expressed in a variety of tissues (e.g. fetal liver, bone marrow, thymus and testis). MLF1IP appears to be a lineage-specific gene whose expression is confined exclusively to the CFU-E erythroid precursor cells, but not in mature erythrocytes. These observations, together with previous data demonstrating a role for MLF1 in suppressing red cell maturation, suggest a possible role for MLF1IP and MLF1 deregulation in the genesis of erythroleukemias.

Practical Application of Model-based Programming and State-based Architecture to Space Missions

NASA Technical Reports Server (NTRS)

Horvath, Gregory A.; Ingham, Michel D.; Chung, Seung; Martin, Oliver; Williams, Brian

2006-01-01

Innovative systems and software engineering solutions are required to meet the increasingly challenging demands of deep-space robotic missions. While recent advances in the development of an integrated systems and software engineering approach have begun to address some of these issues, they are still at the core highly manual and, therefore, error-prone. This paper describes a task aimed at infusing MIT's model-based executive, Titan, into JPL's Mission Data System (MDS), a unified state-based architecture, systems engineering process, and supporting software framework. Results of the task are presented, including a discussion of the benefits and challenges associated with integrating mature model-based programming techniques and technologies into a rigorously-defined domain specific architecture.

Small Molecule Disrupts Abnormal Gene Fusion Associated with Leukemia | Center for Cancer Research

Cancer.gov

Rare chromosomal abnormalities, called chromosomal translocations, in which part of a chromosome breaks off and becomes attached to another chromosome, can result in the generation of chimeric proteins. These aberrant proteins have unpredictable, and sometimes harmful, functions, including uncontrolled cell growth that can lead to cancer. One type of translocation, in which a portion of the gene encoding nucleoporin 98 (NUP98)—one of about 50 proteins comprising the nuclear pore complex through which proteins are shuttled into and out of the nucleus—fuses with another gene, has been shown to result in improper histone modifications. These abnormalities alter the gene expression patterns of certain types of hematopoietic, or blood-forming, stem cells, resulting primarily in overexpression of the Hoxa7, Hoxa9,and Hoxa10 genes. NUP98 chromosomal translocations have been associated with many types of leukemia, including acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia in blast crisis (CML-bc), and myelodysplastic syndrome (MDS).

[Cryotherapy is useful and safe in the prevention of oral mucositis after high-dose melphalan (L-PAM)].

PubMed

Inagaki, Noriko; Ohue, Yukiko; Shigeta, Hiroe; Tasaka, Taizo

2006-11-01

We prospectively assessed the effectiveness of cryotherapy after high-dose L-PAM to prevent oral mucositis. Cryotherapy with ice tips was commenced 15 minutes before L-PAM administration, and continued until the end of administration. Twenty-six patients were enrolled in this study. Thirteen patients with myeloma were treated with 200 mg/m2 L-PAM followed by autologous peripheral blood stem cell transplantation, and 13 patients (4 AML, 4 MDS, 2 ALL, 2 lymphoma and 1 CML) were treated with 140 mg/m2 L-PAM followed by allogeneic stem cell transplantation. Grade 1 mucositis occurred in four of 13 patients (31%) with 200 mg/m2 L-PAM, and 2 of 13 patients (16%) with 140 mg/m2 L-PAM. Only one patient had grade 2 mucositis, and no grade 3 mucositis were observed. The procedure was well tolerated in all patients. These data suggest that cryotherapy is effective to minimize L-PAM-induced oral mucositis.

Detection of 22 common leukemic fusion genes using a single-step multiplex qRT-PCR-based assay.

PubMed

Lyu, Xiaodong; Wang, Xianwei; Zhang, Lina; Chen, Zhenzhu; Zhao, Yu; Hu, Jieying; Fan, Ruihua; Song, Yongping

2017-07-25

Fusion genes generated from chromosomal translocation play an important role in hematological malignancies. Detection of fusion genes currently employ use of either conventional RT-PCR methods or fluorescent in situ hybridization (FISH), where both methods involve tedious methodologies and require prior characterization of chromosomal translocation events as determined by cytogenetic analysis. In this study, we describe a real-time quantitative reverse transcription PCR (qRT-PCR)-based multi-fusion gene screening method with the capacity to detect 22 fusion genes commonly found in leukemia. This method does not require pre-characterization of gene translocation events, thereby facilitating immediate diagnosis and therapeutic management. We performed fluorescent qRT-PCR (F-qRT-PCR) using a commercially-available multi-fusion gene detection kit on a patient cohort of 345 individuals comprising 108 cases diagnosed with acute myeloid leukemia (AML) for initial evaluation; remaining patients within the cohort were assayed for confirmatory diagnosis. Results obtained by F-qRT-PCR were compared alongside patient analysis by cytogenetic characterization. Gene translocations detected by F-qRT-PCR in AML cases were diagnosed in 69.4% of the patient cohort, which was comparatively similar to 68.5% as diagnosed by cytogenetic analysis, thereby demonstrating 99.1% concordance. Overall gene fusion was detected in 53.7% of the overall patient population by F-qRT-PCR, 52.9% by cytogenetic prediction in leukemia, and 9.1% in non-leukemia patients by both methods. The overall concordance rate was calculated to be 99.0%. Fusion genes were detected by F-qRT-PCR in 97.3% of patients with CML, followed by 69.4% with AML, 33.3% with acute lymphoblastic leukemia (ALL), 9.1% with myelodysplastic syndromes (MDS), and 0% with chronic lymphocytic leukemia (CLL). We describe the use of a F-qRT-PCR-based multi-fusion gene screening method as an efficient one-step diagnostic procedure as an effective alternative to lengthy conventional diagnostic procedures requiring both cytogenetic analysis followed by targeted quantitative reverse transcription (qRT-PCR) methods, thus allowing timely patient management.

Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease.

PubMed

Marjanovic, Irena; Kostic, Jelena; Stanic, Bojana; Pejanovic, Nadja; Lucic, Bojana; Karan-Djurasevic, Teodora; Janic, Dragana; Dokmanovic, Lidija; Jankovic, Srdja; Vukovic, Nada Suvajdzic; Tomin, Dragica; Perisic, Ognjen; Rakocevic, Goran; Popovic, Milos; Pavlovic, Sonja; Tosic, Natasa

2016-10-01

The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.

Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo.

PubMed

Woll, Petter S; Kjällquist, Una; Chowdhury, Onima; Doolittle, Helen; Wedge, David C; Thongjuea, Supat; Erlandsson, Rikard; Ngara, Mtakai; Anderson, Kristina; Deng, Qiaolin; Mead, Adam J; Stenson, Laura; Giustacchini, Alice; Duarte, Sara; Giannoulatou, Eleni; Taylor, Stephen; Karimi, Mohsen; Scharenberg, Christian; Mortera-Blanco, Teresa; Macaulay, Iain C; Clark, Sally-Ann; Dybedal, Ingunn; Josefsen, Dag; Fenaux, Pierre; Hokland, Peter; Holm, Mette S; Cazzola, Mario; Malcovati, Luca; Tauro, Sudhir; Bowen, David; Boultwood, Jacqueline; Pellagatti, Andrea; Pimanda, John E; Unnikrishnan, Ashwin; Vyas, Paresh; Göhring, Gudrun; Schlegelberger, Brigitte; Tobiasson, Magnus; Kvalheim, Gunnar; Constantinescu, Stefan N; Nerlov, Claus; Nilsson, Lars; Campbell, Peter J; Sandberg, Rickard; Papaemmanuil, Elli; Hellström-Lindberg, Eva; Linnarsson, Sten; Jacobsen, Sten Eirik W

2014-06-16

Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation. Copyright © 2014 Elsevier Inc. All rights reserved.

[Successful treatment of a patient with two hematologic tumors: double-hit lymphoma and acute myelomonoblastic leukemia].

PubMed

Lukina, A E; Bariakh, E A; Kravchenko, S K; Nareĭko, M V; Kuz'mina, L A; Parovichnikova, E N; Obukhova, T N; Kovrigina, A M; Magomedova, A U

2014-01-01

Double-hit (DH) lymphoma, an extremely aggressive variant of B-cell lymphoma, is accompanied by chromosomal abnormalities leading to the activation of a few oncogenes, one of which is the c-MYC gene in conjunction with BCL2 or BCL6 gene rearrangements. There are most common cases of MYC/8q24 and BCL2/18q21 gene rearrangements (MYC/BCL-2 DH lymphoma). The tumor is characterized by an aggressive clinical course and a poor response to chemotherapy (CT). The median survival in patients with DH lymphomas varies from 4.5 to 18 months. Such patients are generally resistant to CHOP-21 and R-CHOP-21 therapy regimens. For the treatment of patients with DH lymphoma, the Hematology Research Center, Ministry of Health of the Russian Federation, chose an original BL-M-04 polychemotherapy (PCT) protocol in combination with rituximab, followed by autologous stem cell transplantation (allo-SCT). The paper describes the experience in successfully treating a patient with two hematologic tumors: 1) MYC/BCL-2 DH lymphoma with high-dose PCT cycles, followed by allo-SCT, and 2) a metachronously developed second tumor (acute myelomonoblastic leukemia (AMML)) with CT cycles, followed by auto-SCT. The incidence of tumors induced by the previous high-dose CT for aggressive lymphomas for 10 years is 0.7 to 10%. As a rule, the development of secondary AMML is preceded by a history of myelodysplastic syndrome (MDS); characteristic chromosomal abnormalities (deletions of the long arm of chromosomes 5 and 7) are detectable. In this case, the follow-up was 3 months before the development of AMML, during this period the patient was not found to have laboratory signs of MDS (anemia, thrombocytopenia) or chromosomal abnormalities associated with secondary MDS/AML. The presence of a leukemic stem cell is associated with the occurrence and development of hemoblastosis; that of the similar cell populations that may cause B-cell lymphomas remains uncertain. The described case may have defect in a hematopoietic stem cell that gives rise to both germs of hematopoiesis, as well as complete donor chimerism of bone marrow hematopoiesis, which gives hope to long-term remission in both DH lymphoma and AMML.

Lessons from the atomic bomb about secondary MDS.

PubMed

Hata, Tomoko; Imanishi, Daisuke; Miyazaki, Yasushi

2014-12-01

Myelodysplastic syndromes (MDSs) is a hematological neoplasm defined by ineffective hematopoiesis, dysplasia of hematopoietic cells, and risk of progression to acute leukemia. MDS occurs as de novo or secondary, and chemoradiotherapy for cancers is thought to increase the risk of MDS among patients. Recently, an epidemiological study for MDS among A-bomb survivors was performed, and it clearly demonstrated that the exposure to external radiation significantly increased the risk of MDS. Precise epidemiological data among survivors have revealed important clinical factors related to the risk of leukemias. In this review, by comparing data for secondary MDS and leukemia/MDS among survivors, several factors which would affect the risk of MDS, especially secondary MDS, are discussed.

Chromosomal Minimal Critical Regions in Therapy-Related Leukemia Appear Different from Those of De Novo Leukemia by High-Resolution aCGH

PubMed Central

Itzhar, Nathalie; Dessen, Philippe; Toujani, Saloua; Auger, Nathalie; Preudhomme, Claude; Richon, Catherine; Lazar, Vladimir; Saada, Véronique; Bennaceur, Anelyse; Bourhis, Jean Henri; de Botton, Stéphane; Bernheim, Alain

2011-01-01

Therapy-related acute leukemia (t-AML), is a severe complication of cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor, compared to people who develop de novo acute leukemia (p-AML). Cytogenetic abnormalities in t-AML are similar to those found in p-AML but present more frequent unfavorable karyotypes depending on the inducting agent. Losses of chromosome 5 or 7 are observed after alkylating agents while balanced translocations are found after topoisomerase II inhibitors. This study compared t-AML to p-AML using high resolution array CGH in order to find copy number abnormalities (CNA) at a higher resolution than conventional cytogenetics. More CNAs were observed in 30 t-AML than in 36 p-AML: 104 CNAs were observed with 63 losses and 41 gains (mean number 3.46 per case) in t-AML, while in p-AML, 69 CNAs were observed with 32 losses and 37 gains (mean number of 1.9 per case). In primary leukemia with a previously “normal” karyotype, 18% exhibited a previously undetected CNA, whereas in the (few) t-AML with a normal karyotype, the rate was 50%. Several minimal critical regions (MCRs) were found in t-AML and p-AML. No common MCRs were found in the two groups. In t-AML a 40kb deleted MCR pointed to RUNX1 on 21q22, a gene coding for a transcription factor implicated in frequent rearrangements in leukemia and in familial thrombocytopenia. In de novo AML, a 1Mb MCR harboring ERG and ETS2 was observed from patients with complex aCGH profiles. High resolution cytogenomics obtained by aCGH and similar techniques already published allowed us to characterize numerous non random chromosome abnormalities. This work supports the hypothesis that they can be classified into several categories: abnormalities common to all AML; those more frequently found in t-AML and those specifically found in p-AML. PMID:21339820

Chromosomal minimal critical regions in therapy-related leukemia appear different from those of de novo leukemia by high-resolution aCGH.

PubMed

Itzhar, Nathalie; Dessen, Philippe; Toujani, Saloua; Auger, Nathalie; Preudhomme, Claude; Richon, Catherine; Lazar, Vladimir; Saada, Véronique; Bennaceur, Anelyse; Bourhis, Jean Henri; de Botton, Stéphane; Bernheim, Alain

2011-02-14

Therapy-related acute leukemia (t-AML), is a severe complication of cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor, compared to people who develop de novo acute leukemia (p-AML). Cytogenetic abnormalities in t-AML are similar to those found in p-AML but present more frequent unfavorable karyotypes depending on the inducting agent. Losses of chromosome 5 or 7 are observed after alkylating agents while balanced translocations are found after topoisomerase II inhibitors. This study compared t-AML to p-AML using high resolution array CGH in order to find copy number abnormalities (CNA) at a higher resolution than conventional cytogenetics. More CNAs were observed in 30 t-AML than in 36 p-AML: 104 CNAs were observed with 63 losses and 41 gains (mean number 3.46 per case) in t-AML, while in p-AML, 69 CNAs were observed with 32 losses and 37 gains (mean number of 1.9 per case). In primary leukemia with a previously "normal" karyotype, 18% exhibited a previously undetected CNA, whereas in the (few) t-AML with a normal karyotype, the rate was 50%. Several minimal critical regions (MCRs) were found in t-AML and p-AML. No common MCRs were found in the two groups. In t-AML a 40 kb deleted MCR pointed to RUNX1 on 21q22, a gene coding for a transcription factor implicated in frequent rearrangements in leukemia and in familial thrombocytopenia. In de novo AML, a 1 Mb MCR harboring ERG and ETS2 was observed from patients with complex aCGH profiles. High resolution cytogenomics obtained by aCGH and similar techniques already published allowed us to characterize numerous non random chromosome abnormalities. This work supports the hypothesis that they can be classified into several categories: abnormalities common to all AML; those more frequently found in t-AML and those specifically found in p-AML.

MDS classification is improving in an era of the WHO 2016 criteria of MDS: A population-based analysis among 9159 MDS patients diagnosed in the Netherlands.

PubMed

Dinmohamed, Avinash G; Visser, Otto; Posthuma, Eduardus F M; Huijgens, Peter C; Sonneveld, Pieter; van de Loosdrecht, Arjan A; Jongen-Lavrencic, Mojca

2017-10-01

Morphologic and cytogenetic assessments are required to characterize diagnostic and prognostic features of myelodysplastic syndromes (MDS). We assessed whether these assessments were performed among newly diagnosed MDS patients in the Netherlands. MDS cases were retrieved from the nationwide Netherlands Cancer Registry (N=9159; period 2001-2014) and the regional PHAROS MDS registry (N=676; period 2008-2011). The proportion of unclassified MDS decreased from 58% in 2001 to 13% in 2014. Data from the more detailed PHAROS registry revealed that the degree of bone marrow dysplasia was only reported in ∼30% of all evaluable bone marrow aspirates. Further, the International Prognostic Scoring System was undetermined in 55% of patients, primarily owing to unperformed cytogenetics in 46% of patients. The classification of MDS is improving in the Netherlands. Nevertheless, particular diagnostic and prognostic procedures that are essential for the diagnosis and subsequent treatment decision-making of MDS were not fully utilized in particular patient subsets. Copyright © 2017 Elsevier Ltd. All rights reserved.

Osteolytic Bone Lesions - A Rare Presentation of AML M6.

PubMed

Geetha, N; Sreelesh, K P; Priya, M J; Lali, V S; Rekha, N

2015-01-01

Acute myeloid leukemia (AML) M6 is a rare form of AML accounting for < 5 % of all AML. Extramedullary involvement is very rarely seen in this entity. Skeletal lesion has not been described in AML M6 before. We discuss the case of a 17 year old boy with AML M6, who presented with osteolytic lesion of right humerus. He was treated with induction and consolidation chemotherapy. The present case is the first report in literature of AML M6 presenting with skeletal lesions.

Refractory Anemia with Ring Sideroblasts (RARS) and RARS with Thrombocytosis (RARS-T) – “2017 Update on Diagnosis, Risk-stratification, and Management”

PubMed Central

Patnaik, Mrinal M.; Tefferi, Ayalew

2017-01-01

Disease Overview Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). Diagnosis MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥ 450 × 10(9)/L and large atypical megakaryocytes (similar to BCR-ABL1 negative MPN). Mutations and Karyotype Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases. Risk stratification Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-IPSS). Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation. Treatment Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain. PMID:28188970

Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register.

PubMed

Moreno Berggren, Daniel; Folkvaljon, Yasin; Engvall, Marie; Sundberg, Johan; Lambe, Mats; Antunovic, Petar; Garelius, Hege; Lorenz, Fryderyk; Nilsson, Lars; Rasmussen, Bengt; Lehmann, Sören; Hellström-Lindberg, Eva; Jädersten, Martin; Ejerblad, Elisabeth

2018-06-01

The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2·9 per 100 000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0·001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P = 0·05) and for WPSS compared to IPSS (P = 0·07). IPSS-R was superior to both IPSS and WPSS for patients aged ≤70 years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a 'real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power. © 2018 John Wiley & Sons Ltd.

[Acute myeloid leukemia].

PubMed

Tabuchi, Ken

2007-02-01

The annual incident rate of pediatric acute myeloid leukemia (AML) is now 10 per million in Japan, against 5 to 9 per million in the USA and Europe. Overall long-term survival has now been achieved for more than 50% of pediatric patients with AML in the USA and in Europe. The prognostic factors of pediatric AML were analyzed,and patients with AML were classified according to prognostic factors. The t(15;17), inv(16) and t(8;21) have emerged as predictors of good prognosis in children with AML. Monosomy 7, monosomy 5 and del (5 q) abnormalities showed a poor prognosis. In addition to chromosomal deletions, FLT 3/ITD identifies pediatric patients with a particularly poor prognosis. Clinical trials of AML feature intensive chemotherapy with or without subsequent stem cell transplantation. Risk group stratification is becoming increasingly important in planning AML therapy. APL can be distinguished from other subtypes of AML by virtue of its excellent response and overall outcome as a result of differentiation therapy with ATRA. Children with Down syndrome and AML have been shown to have a superior prognosis to AML therapy compared to other children with AML. The results of the Japan Cooperative Study Group protocol ANLL 91 was one of the best previously reported in the literature. With the consideration of quality of life (QOL), risk-adapted therapy was introduced in the AML 99 trial conducted by the Japanese Childhood AML Cooperative Study Group. A high survival rate of 79% at 3 years was achieved for childhood de novo AML in the AML 99 trial. To evaluate the efficacy and safety of the treatment strategy according to risk stratification based on leukemia cell biology and response to the initial induction therapy in children with AML, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) has organized multi-center phase II trials in children with newly diagnosed AML.

2C-Methyl- D- erythritol 2,4-cyclodiphosphate synthase from Stevia rebaudiana Bertoni is a functional gene.

PubMed

Kumar, Hitesh; Singh, Kashmir; Kumar, Sanjay

2012-12-01

Stevia [Stevia rebaudiana (Bertoni)] is a perennial herb which accumulates sweet diterpenoid steviol glycosides (SGs) in its leaf tissue. SGs are synthesized by 2C-methyl-D-erythritol 4-phosphate (MEP) pathway. Of the various enzymes of the MEP pathway, 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (MDS) (encoded by MDS) catalyzes the cyclization of 4-(cytidine 5' diphospho)-2C-methyl-D-erythritol 2-phosphate into 2C-methyl-D-erythritol 2,4-cyclodiphosphate. Complementation of the MDS knockout mutant strain of Escherichia coli, EB370 with putative MDS of stevia (SrMDS) rescued the lethal mutant, suggesting SrMDS to be a functional gene. Experiments conducted in plant growth chamber and in the field suggested SrMDS to be a light regulated gene. Indole 3-acetic acid (IAA; 50, 100 μM) down-regulated the expression of SrMDS at 4 h of the treatment, whereas, abscisic acid did not modulate its expression. A high expression of SrMDS was observed during the light hours of the day as compared to the dark hours. The present work established functionality of SrMDS and showed the role of light and IAA in regulating expression of SrMDS.

Multiparameter flow cytometry reveals myelodysplasia-related aberrant antigen expression in myelodysplastic/myeloproliferative neoplasms.

PubMed

Kern, Wolfgang; Bacher, Ulrike; Schnittger, Susanne; Alpermann, Tamara; Haferlach, Claudia; Haferlach, Torsten

2013-05-01

Within the myelodysplastic/myeloproliferative neoplasm (MDS/MPN) category of the WHO (2008), only chronic myelomonocytic leukemia was so far evaluated by multiparameter flow cytometry (MFC). To investigate the potential of MFC for MDS/MPNs, unclassifiable (MDS/MPNu), and refractory anemia associated with ring sideroblasts and marked thrombocytosis (RARS-T), we studied 91 patients with these entities (60 males/31 females; 35.3-87.4 years) for MDS-related aberrant immunophenotypes (≥ 2 different cell lineages with ≥ 3 aberrantly expressed antigens). Data were correlated with cytomorphology and cytogenetics. MFC identified MDS-related immunophenotypes in 54/91 (59.3%) of patients. Patients with or without MDS-related immunophenotype did not differ significantly by demographic characteristics, blood values, or median overall survival. MDS-related immunophenotype cases showed a higher number of aberrantly expressed antigens (mean ± SD, 4.9 ± 2.4 vs. 2.0 ± 1.4; P < 0.001). Aberrant karyotypes showed a similar frequency in patients with and without MDS-related immunophenotype (11/54; 20.4% vs. 7/37; 18.9%; P = n.s.). MDS-related immunophenotype are present in more than half of patients with MDS/MPNu and RARS-T. MFC therefore may be helpful to separate cases into more "MDS-like" or "MPN-like" subgroups. Copyright © 2012 International Clinical Cytometry Society.

78 FR 54336 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-03

... (March 26, 2013) (SR-Phlx-2013-28) (notice of filing and immediate effectiveness implementing MDS on PSX...) (notice of filing and immediate effectiveness implementing MDS on BX) (the ``BX MDS filing''). No other... effectiveness implementing MDS on NASDAQ) (the ``NASDAQ MDS filing''). Other markets have also implemented a...

Modified multidimensional scaling approach to analyze financial markets.

PubMed

Yin, Yi; Shang, Pengjian

2014-06-01

Detrended cross-correlation coefficient (σDCCA) and dynamic time warping (DTW) are introduced as the dissimilarity measures, respectively, while multidimensional scaling (MDS) is employed to translate the dissimilarities between daily price returns of 24 stock markets. We first propose MDS based on σDCCA dissimilarity and MDS based on DTW dissimilarity creatively, while MDS based on Euclidean dissimilarity is also employed to provide a reference for comparisons. We apply these methods in order to further visualize the clustering between stock markets. Moreover, we decide to confront MDS with an alternative visualization method, "Unweighed Average" clustering method, for comparison. The MDS analysis and "Unweighed Average" clustering method are employed based on the same dissimilarity. Through the results, we find that MDS gives us a more intuitive mapping for observing stable or emerging clusters of stock markets with similar behavior, while the MDS analysis based on σDCCA dissimilarity can provide more clear, detailed, and accurate information on the classification of the stock markets than the MDS analysis based on Euclidean dissimilarity. The MDS analysis based on DTW dissimilarity indicates more knowledge about the correlations between stock markets particularly and interestingly. Meanwhile, it reflects more abundant results on the clustering of stock markets and is much more intensive than the MDS analysis based on Euclidean dissimilarity. In addition, the graphs, originated from applying MDS methods based on σDCCA dissimilarity and DTW dissimilarity, may also guide the construction of multivariate econometric models.

Clinical utility of lenalidomide in the treatment of myelodysplastic syndromes

PubMed Central

Abou Zahr, Abdallah; Saad Aldin, Ehab; Komrokji, Rami S; Zeidan, Amer M

2015-01-01

Myelodysplastic syndromes (MDS) represent a heterogeneous group of acquired clonal hematopoietic disorders characterized by peripheral blood cytopenias, paradoxical BM hypercellularity, ineffective hematopoiesis, and increased risk of leukemic transformation. Risk stratification, using different prognostic scores and markers, is at the core of MDS management. Deletion 5q [del(5q)] MDS is a distinct class of MDS characterized by the haploinsufficiency of specific genes, microRNAs, and proteins, which has been linked to increased sensitivity to the drug lenalidomide. Phase II and III clinical trials have demonstrated the efficacy of lenalidomide in improving clinical outcomes of patients with del(5q) MDS, including reduction in red blood cell transfusion requirements and improvements in quality of life. Lenalidomide has also demonstrated some activity in non-del(5q) lower-risk MDS as well as higher-risk MDS, especially in combination with other agents. In this paper, we review the pathogenesis of del(5q) MDS, the proposed mechanisms of action of lenalidomide, the major clinical trials that documented the activity of lenalidomide in different MDS populations, potential predictors of benefit from the drug and suggested mechanisms of resistance, and the use of combination strategies to expand the clinical utility of lenalidomide in MDS. PMID:25565910

Metachronous and Synchronous Presentation of Acute Myeloid Leukemia and Lung Cancer

PubMed Central

Varadarajan, Ramya; Ford, LaurieAnn; Sait, Sheila NJ; Block, AnneMarie W.; Barcos, Maurice; Wallace, Paul K.; Ramnath, Nithya; Wang, Eunice S.; Wetzler, Meir

2009-01-01

Smoking is associated with both acute myeloid leukemia (AML) and lung cancer. We therefore searched our database for concomitant presentation of AML and lung cancer. Among 775 AML cases and 5225 lung cancer cases presenting to Roswell Park Cancer Institute between the years January 1992 and May 2008 we found 12 (1.5% of AML cases; 0.23% of lung cancer cases) cases (seven metachronous and five synchronous) with AML and lung cancer. All but one patient were smokers. There were no unique characteristic of either AML or lung cancer in these patients. Nine patients succumbed to AML, one died from an unrelated cause while undergoing treatment for AML, one died of lung cancer and one patient is alive after allogeneic transplantation for AML. In summary, this study supports the need for effective smoking cessation programs. PMID:19181380

The level of bone marrow WT1 message is a useful marker to differentiate myelodysplastic syndromes with low blast percentage from cytopenia due to other reasons.

PubMed

Baba, Maki; Hata, Tomoko; Tsushima, Hideki; Mori, Sayaka; Sasaki, Daisuke; Turuta, Kazuto; Hasegawa, Hiroo; Ando, Koji; Sawayama, Yasushi; Imanishi, Daisuke; Taguchi, Jun; Yanagihara, Katsunori; Tomonaga, Masao; Kamihira, Shimeru; Miyazaki, Yasushi

2015-01-01

Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that transform to acute leukemia. Distinguishing MDS from other cytopenias is sometimes difficult even for trained hematologists. WT1, the gene mutated in Wilms' tumor, was found expressed in acute myeloid leukemia and MDS. The amount of WT1 in peripheral blood and bone marrow (BM) is low in low-risk MDS subtypes, and is high in high-risk MDS subtypes. However, the role of WT1 in the differential diagnosis between MDS and other diseases showing cytopenia has not been fully addressed. The present study evaluated whether WT1 expression level can assist in the differential diagnosis of MDS from other cytopenias. The amount of WT1 message was evaluated among 56 MDS patients and 47 patients with cytopenia for various other reasons (cytopenia VR) at the Nagasaki University Hospital. The level of WT1 was significantly related to the percentage of blasts in BM among MDS cases, and the type of French-American-British classification of MDS; refractory anemia (RA) cases showed significantly lower WT1 level than patients with RA with excess blasts. WT1 level was significantly related to the prognostic risk categories of MDS by the International Prognostic Scoring System (IPSS) and the revised IPSS. Although the blast percentage in the BM of RA and cytopenia VR were both less than 5%, there was a significant difference in the level of WT1 between MDS and cytopenia VR. WT1 might be a good marker to differentiate low blast percentage MDS and cytopenia VR.

Development of acute myeloid leukemia in patients with untreated chronic lymphocytic leukemia.

PubMed

Ito, Shoko; Fujiwara, Shin-Ichiro; Mashima, Kiyomi; Umino, Kento; Minakata, Daisuke; Nakano, Hirofumi; Yamasaki, Ryoko; Kawasaki, Yasufumi; Sugimoto, Miyuki; Ashizawa, Masahiro; Yamamoto, Chihiro; Hatano, Kaoru; Okazuka, Kiyoshi; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kanda, Yoshinobu

2017-05-01

The development of acute myeloid leukemia (AML) in patients with untreated chronic lymphocytic leukemia (CLL) is rare. We experienced a 65-year-old man who developed AML with aberrant CD7 expression and monoallelic CEBPA mutation during watchful waiting for CLL. He failed to achieve complete response (CR) by standard induction therapy for AML. We retrospectively reviewed 27 patients who developed AML with untreated CLL published between 1973 and 2016. The median age at diagnosis of AML was 68 years, and the median duration between the diagnoses of AML and CLL was 4.2 years. Diagnosis of AML and CLL was made simultaneously in 16 patients. The CR rate of AML was 42.9%, and the median survival was only 1.5 months after the diagnosis of AML. Patients who achieved CR tended to survive longer than those who did not. Our results demonstrated that the development of AML in patients with untreated CLL was associated with a poor response to chemotherapy and an extremely poor prognosis.

AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein.

PubMed

Steffen, Björn; Knop, Markus; Bergholz, Ulla; Vakhrusheva, Olesya; Rode, Miriam; Köhler, Gabriele; Henrichs, Marcel-Philipp; Bulk, Etmar; Hehn, Sina; Stehling, Martin; Dugas, Martin; Bäumer, Nicole; Tschanter, Petra; Brandts, Christian; Koschmieder, Steffen; Berdel, Wolfgang E; Serve, Hubert; Stocking, Carol; Müller-Tidow, Carsten

2011-04-21

The most frequent translocation t(8;21) in acute myeloid leukemia (AML) generates the chimeric AML1/ETO protein, which blocks differentiation and induces self-renewal in hematopoietic progenitor cells. The underlying mechanisms mediating AML1/ETO-induced self-renewal are largely unknown. Using expression microarray analysis, we identified the Groucho-related amino-terminal enhancer of split (AES) as a consistently up-regulated AML1/ETO target. Elevated levels of AES mRNA and protein were confirmed in AML1/ETO-expressing leukemia cells, as well as in other AML specimens. High expression of AES mRNA or protein was associated with improved survival of AML patients, even in the absence of t(8;21). On a functional level, knockdown of AES by RNAi in AML1/ETO-expressing cell lines inhibited colony formation. Similarly, self-renewal induced by AML1/ETO in primary murine progenitors was inhibited when AES was decreased or absent. High levels of AES expression enhanced formation of immature colonies, serial replating capacity of primary cells, and colony formation in colony-forming unit-spleen assays. These findings establish AES as a novel AML1/ETO-induced target gene that plays an important role in the self-renewal phenotype of t(8;21)-positive AML.

NAD(P)H: Quinone Oxidoreductase 1 Deficiency Conjoint with Marginal Vitamin C Deficiency Causes Cigarette Smoke Induced Myelodysplastic Syndromes

PubMed Central

Das, Archita; Dey, Neekkan; Ghosh, Arunava; Das, Tanusree; Chatterjee, Indu B.

2011-01-01

Background The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs. Methodology and Principal Findings Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective. Conclusions and Significance CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS. PMID:21655231

Longitudinal construct validity of the minimum data set health status index.

PubMed

Jones, Aaron; Feeny, David; Costa, Andrew P

2018-05-24

The Minimum Data Set Health Status Index (MDS-HSI) is a generic, preference-based health-related quality of life (HRQOL) measure derived by mapping items from the Resident Assessment Instrument - Minimum Data Set (RAI-MDS) assessment onto the Health Utilities Index Mark 2 classification system. While the validity of the MDS-HSI has been examined in cross-sectional settings, the longitudinal validity has not been explored. The objective of this study was to investigate the longitudinal construct validity of the MDS-HSI in a home care population. This study utilized a retrospective cohort of home care patients in the Hamilton-Niagara-Haldimand-Brant health region of Ontario, Canada with at least two RAI-MDS Home Care assessments between January 2010 and December 2014. Convergent validity was assessed by calculating Spearman rank correlations between the change in MDS-HSI and changes in six validated indices of health domains that can be calculated from the RAI-MDS assessment. Known-groups validity was investigated by fitting multivariable linear regression models to estimate the mean change in MDS-HSI associated with clinically important changes in the six health domain indices and 15 disease symptoms from the RAI-MDS Home Care assessment, controlling for age and sex. The cohort contained 25,182 patients with two RAI-MDS Home Care assessments. Spearman correlations between the MDS-HSI change and changes in the health domain indices were all statistically significant and in the hypothesized small to moderate range [0.1 < ρ < 0.5]. Clinically important changes in all of the health domain indices and 13 of the 15 disease symptoms were significantly associated with clinically important changes in the MDS-HSI. The findings of this study support the longitudinal construct validity of the MDS-HSI in home care populations. In addition to evaluating changes in HRQOL among home care patients in clinical research, economic evaluation, and health technology assessment, the MDS-HSI may be used in system-level applications using routinely collected population-level data.

Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

PubMed Central

Geiselhart, Anja; Lier, Amelie; Walter, Dagmar; Milsom, Michael D.

2012-01-01

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients. PMID:22675615

Subcellular localization of full-length human myeloid leukemia factor 1 (MLF1) is independent of 14-3-3 proteins.

PubMed

Molzan, Manuela; Ottmann, Christian

2013-03-01

Myeloid leukemia factor 1 (MLF1) is associated with the development of leukemic diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, information on the physiological function of MLF1 is limited and mostly derived from studies identifying MLF1 interaction partners like CSN3, MLF1IP, MADM, Manp and the 14-3-3 proteins. The 14-3-3-binding site surrounding S34 is one of the only known functional features of the MLF1 sequence, along with one nuclear export sequence (NES) and two nuclear localization sequences (NLS). It was recently shown that the subcellular localization of mouse MLF1 is dependent on 14-3-3 proteins. Based on these findings, we investigated whether the subcellular localization of human MLF1 was also directly 14-3-3-dependent. Live cell imaging with GFP-fused human MLF1 was used to study the effects of mutations and deletions on its subcellular localization. Surprisingly, we found that the subcellular localization of full-length human MLF1 is 14-3-3-independent, and is probably regulated by other as-yet-unknown proteins.

Successful treatment of congenital acute myeloid leukemia (AML-M6) in a premature infant.

PubMed

van Dongen, Joyce C A; Dalinghaus, Michiel; Kroon, Andre A; de Vries, Andrica C H; van den Heuvel-Eibrink, Marry M

2009-11-01

Congenital acute myeloid leukemia (AML), and especially AML-M6 is a rare disease with a poor prognosis. Moreover, reports of treatment outcome of congenital AML-M6 in premature infants are not available. We report the first treated case of congenital AML-M6 in a premature girl, who received a full AML protocol. She presented with blueberry-muffin spots, anemia, high white blood cell count, and serious cardiopulmonary distress. Peripheral blood smears showed AML-M6 blasts. After treatment with a sequential low-dose cytarabine after birth and full-dose AML treatment according to the MRC-12 protocol at the age of 2 months, she now is in continuous complete remission for 4 years.

Acute myeloid leukemia and diabetes insipidus with monosomy 7.

PubMed

Harb, Antoine; Tan, Wei; Wilding, Gregory E; Battiwalla, Minoo; Sait, Sheila N J; Wang, Eunice S; Wetzler, Meir

2009-04-15

The predisposition of monosomy 7 to diabetes insipidus (DI) in acute myeloid leukemia (AML) led us to ask whether AML associated with monosomy 7 and DI will differ from AML associated with other karyotype aberrations and DI and whether the outcome of patients with AML and DI will differ from those without DI. We describe 2 patients from Roswell Park Cancer Institute and discuss 29 additional cases from the literature. AML with monosomy 7 and DI (n = 25) had a trend towards a lower complete remission (p = 0.0936) and worse survival (p = 0.0480) than AML with other karyotype changes and DI (n = 6). Further, AML with monosomy 7 and DI had worse complete remission rate and overall survival than AML with monosomy 7 but without DI. In conclusion, it appears that AML with monosomy 7 and DI is a disease entity with specifically poor outcome.

Remission of relapsing polychondritis after successful treatment of myelodysplastic syndrome with azacitidine: a case and review of the literature.

PubMed

Erden, Abdulsamet; Bilgin, Emre; Kılıç, Levent; Sarı, Alper; Armağan, Berkan; Büyükaşık, Yahya; Kalyoncu, Umut

2018-05-01

Relapsing polychondritis (RP) is a rare autoimmune disorder, and myelodysplastic syndrome (MDS) is accompanied by RP at variable rates. Herein, we report a case with RP and MDS who responded dramatically to 5-azacitidine for MDS. With conventional immunosuppressive treatment, our patient had several episodes of different side effects, including infections. With the diagnosis of MDS and initiation of azacitidine treatment, all the manifestations of RP disappeared, and remission was achieved for MDS. Although he had relapses of either RP or MDS after several years of azacitidine treatment, all relapses were controlled well with the initiation of azacitidine treatment every time. Azacitidine should be kept in mind as a treatment option for RP patients with MDS.

Premature exhaustion of mesenchymal stromal cells from myelodysplastic syndrome patients.

PubMed

Pang, Yanbin; Deng, Chengxin; Geng, Suxia; Weng, Jianyu; Lai, Peilong; Liao, Pengjun; Zeng, Lingji; Lu, Zesheng; Zhang, Jing; Du, Xin

2017-01-01

Myelodysplastic syndrome (MDS) predominantly occurs in aging people. Over the past decades, the cellular and molecular pathologies of MDS cells have been intensively investigated. However, how the bone marrow stromal niches are altered during MDS development remains elusive. In this study, we attempted to isolate and characterize mesenchymal stromal cells (MSCs) from 30 MDS patients. We observed that only 9/30 bone marrow aspirations from MDS patients successfully formed a monolayer in vitro, while 17/17 bone marrow aspirations from normal donors (median age 45 years, range: 22-73 years) succeeded in this process. Compared to normal MSCs, the MDS MSCs showed premature exhaustion, including reduced osteogenic differentiation ability, slower passage rate, and extremely limited passage times. These functional defects were associated with downregulation of Osterix and Runx2 genes and increased cell cycle arrest and apoptosis. However, the premature exhaustion of MDS MSCs did not correlate with patients' ages, indicating that natural aging is not the cause of dysfunction in MDS MSCs. Our result provides a strong rational to target prematurely exhausting MSCs in future MDS treatment.

Essentials of MDS 3.0 section M: skin conditions.

PubMed

Levine, Jeffrey M; Roberson, Sharon; Ayello, Elizabeth A

2010-06-01

To provide information about the impending changes in the Minimum Data Set (MDS) Section M on skin conditions and its implications for practice. This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. After participating in this educational activity, the participant should be better able to: 1. Compare section M of MDS version 2.0 to MDS version 3.0. 2. Apply the complexities of the MDS 3.0 section M for coding. 3. Demonstrate accurate and complete documentation of wounds as per MDS 3.0 section M.

Temporal and Geographic variation in the validity and internal consistency of the Nursing Home Resident Assessment Minimum Data Set 2.0.

PubMed

Mor, Vincent; Intrator, Orna; Unruh, Mark Aaron; Cai, Shubing

2011-04-15

The Minimum Data Set (MDS) for nursing home resident assessment has been required in all U.S. nursing homes since 1990 and has been universally computerized since 1998. Initially intended to structure clinical care planning, uses of the MDS expanded to include policy applications such as case-mix reimbursement, quality monitoring and research. The purpose of this paper is to summarize a series of analyses examining the internal consistency and predictive validity of the MDS data as used in the "real world" in all U.S. nursing homes between 1999 and 2007. We used person level linked MDS and Medicare denominator and all institutional claim files including inpatient (hospital and skilled nursing facilities) for all Medicare fee-for-service beneficiaries entering U.S. nursing homes during the period 1999 to 2007. We calculated the sensitivity and positive predictive value (PPV) of diagnoses taken from Medicare hospital claims and from the MDS among all new admissions from hospitals to nursing homes and the internal consistency (alpha reliability) of pairs of items within the MDS that logically should be related. We also tested the internal consistency of commonly used MDS based multi-item scales and examined the predictive validity of an MDS based severity measure viz. one year survival. Finally, we examined the correspondence of the MDS discharge record to hospitalizations and deaths seen in Medicare claims, and the completeness of MDS assessments upon skilled nursing facility (SNF) admission. Each year there were some 800,000 new admissions directly from hospital to US nursing homes and some 900,000 uninterrupted SNF stays. Comparing Medicare enrollment records and claims with MDS records revealed reasonably good correspondence that improved over time (by 2006 only 3% of deaths had no MDS discharge record, only 5% of SNF stays had no MDS, but over 20% of MDS discharges indicating hospitalization had no associated Medicare claim). The PPV and sensitivity levels of Medicare hospital diagnoses and MDS based diagnoses were between .6 and .7 for major diagnoses like CHF, hypertension, diabetes. Internal consistency, as measured by PPV, of the MDS ADL items with other MDS items measuring impairments and symptoms exceeded .9. The Activities of Daily Living (ADL) long form summary scale achieved an alpha inter-consistency level exceeding .85 and multi-item scale alpha levels of .65 were achieved for well being and mood, and .55 for behavior, levels that were sustained even after stratification by ADL and cognition. The Changes in Health, End-stage disease and Symptoms and Signs (CHESS) index, a summary measure of frailty was highly predictive of one year survival. The MDS demonstrates a reasonable level of consistency both in terms of how well MDS diagnoses correspond to hospital discharge diagnoses and in terms of the internal consistency of functioning and behavioral items. The level of alpha reliability and validity demonstrated by the scales suggest that the data can be useful for research and policy analysis. However, while improving, the MDS discharge tracking record should still not be used to indicate Medicare hospitalizations or mortality. It will be important to monitor the performance of the MDS 3.0 with respect to consistency, reliability and validity now that it has replaced version 2.0, using these results as a baseline that should be exceeded.

Official Japanese Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale: validation against the original English version.

PubMed

Kashihara, Kenichi; Kondo, Tomoyoshi; Mizuno, Yoshikuni; Kikuchi, Seiji; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Mochizuki, Hideki; Mori, Hideo; Murata, Miho; Nomoto, Masahiro; Takahashi, Ryosuke; Takeda, Atsushi; Tsuboi, Yoshio; Ugawa, Yoshikazu; Yamanmoto, Mitsutoshi; Yokochi, Fusako; Yoshii, Fumihito; Stebbins, Glenn T; Tilley, Barbara C; Luo, Sheng; Wang, Lu; LaPelle, Nancy R; Goetz, Christopher G

2014-09-01

The Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease (PD) Rating Scale (UPDRS) (MDS-UPDRS) has been developed and is now available in English. Part of the overall program includes the establishment of official non-English translations of the MDS-UPDRS. We present the process for completing the official Japanese translation of the MDS-UPDRS with clinimetric testing results. In this trial, the MDS-UPDRS was translated into Japanese, underwent cognitive pre-testing, and the translation was modified after taking the results into account. The final translation was approved as Official Working Draft of the MDS-UPDRS Japanese version and tested in 365 native-Japanese-speaking patients with PD. Confirmatory analyses were used to determine whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Official Working Draft of the Japanese translation. As a secondary analysis, we used exploratory factor analyses to examine the underlying factor structure without the constraint of a pre-specified factor organization. Confirmatory factor analysis revealed that Comparative Fit Index for all Parts of the MDS-UPDRS exceeded the minimal standard of 0.90 relative to the English version and therefore Japanese translation met the pre-specified criterion to be designated called an OFFICIAL MDS TRANSLATION. Secondary analyses revealed some differences between the English-language MDS-UPDRS and the Japanese translation, however, these differences were considered to be within an acceptable range. The Japanese version of the MDS-UPDRS met the criterion as an Official MDS Translation and is now available for use (www.movementdisorders.org).

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.

PubMed

Malani, D; Murumägi, A; Yadav, B; Kontro, M; Eldfors, S; Kumar, A; Karjalainen, R; Majumder, M M; Ojamies, P; Pemovska, T; Wennerberg, K; Heckman, C; Porkka, K; Wolf, M; Aittokallio, T; Kallioniemi, O

2017-05-01

We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P=0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3.

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML

PubMed Central

Malani, D; Murumägi, A; Yadav, B; Kontro, M; Eldfors, S; Kumar, A; Karjalainen, R; Majumder, M M; Ojamies, P; Pemovska, T; Wennerberg, K; Heckman, C; Porkka, K; Wolf, M; Aittokallio, T; Kallioniemi, O

2017-01-01

We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P=0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3. PMID:27833094

Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO.

PubMed

Roh, Soung-Hun; Kasembeli, Moses; Galaz-Montoya, Jesús G; Trnka, Mike; Lau, Wilson Chun-Yu; Burlingame, Alma; Chiu, Wah; Tweardy, David J

2016-02-26

AML1-ETO is the most common fusion oncoprotein causing acute myeloid leukemia (AML), a disease with a 5-year survival rate of only 24%. AML1-ETO functions as a rogue transcription factor, altering the expression of genes critical for myeloid cell development and differentiation. Currently, there are no specific therapies for AML1-ETO-positive AML. While known for decades to be the translational product of a chimeric gene created by the stable chromosome translocation t(8;21)(q22;q22), it is not known how AML1-ETO achieves its native and functional conformation or whether this process can be targeted for therapeutic benefit. Here, we show that the biosynthesis and folding of the AML1-ETO protein is facilitated by interaction with the essential eukaryotic chaperonin TRiC (or CCT). We demonstrate that a folding intermediate of AML1-ETO binds to TRiC directly, mainly through its β-strand rich, DNA-binding domain (AML-(1-175)), with the assistance of HSP70. Our results suggest that TRiC contributes to AML1-ETO proteostasis through specific interactions between the oncoprotein's DNA-binding domain, which may be targeted for therapeutic benefit. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Gene expression profiling of acute myeloid leukemia samples from adult patients with AML-M1 and -M2 through boutique microarrays, real-time PCR and droplet digital PCR.

PubMed

Handschuh, Luiza; Kaźmierczak, Maciej; Milewski, Marek C; Góralski, Michał; Łuczak, Magdalena; Wojtaszewska, Marzena; Uszczyńska-Ratajczak, Barbara; Lewandowski, Krzysztof; Komarnicki, Mieczysław; Figlerowicz, Marek

2018-03-01

Acute myeloid leukemia (AML) is the most common and severe form of acute leukemia diagnosed in adults. Owing to its heterogeneity, AML is divided into classes associated with different treatment outcomes and specific gene expression profiles. Based on previous studies on AML, in this study, we designed and generated an AML-array containing 900 oligonucleotide probes complementary to human genes implicated in hematopoietic cell differentiation and maturation, proliferation, apoptosis and leukemic transformation. The AML-array was used to hybridize 118 samples from 33 patients with AML of the M1 and M2 subtypes of the French-American‑British (FAB) classification and 15 healthy volunteers (HV). Rigorous analysis of the microarray data revealed that 83 genes were differentially expressed between the patients with AML and the HV, including genes not yet discussed in the context of AML pathogenesis. The most overexpressed genes in AML were STMN1, KITLG, CDK6, MCM5, KRAS, CEBPA, MYC, ANGPT1, SRGN, RPLP0, ENO1 and SET, whereas the most underexpressed genes were IFITM1, LTB, FCN1, BIRC3, LYZ, ADD3, S100A9, FCER1G, PTRPE, CD74 and TMSB4X. The overexpression of the CPA3 gene was specific for AML with mutated NPM1 and FLT3. Although the microarray-based method was insufficient to differentiate between any other AML subgroups, quantitative PCR approaches enabled us to identify 3 genes (ANXA3, S100A9 and WT1) whose expression can be used to discriminate between the 2 studied AML FAB subtypes. The expression levels of the ANXA3 and S100A9 genes were increased, whereas those of WT1 were decreased in the AML-M2 compared to the AML-M1 group. We also examined the association between the STMN1, CAT and ABL1 genes, and the FLT3 and NPM1 mutation status. FLT3+/NPM1- AML was associated with the highest expression of STMN1, and ABL1 was upregulated in FLT3+ AML and CAT in FLT3- AML, irrespectively of the NPM1 mutation status. Moreover, our results indicated that CAT and WT1 gene expression levels correlated with the response to therapy. CAT expression was highest in patients who remained longer under complete remission, whereas WT1 expression increased with treatment resistance. On the whole, this study demonstrates that the AML-array can potentially serve as a first-line screening tool, and may be helpful for the diagnosis of AML, whereas the differentiation between AML subgroups can be more successfully performed with PCR-based analysis of a few marker genes.

Progression of MDS-UPDRS Scores Over Five Years in De Novo Parkinson Disease from the Parkinson's Progression Markers Initiative Cohort.

PubMed

Holden, Samantha K; Finseth, Taylor; Sillau, Stefan H; Berman, Brian D

2018-01-01

The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established. Determine progression rates of MDS-UPDRS scores in de novo PD. 362 participants from the Parkinson's Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression. MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year. The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.

Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel.

PubMed

Creutzig, Ursula; van den Heuvel-Eibrink, Marry M; Gibson, Brenda; Dworzak, Michael N; Adachi, Souichi; de Bont, Eveline; Harbott, Jochen; Hasle, Henrik; Johnston, Donna; Kinoshita, Akitoshi; Lehrnbecher, Thomas; Leverger, Guy; Mejstrikova, Ester; Meshinchi, Soheil; Pession, Andrea; Raimondi, Susana C; Sung, Lillian; Stary, Jan; Zwaan, Christian M; Kaspers, Gertjan J L; Reinhardt, Dirk

2012-10-18

Despite major improvements in outcome over the past decades, acute myeloid leukemia (AML) remains a life-threatening malignancy in children, with current survival rates of ∼70%. State-of-the-art recommendations in adult AML have recently been published in this journal by Döhner et al. The primary goal of an international expert panel of the International BFM Study Group AML Committee was to set standards for the management, diagnosis, response assessment, and treatment in childhood AML. This paper aims to discuss differences between childhood and adult AML, and to highlight recommendations that are specific to children. The particular relevance of new diagnostic and prognostic molecular markers in pediatric AML is presented. The general management of pediatric AML, the management of specific pediatric AML cohorts (such as infants) or subtypes of the disease occurring in children (such as Down syndrome related AML), as well as new therapeutic approaches, and the role of supportive care are discussed.

Comprehensive clinical assessment in community setting: applicability of the MDS-HC.

PubMed

Morris, J N; Fries, B E; Steel, K; Ikegami, N; Bernabei, R; Carpenter, G I; Gilgen, R; Hirdes, J P; Topinková, E

1997-08-01

To describe the results of an international trial of the home care version of the MDS assessment and problem identification system (the MDS-HC), including reliability estimates, a comparison of MDS-HC reliabilities with reliabilities of the same items in the MDS 2.0 nursing home assessment instrument, and an examination of the types of problems found in home care clients using the MDS-HC. Independent, dual assessment of clients of home-care agencies by trained clinicians using a draft of the MDS-HC, with additional descriptive data regarding problem profiles for home care clients. Reliability data from dual assessments of 241 randomly selected clients of home care agencies in five countries, all of whom volunteered to test the MDS-HC. Also included are an expanded sample of 780 home care assessments from these countries and 187 dually assessed residents from 21 nursing homes in the United States. The array of MDS-HC assessment items included measures in the following areas: personal items, cognitive patterns, communication/hearing, vision, mood and behavior, social functioning, informal support services, physical functioning, continence, disease diagnoses health conditions and preventive health measures, nutrition/hydration, dental status, skin condition, environmental assessment, service utilization, and medications. Forty-seven percent of the functional, health status, social environment, and service items in the MDS-HC were taken from the MDS 2.0 for nursing homes. For this item set, it is estimated that the average weighted Kappa is .74 for the MDS-HC and .75 for the MDS 2.0. Similarly, high reliability values were found for items newly introduced in the MDS-HC (weighted Kappa = .70). Descriptive findings also characterize the problems of home care clients, with subanalyses within cognitive performance levels. Findings indicate that the core set of items in the MDS 2.0 work equally well in community and nursing home settings. New items are highly reliable. In tandem, these instruments can be used within the international community, assisting and planning care for older adults within a broad spectrum of service settings, including nursing homes and home care programs. With this community-based, second-generation problem and care plan-driven assessment instrument, disability assessment can be performed consistently across the world.

AML Guide: Information for Patients and Caregivers

MedlinePlus

The AML Guide Information for Patients and Caregivers Acute Myeloid Leukemia Emily , AML survivor Revised 2012 A ... day most people who have been diagnosed with acute myeloid leukemia (AML) will be cured or will ...

Targeting CD157 in AML using a novel, Fc-engineered antibody construct

PubMed Central

Krupka, Christina; Lichtenegger, Felix S.; Köhnke, Thomas; Bögeholz, Jan; Bücklein, Veit; Roiss, Michael; Altmann, Torben; Do, To Uyen; Dusek, Rachel; Wilson, Keith; Bisht, Arnima; Terrett, Jon; Aud, Dee; Pombo-Villar, Esteban; Rohlff, Christian; Hiddemann, Wolfgang; Subklewe, Marion

2017-01-01

Antibody-based immunotherapy represents a promising strategy to eliminate chemorefractory leukemic cells in acute myeloid leukemia (AML). In this study, we evaluated a novel Fc-engineered antibody against CD157 (MEN1112) for its suitability as immunotherapy in AML. CD157 was expressed in 97% of primary AML patient samples. A significant, albeit lower expression level of CD157 was observed within the compartment of leukemia-initiating cells, which are supposed to be the major source of relapse. In healthy donor bone marrow, CD157 was expressed on CD34+ cells. In ex vivo assays, MEN1112 triggered natural killer (NK) cell-mediated cytotoxicity against AML cell lines and primary AML cells. Compared to its parental analogue, the Fc-engineered antibody exhibited higher antibody dependent cellular cytotoxicity responses. Using NK cells from AML patients, we observed heterogeneous MEN1112-mediated cytotoxicity against AML cells, most likely due to well-documented defects in AML-NK cells and corresponding inter-patient variations in NK cell function. Cytotoxicity could not be correlated to the time after completion of chemotherapy. In summary, we could demonstrate that CD157 is strongly expressed in AML. MEN1112 is a promising antibody construct that showed high cytotoxicity against AML cells and warrants further clinical testing. Due to variability in NK-cell function of AML patients, the time of application during the course of the disease as well as combinatorial strategies might influence treatment results. PMID:28415689

Interprofessional collaboration and job satisfaction of chiropractic physicians.

PubMed

Konrad, Thomas R; Fletcher, Grant S; Carey, Timothy S

2004-05-01

Despite the fact that chiropractic physicians (DCs) are growing in number and legitimacy in the community of health care professionals, little recent research describes how their relationships with medical doctors (MDs) affect their job and career perceptions. This study explores interprofessional relations by identifying factors associated with variations in how DCs evaluate their interaction with MDs. It also adapts a previously validated multifaceted measure of MD job satisfaction for use with DCs. Cross-sectional survey of 311 DC physicians in North Carolina. The hypothesized multifaceted nature of DC job satisfaction was confirmed. Four distinct job facets and global career satisfaction were measured effectively in DCs. DCs' career satisfaction is related to satisfaction with compensation, intrinsic motivation of relating to patients, and having positive relationships with DC colleagues. DCs report referring patients to MDs more often than they report MDs referring patients to them. Satisfaction with relationships between DCs and MDs is relatively low and is strongly linked to the quantity of referrals from MDs and the perception that MDs practice collaboratively with DCs. However, DCs' global career satisfaction is unrelated to their relationships with MDs. Global career satisfaction of DCs is relatively high and unaffected by the low level of satisfaction DCs report having with their relationships with MDs. These findings suggest that despite increasing interaction and interdependence, DCs' relationship with MDs is of minor importance in their professional self-image.

MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia.

PubMed

Rauch, Philipp J; Ellegast, Jana M; Widmer, Corinne C; Fritsch, Kristin; Goede, Jeroen S; Valk, Peter J M; Löwenberg, Bob; Takizawa, Hitoshi; Manz, Markus G

2016-11-03

Although the molecular pathways that cause acute myeloid leukemia (AML) are increasingly well understood, the pathogenesis of peripheral blood cytopenia, a major cause of AML mortality, remains obscure. A prevailing assumption states that AML spatially displaces nonleukemic hematopoiesis from the bone marrow. However, examining an initial cohort of 223 AML patients, we found no correlation between bone marrow blast content and cytopenia, questioning the displacement theory. Measuring serum concentration of thrombopoietin (TPO), a key regulator of hematopoietic stem cells and megakaryocytes, revealed loss of physiologic negative correlation with platelet count in AML cases with blasts expressing MPL, the thrombopoietin (scavenging) receptor. Mechanistic studies demonstrated that MPL hi blasts could indeed clear TPO, likely therefore leading to insufficient cytokine levels for nonleukemic hematopoiesis. Microarray analysis in an independent multicenter study cohort of 437 AML cases validated MPL expression as a central predictor of thrombocytopenia and neutropenia in AML. Moreover, t(8;21) AML cases demonstrated the highest average MPL expression and lowest average platelet and absolute neutrophil counts among subgroups. Our work thus explains the pathophysiology of peripheral blood cytopenia in a relevant number of AML cases. © 2016 by The American Society of Hematology.

Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors.

PubMed

Iwanaga, Masako; Hsu, Wan-Ling; Soda, Midori; Takasaki, Yumi; Tawara, Masayuki; Joh, Tatsuro; Amenomori, Tatsuhiko; Yamamura, Masaomi; Yoshida, Yoshiharu; Koba, Takashi; Miyazaki, Yasushi; Matsuo, Tatsuki; Preston, Dale L; Suyama, Akihiko; Kodama, Kazunori; Tomonaga, Masao

2011-02-01

The risk of myelodysplastic syndromes (MDS) has not been fully investigated among people exposed to ionizing radiation. We investigate MDS risk and radiation dose-response in Japanese atomic bomb survivors. We conducted a retrospective cohort study by using two databases of Nagasaki atomic bomb survivors: 64,026 people with known exposure distance in the database of Nagasaki University Atomic-Bomb Disease Institute (ABDI) and 22,245 people with estimated radiation dose in the Radiation Effects Research Foundation Life Span Study (LSS). Patients with MDS diagnosed from 1985 to 2004 were identified by record linkage between the cohorts and the Nagasaki Prefecture Cancer Registry. Cox and Poisson regression models were used to estimate relationships between exposure distance or dose and MDS risk. There were 151 patients with MDS in the ABDI cohort and 47 patients with MDS in the LSS cohort. MDS rate increased inversely with exposure distance, with an excess relative risk (ERR) decay per km of 1.2 (95% CI, 0.4 to 3.0; P < .001) for ABDI. MDS risk also showed a significant linear response to exposure dose level (P < .001) with an ERR per Gy of 4.3 (95% CI, 1.6 to 9.5; P < .001). After adjustment for sex, attained age, and birth year, the MDS risk was significantly greater in those exposed when young. A significant linear radiation dose-response for MDS exists in atomic bomb survivors 40 to 60 years after radiation exposure. Clinicians should perform careful long-term follow-up of irradiated people to detect MDS as early as possible.

Inhibition of autophagy as a treatment strategy for p53 wild-type acute myeloid leukemia

PubMed Central

Folkerts, Hendrik; Hilgendorf, Susan; Wierenga, Albertus T J; Jaques, Jennifer; Mulder, André B; Coffer, Paul J; Schuringa, Jan Jacob; Vellenga, Edo

2017-01-01

Here we have explored whether inhibition of autophagy can be used as a treatment strategy for acute myeloid leukemia (AML). Steady-state autophagy was measured in leukemic cell lines and primary human CD34+ AML cells with a large variability in basal autophagy between AMLs observed. The autophagy flux was higher in AMLs classified as poor risk, which are frequently associated with TP53 mutations (TP53mut), compared with favorable- and intermediate-risk AMLs. In addition, the higher flux was associated with a higher expression level of several autophagy genes, but was not affected by alterations in p53 expression by knocking down p53 or overexpression of wild-type p53 or p53R273H. AML CD34+ cells were more sensitive to the autophagy inhibitor hydroxychloroquine (HCQ) than normal bone marrow CD34+ cells. Similar, inhibition of autophagy by knockdown of ATG5 or ATG7 triggered apoptosis, which coincided with increased expression of p53. In contrast to wild-type p53 AML (TP53wt), HCQ treatment did not trigger a BAX and PUMA-dependent apoptotic response in AMLs harboring TP53mut. To further characterize autophagy in the leukemic stem cell-enriched cell fraction AML CD34+ cells were separated into ROSlow and ROShigh subfractions. The immature AML CD34+-enriched ROSlow cells maintained higher basal autophagy and showed reduced survival upon HCQ treatment compared with ROShigh cells. Finally, knockdown of ATG5 inhibits in vivo maintenance of AML CD34+ cells in NSG mice. These results indicate that targeting autophagy might provide new therapeutic options for treatment of AML since it affects the immature AML subfraction. PMID:28703806

Identification of novel molecular markers for prognosis estimation of acute myeloid leukemia: over-expression of PDCD7, FIS1 and Ang2 may indicate poor prognosis in pretreatment patients with acute myeloid leukemia.

PubMed

Tian, Yiming; Huang, Zoufang; Wang, Zhixiang; Yin, Changxin; Zhou, Lanlan; Zhang, Lingxiu; Huang, Kaikai; Zhou, Hongsheng; Jiang, Xuejie; Li, Jinming; Liao, Libin; Yang, Mo; Meng, Fanyi

2014-01-01

Numerous factors impact on the prognosis of acute myeloid leukemia (AML), among which molecular genetic abnormalities are developed increasingly, however, accurate prediction for newly diagnosed AML patients remains unsatisfied. For further improving the prognosis evaluation system, we investigated the transcripts levels of PDCD7, FIS1, FAM3A, CA6, APP, KLRF1, ATCAY, GGT5 and Ang2 in 97 AML patients and 30 non-malignant controls, and validated using the published microarray data from 225 cytogenetically normal AML (CN-AML) patients treated according to the German AMLCG-1999 protocol. Real-time quantitative polymerase chain reaction and western blot were carried out, and clinical data were collected and analyzed. High Ang2 and FIS1 expression discriminated the CR rate of AML patients (62.5% versus 82.9% for Ang2, P = 0.011; 61.4% versus 82.2% for FIS1, P = 0.029). In CN-AML, patients with high FIS1 expression were more likely to be resistant to two courses of induction (P = 0.035). Overall survival (OS) and relapse-free survival (RFS) were shorter in CN-AML patients with high PDCD7 expression (P<0.001; P = 0.006), and PDCD7 was revealed to be an independent risk factor for OS in CN-AML (P = 0.004). In the analysis of published data from 225 CN-AML patients, PDCD7 remained independently predicting OS in CN-AML (P = 0.039). As a conclusion, Ang2 and FIS1 seem related to decreased CR rate of AML patients, and PDCD7 is associated with shorter OS and RFS in CN-AML. Hence, PDCD7, Ang2 and FIS1 may indicate a more aggressive form and poor prognosis of AML.

Identification of Novel Molecular Markers for Prognosis Estimation of Acute Myeloid Leukemia: Over-Expression of PDCD7, FIS1 and Ang2 May Indicate Poor Prognosis in Pretreatment Patients with Acute Myeloid Leukemia

PubMed Central

Tian, Yiming; Huang, Zoufang; Wang, Zhixiang; Yin, Changxin; Zhou, Lanlan; Zhang, Lingxiu; Huang, Kaikai; Zhou, Hongsheng; Jiang, Xuejie; Li, Jinming; Liao, Libin; Yang, Mo; Meng, Fanyi

2014-01-01

Numerous factors impact on the prognosis of acute myeloid leukemia (AML), among which molecular genetic abnormalities are developed increasingly, however, accurate prediction for newly diagnosed AML patients remains unsatisfied. For further improving the prognosis evaluation system, we investigated the transcripts levels of PDCD7, FIS1, FAM3A, CA6, APP, KLRF1, ATCAY, GGT5 and Ang2 in 97 AML patients and 30 non-malignant controls, and validated using the published microarray data from 225 cytogenetically normal AML (CN-AML) patients treated according to the German AMLCG-1999 protocol. Real-time quantitative polymerase chain reaction and western blot were carried out, and clinical data were collected and analyzed. High Ang2 and FIS1 expression discriminated the CR rate of AML patients (62.5% versus 82.9% for Ang2, P = 0.011; 61.4% versus 82.2% for FIS1, P = 0.029). In CN-AML, patients with high FIS1 expression were more likely to be resistant to two courses of induction (P = 0.035). Overall survival (OS) and relapse-free survival (RFS) were shorter in CN-AML patients with high PDCD7 expression (P<0.001; P = 0.006), and PDCD7 was revealed to be an independent risk factor for OS in CN-AML (P = 0.004). In the analysis of published data from 225 CN-AML patients, PDCD7 remained independently predicting OS in CN-AML (P = 0.039). As a conclusion, Ang2 and FIS1 seem related to decreased CR rate of AML patients, and PDCD7 is associated with shorter OS and RFS in CN-AML. Hence, PDCD7, Ang2 and FIS1 may indicate a more aggressive form and poor prognosis of AML. PMID:24416201

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia.

PubMed

Pillinger, Genevra; Abdul-Aziz, Amina; Zaitseva, Lyubov; Lawes, Matthew; MacEwan, David J; Bowles, Kristian M; Rushworth, Stuart A

2015-08-21

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML.

New Insights into the Pathogenesis of MDS and the rational therapeutic opportunities.

PubMed

Abou Zahr, Abdallah; Bernabe Ramirez, Carolina; Wozney, Jocelyn; Prebet, Thomas; Zeidan, Amer M

2016-01-01

Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. The clinical heterogeneity in MDS is a reflection of its molecular heterogeneity. Better understanding of aberrant epigenetics, dysregulation of immune responses, and del(5q) MDS has provided the rationale for well-established treatments in MDS. Further understanding of abnormal signal transduction and aberrant apoptosis pathways has led to development of new rational therapies that are in advanced phases of clinical translation. This review seeks to describe recent developments in our understanding of the pathogenesis of MDS and the potential therapeutic implications of these observations.

AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer.

PubMed

Tian, Ying; Wang, Genjie; Hu, Qingzhu; Xiao, Xichun; Chen, Shuxia

2018-04-01

The AML1/ETO onco-fusion protein is crucial for the genesis of t(8;21) acute myeloid leukemia (AML) and is well documented as a transcriptional repressor through dominant-negative effect. However, little is known about the transactivation mechanism of AML1/ETO. Through large cohort of patient's expression level data analysis and a series of experimental validation, we report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. Gene expression analyses verify that c-KIT expression is significantly high in t(8;21) AML. Further ChIP-seq analysis and motif scanning identify two regulatory regions located in the promoter and intronic enhancer region of c-KIT, respectively. Both regions are enriched by co-factors of AML1/ETO, such as AML1, CEBPe, c-Jun, and c-Fos. Further luciferase reporter assays show that AML1/ETO trans-activates c-KIT promoter activity through directly recognizing the AML1 motif and the co-existence of co-factors. The induction of c-KIT promoter activity is reinforced with the existence of intronic enhancer region. Furthermore, ChIP-3C-qPCR assays verify that AML1/ETO mediates the formation of DNA-looping between the c-KIT promoter and intronic enhancer region through the long-range interaction. Collectively, our data uncover a novel transcriptional activity mechanism of AML1/ETO and enrich our knowledge of the onco-fusion protein mediated transcription regulation. © 2017 Wiley Periodicals, Inc.

Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

PubMed Central

Velloso, E.D.R.P.; Chauffaille, M.L.; Peliçario, L.M.; Tanizawa, R.S.S.; Toledo, S.R.C.; Gaiolla, R.D.; Lopes, L.F.

2013-01-01

Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis. PMID:23314345

Management of lower-risk myelodysplastic syndromes without del5q: current approach and future trends.

PubMed

Stahl, Maximilian; Zeidan, Amer M

2017-04-01

Myelodysplastic syndromes (MDS) are characterized by progressive bone marrow failure manifesting as blood cytopenia and a variable risk of progression into acute myeloid leukemia. MDS is heterogeneous in biology and clinical behavior. MDS are generally divided into lower-risk (LR) and higher-risk (HR) MDS. Goals of care in HR-MDS focus on changing the natural history of the disease, whereas in LR-MDS symptom control and quality of life are the main goals. Areas covered: We review the epidemiology, tools of risk assessment, and the available therapeutic modalities for LR-MDS. We discuss the use of erythropoiesis stimulating agents (ESAs), immunosuppressive therapy (IST), lenalidomide and the hypomethylating agents (HMAs). We also discuss the predictors of response, combination treatment modalities, and management of iron overload. Lastly, we overview the most promising investigational agents for LR-MDS. Expert commentary: It remains unclear how to best incorporate a wealth of new genetic and epigenetic prognostic markers into risk assessment tools especially for LR-MDS patients. Only a subset of patients respond to current treatment modalities and most responders eventually lose their response. Once standard therapeutic options fail, management becomes more challenging. Combination-based approaches have been largely unsuccessful. Among the most promising investigational are the TPO agonists, TGF- β pathway inhibitors, telomerase inhibitors, and the splicing modifiers.

Chromosome and molecular abnormalities in myelodysplastic syndromes.

PubMed

Fenaux, Pierre

2001-06-01

Cytogenetic abnormalities are seen in approximately 50% of cases of myelodysplastic syndrome (MDS) and 80% of cases of secondary MDS (following chemotherapy or radiotherapy). These abnormalities generally consist of partial or complete chromosome deletion or addition (del5q, -7, +8, -Y, del20q), whereas balanced or unbalanced translocations are rarely found in MDS. Fluorescence hybridization techniques (fluorescence in situ hybridization [FISH], multiplex FISH, and spectral karyotyping) are useful in detecting chromosomal anomalies in cases in which few mitoses are obtained or rearrangements are complex. Ras mutations are the molecular abnormalities most frequently found in MDS, followed by p15 gene hypermethylation, FLT3 duplications, and p53 mutations, but none of these abnormalities are specific for MDS. The rare cases of balanced translocations in MDS have allowed the identification of genes whose rearrangements appear to play a role in the pathogenesis of some cases of MDS. These genes include MDS1-EVI1 in t(3;3) or t(3;21) translocations, TEL in t(5;12), HIP1 in t(5;7), MLF1 in t(3;5), and MEL1 in t(1;3). Genes more frequently implicated in the pathogenesis of MDS cases, such as those involving del5q, remain unknown, although some candidate genes are currently being studied. Cytogenetic and known molecular abnormalities generally carry a poor prognosis in MDS and can be incorporated into prognostic scoring systems such as the International Prognostic Scoring System.

Screening cognitive impairment among institutionalized older Chinese men in Taiwan: a new minimum data set-based dementia screening tool is needed.

PubMed

Lin, Chu-Sheng; Lin, Ming-Hsien; Peng, Li-Ning; Chen, Liang-Kung; Hwang, Shinn-Jang; Lan, Chung-Fu

2011-01-01

Dementia screening is of great importance in various health settings for older people, long-term care facilities are no exception. The need for an effective dementia screening tool being culture sensitive is important. Minimum data set (MDS) is a population instrument for health care management in the world, which also covers dementia screening. The main purpose of this study was to evaluate the effectiveness of the MDS-based dementia screening tools among older Chinese men in the Veteran Home in Taiwan. Overall, 576 participants (mean age: 80.9±5.3 years, all males, 92.7% physically independent), 18.6% had cognitive impairment according to the mini-mental state examination (MMSE) (mean score: 26.7±3.9). However, the prevalence of cognitive impairment was 5.5% by MDS cognitive performance scale (CPS) and 18.9% by MDS cognition scale (MDS-COGS). The screening results of CPS and MDS-COGS were highly interrelated (γ=0.93, p<0.001), and MMSE scores were also significantly associated with CPS and MDS-COGS status (γ=-0.50, p<0.001 and γ=-0.52, p<0.001, respectively). Although the prevalence of cognitive impairment by MMSE and MDS-COGS are similar, the results are significantly inconsistent (p<0.001). In conclusion, both MDS-COGS and CPS were significantly correlated with MMSE scores, but significant inconsistence was noted between screening results of MMSE, CPS and MDS-COGS. Further study is needed to develop MDS-based dementia screening tools for older Chinese men in Taiwan. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia

PubMed Central

Parkin, Brian; Ouillette, Peter; Li, Yifeng; Keller, Jennifer; Lam, Cindy; Roulston, Diane; Li, Cheng; Shedden, Kerby

2013-01-01

The frequent occurrence of persistent or relapsed disease after induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we used SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients who achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease after induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases, we demonstrate that relapsed AML invariably represents re-emergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with 2 coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research. PMID:23175688

MicroRNA-155 expression and function in AML: An evolving paradigm.

PubMed

Narayan, Nisha; Bracken, Cameron P; Ekert, Paul G

2018-06-01

Acute myeloid leukemia (AML) arises when immature myeloid blast cells acquire multiple, recurrent genetic and epigenetic changes that result in dysregulated proliferation. Acute leukemia is the most common form of pediatric cancer, with AML accounting for ~20% of all leukemias in children. The genomic aberrations that drive AML inhibit myeloid differentiation and activate signal transduction pathways that drive proliferation. MicroRNAs, a class of small (~22 nucleotide) noncoding RNAs that posttranscriptionally suppress the expression of specifically targeted transcripts, are also frequently dysregulated in AML, which may prove useful for the purposes of disease classification, prognosis, and future therapeutic approaches. MicroRNA expression profiles are associated with patient prognosis and responses to standard chemotherapy, including predicting therapy resistance in AML. miR-155 is the primary focus of this review because it has been repeatedly associated with poorer survival across multiple cohorts of adult and pediatric AML. We discuss some novel features of miR-155 expression in AML, in particular how the levels of expression can critically influence function. Understanding the role of microRNAs in AML and the ways in which microRNA expression influences AML biology is one means to develop novel and more targeted therapies. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

A novel glycogen synthase kinase-3 inhibitor optimized for acute myeloid leukemia differentiation activity

PubMed Central

Stetson, Lindsay; Ignatz-Hoover, James; Moreton, Stephen; Chakrabarti, Amit; Xia, Zhiqiang; Karan, Goutam; de Lima, Marcos; Agrawal, Mukesh K; Wald, David N

2016-01-01

Standard therapies used for the treatment of Acute Myeloid Leukemia (AML) are cytotoxic agents that target rapidly proliferating cells. Unfortunately, this therapeutic approach has limited efficacy and significant toxicity and the majority of AML patients still die of their disease. In contrast to the poor prognosis of most AML patients, most individuals with a rare subtype of AML, Acute Promyelocytic Leukemia (APL), can be cured by differentiation therapy using regimens containing all-trans retinoic acid. GSK3 has previously been identified as a therapeutic target in AML where its inhibition can lead to the differentiation and growth arrest of leukemic cells. Unfortunately, existing GSK3 inhibitors lead to suboptimal differentiation activity making them less useful as clinical AML differentiation agents. Here we describe the discovery of a novel GSK3 inhibitor, GS87. GS87 was discovered in efforts to optimize GSK3 inhibition for AML differentiation activity. Despite GS87's dramatic ability to induce AML differentiation, kinase profiling reveals its high specificity in targeting GSK3 as compared to other kinases. GS87 demonstrates high efficacy in a mouse AML model system and unlike current AML therapeutics, exhibits little effect on normal bone marrow cells. GS87 induces potent differentiation by more effectively activating GSK3-dependent signaling components including MAPK signaling as compared to other GSK3 inhibitors. GS87 is a novel GSK3 inhibitor with therapeutic potential as a differentiation agent for non-promyelocytic AML. PMID:27196775

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

PubMed Central

Duployez, Nicolas; Marceau-Renaut, Alice; Boissel, Nicolas; Petit, Arnaud; Bucci, Maxime; Geffroy, Sandrine; Lapillonne, Hélène; Renneville, Aline; Ragu, Christine; Figeac, Martin; Celli-Lebras, Karine; Lacombe, Catherine; Micol, Jean-Baptiste; Abdel-Wahab, Omar; Cornillet, Pascale; Ifrah, Norbert; Dombret, Hervé; Leverger, Guy; Jourdan, Eric

2016-01-01

Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group of diseases, and relapse incidence reaches up to 40%. Moreover, translocations involving CBFs are not sufficient to induce AML on its own and the full spectrum of mutations coexisting with CBF translocations has not been elucidated. To address these issues, we performed extensive mutational analysis by high-throughput sequencing in 215 patients with CBF-AML enrolled in the Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor Acute Myeloid Leukemia and Treating Patients with Childhood Acute Myeloid Leukemia with Interleukin-2 trials (age, 1-60 years). Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML. PMID:26980726

Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models.

PubMed

Portwood, Scott; Lal, Deepika; Hsu, Yung-Chun; Vargas, Rodrigo; Johnson, Megan K; Wetzler, Meir; Hart, Charles P; Wang, Eunice S

2013-12-01

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. ©2013 AACR.

Disrupting Threat Finances: Utilization of Financial Information to Disrupt Terrorist Organization in the Twenty-First Century

DTIC Science & Technology

2007-04-01

with the FATF for conducting comprehensive Anti-Money Laundering/Counter-Financing of Terrorism ( AML / CFT ) assessments of countries’ compliance with... AML / CFT ) (September 2002) • http://www.imf.org/external/np/mae/am/2002/eng/092523.htm (Comprehensive Methodology on AML / CFT ) International...of Rwanda AML : Anti-Money Laundering AML / CFT : Anti-Money Laundering/Counter-Financing of Terrorism ANO: Abu Nidal Organization AOR: Area of

Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists

PubMed Central

Zhong, RuiKun; Li, Hongying; Messer, Karen; Lane, Thomas A.; Zhou, Jiehua; Ball, Edward D.

2016-01-01

This study investigated whether TNF-α, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-α, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLADR and CD86 expression of AML cells was observed by addition of TNF-α, LPS, R848 alone or combinations. Induced CD80 expression of AML cells was significantly higher through the combination of TNF-α, LPS and R848 (T + L + R) than that by T alone. CTL induced from T + L + R, T + R, T + L, L + R and R, but not T, L alone stimulated cultures showed significantly higher IFN-γ release than the medium control in response to autologous AML cells. IFN-γ release by T + L + R was significantly higher than T or L alone, and T + R was significantly higher than T alone. CTL generated from T + L + R, T + L, T + R, L + R and L alone exerted significantly higher AML cell killing than medium control. AML cell killing by T + L + R and T + R was significantly higher than T or R alone. These results indicate that the combination of T + L + R induces a significantly enhanced antigen presentation effect of AML-DC. We speculate that the complementary effects of reagent combinations may better address the heterogeneity of responses to any single agent in AML cells from different patients. PMID:25795133

Diagnostic and Prognostic Utility of Fluorescence In situ Hybridization (FISH) Analysis in Acute Myeloid Leukemia.

PubMed

Gonzales, Patrick R; Mikhail, Fady M

2017-12-01

Acute myeloid leukemia (AML) is a hematologic neoplasia consisting of incompletely differentiated hematopoietic cells of the myeloid lineage that proliferate in the bone marrow, blood, and/or other tissues. Clinical implementation of fluorescence in situ hybridization (FISH) in cytogenetic laboratories allows for high-resolution analysis of recurrent structural chromosomal rearrangements specific to AML, especially in AML with normal karyotypes, which comprises approximately 33-50% of AML-positive specimens. Here, we review the use of several FISH probe strategies in the diagnosis of AML. We also review the standards and guidelines currently in place for use by clinical cytogenetic laboratories in the evaluation of AML. Updated standards and guidelines from the WHO, ACMG, and NCCN have further defined clinically significant, recurring cytogenetic anomalies in AML that are detectable by FISH. FISH continues to be a powerful technique in the diagnosis of AML, with higher resolution than conventional cytogenetic analysis, rapid turnaround time, and a considerable diagnostic and prognostic utility.

Repression of GSK3 restores NK cell cytotoxicity in AML patients

PubMed Central

Parameswaran, Reshmi; Ramakrishnan, Parameswaran; Moreton, Stephen A.; Xia, Zhiqiang; Hou, Yongchun; Lee, Dean A.; Gupta, Kalpana; deLima, Marcos; Beck, Rose C.; Wald, David N.

2016-01-01

Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3β) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy. PMID:27040177

Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia.

PubMed

Gao, Yanan; Gao, Juan; Li, Minghao; Zheng, Yawei; Wang, Yajie; Zhang, Hongyan; Wang, Weili; Chu, Yajing; Wang, Xiaomin; Xu, Mingjiang; Cheng, Tao; Ju, Zhenyu; Yuan, Weiping

2016-04-12

The constitutive hyper-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways has frequently been associated with acute myeloid leukemia (AML). While many inhibitors targeting these pathways have been developed, the anti-leukemic effect was not as robust as expected. As part of the molecular link between PI3K/Akt and mTOR kinase, the role of Rheb1 in AML remains unexplored. Our study aims to explore the role of Rheb1 in AML and estimate whether Rheb1 could be a potential target of AML treatment. The expressions of Rheb1 and other indicated genes were analyzed using real-time PCR. AML mouse model was established by retrovirus transduction. Leukemia cell properties and related signaling pathways were dissected by in vitro and in vivo studies. The transcriptional changes were analyzed via gene chip analysis. Molecular reagents including mTOR inhibitor and mTOR activator were used to evaluate the function of related signaling pathway in the mouse model. We observed that Rheb1 is overexpressed in AML patients and the change of Rheb1 level in AML patients is associated with their median survival. Using a Rheb1-deficient MLL-AF9 murine AML model, we revealed that Rheb1 deletion prolonged the survival of AML mice by weakening LSC function. In addition, Rheb1 deletion arrested cell cycle progression and enhanced apoptosis of AML cells. Furthermore, while Rheb1 deletion reduced mTORC1 activity in AML cells, additional rapamycin treatment further decreased mTORC1 activity and increased the apoptosis of Rheb1 (Δ/Δ) AML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis in Rheb1 (Δ/Δ) AML cells. Our data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting Rheb1 and mTOR might have a better therapeutic effect on leukemia.

Histone deacetylase inhibitors reduce differentiating osteoblast-mediated protection of acute myeloid leukemia cells from cytarabine

PubMed Central

Sterner, Rosalie M.; Kremer, Kimberly N.; Al-Kali, Aref; Patnaik, Mrinal M.; Gangat, Naseema; Litzow, Mark R.; Kaufmann, Scott H.; Westendorf, Jennifer J.; van Wijnen, Andre J.; Hedin, Karen E.

2017-01-01

The bone marrow microenvironment protects acute myeloid leukemia (AML) cells during chemotherapy and is a major factor in relapse. Here, we examined which type(s) of bone marrow cells are responsible for the relapse of AML following treatment with cytarabine (Ara-C), and we identified a means to inhibit this protection. To determine the protective cell type(s), AML cells were treated with Ara-C, and AML cell survival in the presence or absence of osteoblast lineage cells was assessed. Cultured AML cells and patient bone marrow isolates were each significantly protected from Ara-C-induced apoptosis by co-culture with differentiating osteoblasts. Moreover, pretreating differentiating osteoblasts with the histone deacetylase inhibitors (HDACi) vorinostat and panobinostat abrogated the ability of the differentiating osteoblasts to protect AML cells. Together, our results indicate that differentiating osteoblasts have the potential to promote residual AML in the bone marrow following standard chemotherapy and act via a mechanism requiring HDACi-sensitive gene expression. Using HDACi to target the leukemic microenvironment in combination with Ara-C could potentially improve treatment of AML. Moreover, other strategies for manipulating bone marrow osteoblasts may also help eradicate AML cells and reduce relapse. PMID:29212250

Perception and attitude of medical doctors in Dhaka, Bangladesh, with regard to Ayurvedic medicine.

PubMed

Yoshida, Yoshitoku; Alim, Md Abdul; Alam, Zakia; Asaduzzaman, Mohammad; Yoshida, Yasuko; Manikdrs, Shahabuddin

2017-02-01

The World Health Organization (WHO) Traditional Medicine Strategy (2014-2023) aimed to help member states promote the safe and effective use of traditional medicine. While economic conditions have markedly improved in Bangladesh, the country is experiencing significant public health problems. Because of limited medical resources, there is a strong incentive to enhance complementary and alternative medicine usage in Bangladesh. Therefore, this study aimed to confirm the perceptions and attitudes of medical doctors (MDs) in Dhaka, Bangladesh, with regard to Ayurvedic medicine (AM). A total number of 159 MDs in Dhaka were interviewed by face-to-face between February and June 2015. The study revealed that 62.0% of MDs had treated patients with AM and 55.3% believed that AM should be regarded as its own specialty, whereas 39.7% of MDs believed that AM should be part of the conventional medical curriculum and 32.7% thought that AM did not seem scientific. In terms of gender, 45.3% of male MDs agreed or strongly agreed that AM only had a placebo effect. On the other hand, 65.8% of female MDs disagreed or strongly disagreed it. In terms of age, 77.0% of MDs aged 36 or elder (elder MDs) believed they were more likely to recommend AM use and 80.3% of elder MDs believed that the government should encourage more initiatives to promote AM. To enhance AM use, scientifically robust information on the efficacy, safety and scientific basis of AM should be more effectively conveyed to male MDs.

Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease

PubMed Central

Visconte, Valeria; Tiu, Ramon V.

2014-01-01

Myelodysplastic syndromes (MDS) are a group of clonal disorders arising from hematopoietic stem cells generally characterized by inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages, and variable degrees of cytopenias. Most MDS patients are diagnosed in their late 60s to early 70s. The estimated incidence of MDS in the United States and in Europe are 4.3 and 1.8 per 100,000 individuals per year, respectively with lower rates reported in some Asian countries and less well estimated in other parts of the world. Evolution to acute myeloid leukemia can occur in 10-15% of MDS patients. Three drugs are currently approved for the treatment of patients with MDS: immunomodulatory agents (lenalidomide), and hypomethylating therapy [HMT (decitabine and 5-azacytidine)]. All patients will eventually lose their response to therapy, and the survival outcome of MDS patients is poor (median survival of 4.5 months) especially for patients who fail (refractory/relapsed) HMT. The only potential curative treatment for MDS is hematopoietic cell transplantation. Genomic/chromosomal instability and various mechanisms contribute to the pathogenesis and prognosis of the disease. High throughput genetic technologies like single nucleotide polymorphism array analysis and next generation sequencing technologies have uncovered novel genetic alterations and increased our knowledge of MDS pathogenesis. We will review various genetic and non-genetic causes that are involved in the pathogenesis of MDS. PMID:25548754

The formation of double-strand breaks at multiply damaged sites is driven by the kinetics of excision/incision at base damage in eukaryotic cells

PubMed Central

Kozmin, Stanislav G.; Sedletska, Yuliya; Reynaud-Angelin, Anne; Gasparutto, Didier; Sage, Evelyne

2009-01-01

It has been stipulated that repair of clustered DNA lesions may be compromised, possibly leading to the formation of double-strand breaks (DSB) and, thus, to deleterious events. Using a variety of model multiply damaged sites (MDS), we investigated parameters that govern the formation of DSB during the processing of MDS. Duplexes carrying MDS were inserted into replicative or integrative vectors, and used to transform yeast Saccharomyces cerevisiae. Formation of DSB was assessed by a relevant plasmid survival assay. Kinetics of excision/incision and DSB formation at MDS was explored using yeast cell extracts. We show that MDS composed of two uracils or abasic sites, were rapidly incised and readily converted into DSB in yeast cells. In marked contrast, none of the MDS carrying opposed oG and hU separated by 3–8 bp gave rise to DSB, despite the fact that some of them contained preexisting single-strand break (a 1-nt gap). Interestingly, the absence of DSB formation in this case correlated with slow excision/incision rates of lesions. We propose that the kinetics of the initial repair steps at MDS is a major parameter that direct towards the conversion of MDS into DSB. Data provides clues to the biological consequences of MDS in eukaryotic cells. PMID:19174565

Acute myeloid leukaemia with myelodysplastic features in children: a report of Japanese Paediatric Leukaemia/Lymphoma Study Group.

PubMed

Kinoshita, Akitoshi; Miyachi, Hayato; Matsushita, Hiromichi; Yabe, Miharu; Taki, Tomohiko; Watanabe, Tomoyuki; Saito, Akiko M; Tomizawa, Daisuke; Taga, Takashi; Takahashi, Hiroyuki; Matsuo, Hidemasa; Kodama, Kumi; Ohki, Kentaro; Hayashi, Yasuhide; Tawa, Akio; Horibe, Keizo; Adachi, Souichi

2014-10-01

The clinical characteristics and prognostic relevance of acute myeloid leukaemia (AML) with myelodysplastic features remains to be clarified in children. We prospectively examined 443 newly diagnosed patients in a multicentre clinical trial for paediatric de novo AML, and found 'AML with myelodysplasia-related changes' (AML-MRC) according to the 2008 World Health Organization classification in 93 (21·0%), in whom 59 were diagnosed from myelodysplasia-related cytogenetics alone, 28 from multilineage dysplasia alone and six from a combination of both. Compared with 111 patients with 'AML, not otherwise specified' (AML-NOS), patients with 'AML-MRC' presented at a younger age, with a lower white blood cell count, higher incidence of 20-30% bone marrow blasts, unfavourable cytogenetics and a lower frequency of Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), NPM1 and CEBPA mutations. Complete remission rate and 3-year probability of event-free survival were significantly worse in 'AML-MRC' patients (67·7 vs. 85·6%, P < 0·01, 37·1% vs. 53·8%, P = 0·02, respectively), but 3-year overall survival and relapse-free survival were comparable with 'AML-NOS' patients. By multivariate analysis, FLT3-ITD was solely associated with worse overall survival. These results support the distinctive features of the category 'AML-MRC' even in children. © 2014 John Wiley & Sons Ltd.

Downregulation of miR‑135a predicts poor prognosis in acute myeloid leukemia and regulates leukemia progression via modulating HOXA10 expression.

PubMed

Xu, Hongwei; Wen, Quan

2018-05-23

MicroRNA‑135a (miR‑135a) has been shown to exert important roles in various human cancer types, such as glioblastoma, thyroid carcinoma and renal carcinoma. However, the function of miR‑135a in acute myeloid leukemia (AML) remains largely unknown. In the present study, it was demonstrated that miR‑135a expression was significantly downregulated in AML cells compared with normal control cells. Furthermore, the downregulation of miR‑135a in patients with AML predicted poor prognosis. Through functional experiments, overexpression of miR‑135a was demonstrated to significantly inhibit the proliferation and cell cycle of AML cells, while it promoted cellular apoptosis. miR‑135a directly targeted HOXA10 in AML cells. miR‑135a overexpression significantly suppressed the mRNA and protein levels of HOXA10 in AML cells. Moreover, there was an inverse association between miR‑135a expression and HOXA10 level in AML samples. Additionally, by ectopic expression of HOXA10, restoration of HOXA10 significantly abolished the effects of miR‑135a overexpression on AML cell proliferation, cell cycle and apoptosis. In conclusion, the present study demonstrated that miR‑135a serves as a tumor suppressor in AML by targeting HOXA10, and miR‑135a may be a promising prognostic biomarker for AML patients.

Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia.

PubMed

Roboz, Gail J; Montesinos, Pau; Selleslag, Dominik; Wei, Andrew; Jang, Jun-Ho; Falantes, Jose; Voso, Maria T; Sayar, Hamid; Porkka, Kimmo; Marlton, Paula; Almeida, Antonio; Mohan, Sanjay; Ravandi, Farhad; Garcia-Manero, Guillermo; Skikne, Barry; Kantarjian, Hagop

2016-02-01

Older patients with acute myeloid leukemia (AML) have worse rates of complete remission and shorter overall survival than younger patients. The epigenetic modifier CC-486 is an oral formulation of azacitidine with promising clinical activity in patients with AML in Phase I studies. The Phase III, randomized, double-blind, placebo-controlled QUAZAR AML Maintenance trial (CC-486-AML-001) examines CC-486 maintenance therapy (300 mg/day for 14 days of 28-day treatment cycles) for patients aged ≥55 years with AML in first complete remission. The primary end point is overall survival. Secondary end points include relapse-free survival, safety, health-related quality of life and healthcare resource utilization. This trial will investigate whether CC-486 maintenance can prolong remission and improve survival for older patients with AML.

Evaluation of the efficacy and tolerability of fixed-dose combination therapy of azilsartan and amlodipine besylate in Japanese patients with grade I to II essential hypertension.

PubMed

Rakugi, Hiromi; Nakata, Emi; Sasaki, Emma; Kagawa, Tomoya

2014-05-01

Guidelines for the management of hypertension recommend using drugs with different mechanisms of action in antihypertensive regimens that include simple single-pill fixed-dose combination (FDC) products. The objective of this study was to compare the efficacy and tolerability of the FDC of azilsartan (AZI) and amlodipine besylate (AML) with those of AZI monotherapy and AML monotherapy in Japanese patients with grade 1 to 2 essential hypertension. This was a multicenter, randomized, double-blind, parallel-group study. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive 1 of the following 5 treatments for 8 weeks: FDC containing AZI 20 mg and AML 5 mg (AZI/AML 20/5 mg), FDC containing AZI 20 mg and AML 2.5 mg (AZI/AML 20/2.5 mg), AZI 20 mg, AML 5 mg, or AML 2.5 mg once daily in a fasting or fed state. The primary end point was the change from baseline (week 0) in the seated trough diastolic blood pressure at week 8 (last observation carried forward [LOCF]), and the secondary end point was the change from baseline in the seated trough systolic blood pressure at week 8 (LOCF). Tolerability was assessed based on adverse events, vital signs, and physical examination findings. Of the 800 patients who provided informed consent, 603 were randomized to receive AZI/AML 20/5 mg (150 patients), AZI/AML 20/2.5 mg (151 patients), AZI 20 mg (151 patients), AML 5 mg (75 patients), or AML 2.5 mg (76 patients). The mean baseline systolic/diastolic blood pressure was 160.7/100.3 mm Hg. The mean change from baseline in seated blood pressure at week 8 (LOCF) was -35.3/-22.3 mm Hg in the AZI/AML 20/5 mg group and -31.4/-19.2 mm Hg in the AZI/AML 20/2.5 mg group, indicating a reduction significantly greater than that in corresponding monotherapy groups (-21.5/-13.9 mm Hg in the AZI 20 mg group, -26.4/-15.5 mm Hg in the AML 5 mg group, and -19.3/-11.6 mm Hg in the AML 2.5 mg group; p < 0.0001 for all contrast tests). No remarkable difference was found in the incidences of adverse events, vital signs, and physical examination findings among the treatment groups. This study found that the FDC of AZI/AML 20/5 mg and 20/2.5 mg exhibited greater antihypertensive effects compared with each monotherapy. The FDC of AZI/AML had a similar safety profile to that of each monotherapy and was tolerable to Japanese patients with grade 1 to 2 essential hypertension. Japic CTI-111606. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group

PubMed Central

Pleyer, Lisa; Döhner, Hartmut; Dombret, Hervé; Seymour, John F.; Schuh, Andre C.; Beach, CL; Swern, Arlene S.; Burgstaller, Sonja; Stauder, Reinhard; Girschikofsky, Michael; Sill, Heinz; Schlick, Konstantin; Thaler, Josef; Halter, Britta; Machherndl Spandl, Sigrid; Zebisch, Armin; Pichler, Angelika; Pfeilstöcker, Michael; Autzinger, Eva M.; Lang, Alois; Geissler, Klaus; Voskova, Daniela; Sperr, Wolfgang R.; Hojas, Sabine; Rogulj, Inga M.; Andel, Johannes; Greil, Richard

2017-01-01

We recently published a clinically-meaningful improvement in median overall survival (OS) for patients with acute myeloid leukaemia (AML), >30% bone marrow (BM) blasts and white blood cell (WBC) count ≤15 G/L, treated with front-line azacitidine versus conventional care regimens within a phase 3 clinical trial (AZA-AML-001; NCT01074047; registered: February 2010). As results obtained in clinical trials are facing increased pressure to be confirmed by real-world data, we aimed to test whether data obtained in the AZA-AML-001 trial accurately represent observations made in routine clinical practice by analysing additional AML patients treated with azacitidine front-line within the Austrian Azacitidine Registry (AAR; NCT01595295; registered: May 2012) and directly comparing patient-level data of both cohorts. We assessed the efficacy of front-line azacitidine in a total of 407 patients with newly-diagnosed AML. Firstly, we compared data from AML patients with WBC ≤ 15 G/L and >30% BM blasts included within the AZA-AML-001 trial treated with azacitidine (“AML-001” cohort; n = 214) with AAR patients meeting the same inclusion criteria (“AAR (001-like)” cohort; n = 95). The current analysis thus represents a new sub-analysis of the AML-001 trial, which is directly compared with a new sub-analysis of the AAR. Baseline characteristics, azacitidine application, response rates and OS were comparable between all patient cohorts within the trial or registry setting. Median OS was 9.9 versus 10.8 months (p = 0.616) for “AML-001” versus “AAR (001-like)” cohorts, respectively. Secondly, we pooled data from both cohorts (n = 309) and assessed the outcome. Median OS of the pooled cohorts was 10.3 (95% confidence interval: 8.7, 12.6) months, and the one-year survival rate was 45.8%. Thirdly, we compared data from AAR patients meeting AZA-AML-001 trial inclusion criteria (n = 95) versus all AAR patients with World Health Organization (WHO)-defined AML (“AAR (WHO-AML)” cohort; n = 193). Within the registry population, median OS for AAR patients meeting trial inclusion criteria versus all WHO-AML patients was 10.8 versus 11.8 months (p = 0.599), respectively. We thus tested and confirmed the efficacy of azacitidine as a front-line agent in patients with AML, >30% BM blasts and WBC ≤ 15 G/L in a routine clinical practice setting. We further show that the efficacy of azacitidine does not appear to be limited to AML patients who meet stringent clinical trial inclusion criteria, but instead appears efficacious as front-line treatment in all patients with WHO-AML. PMID:28212292

Effects of Selective Checkpoint Kinase 1 Inhibition on Cytarabine Cytotoxicity in Acute Myelogenous Leukemia Cells in Vitro

PubMed Central

Schenk, Erin L.; Koh, Brian D.; Flatten, Karen S.; Peterson, Kevin L.; Parry, David; Hess, Allan D.; Smith, B. Douglas; Karp, Judith E.; Karnitz, Larry M.; Kaufmann, Scott H.

2012-01-01

Purpose Previous studies have demonstrated that the replication checkpoint, which involves the kinases ATR and Chk1, contributes to cytarabine resistance in cell lines. In the present study, we examined whether this checkpoint is activated in clinical AML during cytarabine infusion in vivo and then assessed the impact of combining cytarabine with the recently described Chk1 inhibitor SCH 900776 in vitro. Experimental design AML marrow aspirates harvested before and during cytarabine infusion were examined by immunoblotting. Human AML lines treated with cytarabine in the absence or presence of SCH 900776 were assayed for checkpoint activation by immunoblotting, nucleotide incorporation into DNA and flow cytometry. Long-term effects in AML lines, clinical AML isolates, and normal myeloid progenitors were assayed using clonogenic assays. Results Immunoblotting demonstrated increased Chk1 phosphorylation, a marker of checkpoint activation, in over half of Chk1-containing AMLs after 48 h of cytarabine infusion. In human AML lines, SCH 900776 not only disrupted cytarabine-induced Chk1 activation and S phase arrest, but also markedly increased cytarabine-induced apoptosis. Clonogenic assays demonstrated that SCH 900776 enhanced the anti-proliferative effects of cytarabine in AML cell lines and clinical AML samples at concentrations that had negligible impact on normal myeloid progenitors. Conclusions These results not only provide evidence for cytarabine-induced S phase checkpoint activation in AML in the clinical setting, but also show that a selective Chk1 inhibitor can overcome the S phase checkpoint and enhance the cytotoxicity of cytarabine. Accordingly, further investigation of the cytarabine/SCH 900776 combination in AML appears warranted. PMID:22869869

Daunorubicin and Cytarabine Liposome in Newly Diagnosed Therapy-Related Acute Myeloid Leukemia (AML) or AML With Myelodysplasia-Related Changes.

PubMed

Kim, Miryoung; Williams, Sherry

2018-03-01

To evaluate the efficacy and safety of daunorubicin and cytarabine liposome in older adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). A literature search of PubMed and MEDLINE (January 2017 to January 2018) was performed using the terms CPX-351, Vyxeos, daunorubicin and cytarabine liposome, and acute myeloid leukemia. Phase I, II, and III clinical trials evaluating the efficacy and safety of daunorubicin and cytarabine liposome were reviewed with a specific focus on its use in older patients with newly diagnosed AML. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. The phase II trial demonstrated that daunorubicin and cytarabine liposome improved response rates (RR), but there was no difference in event-free survival and overall survival in the overall patient population. However, clinical benefit was most pronounced in secondary AML with an increased RR and survival. The phase III trial illustrated that daunorubicin and cytarabine liposome improved survival and RR with tolerable toxicity compared with standard 7 plus 3 (daunorubicin and cytarabine) in patients 60 to 75 years of age with t-AML or AML-MRC. More patients proceeded to a stem cell transplant, and 30-day and 60-day mortality was lower with daunorubicin and cytarabine liposome. Grade 3 to 5 toxicities were similar between the 2 groups, except daunorubicin and cytarabine liposome had prolonged cytopenia and a higher risk of hemorrhage. Daunorubicin and cytarabine liposome improves RR and survival, with tolerable toxicity in older patients with t-AML or AML-MRC.

Comparison of nested competitive RT-PCR and real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21) positive acute myelogenous leukemia.

PubMed

Wattjes, M P; Krauter, J; Nagel, S; Heidenreich, O; Ganser, A; Heil, G

2000-02-01

The chromosomal translocation t(8;21)(q22;q22) is one of the most frequent karyotypic aberrations in acute myeloid leukemia (AML) and results in a chimeric fusion transcript AML1/MTG8. Since AML1/MTG8 fusion transcripts remain detectable by RT-PCR in t(8;21) AML patients in long-term hematological remission, quantitative assessment of AML1/MTG8 transcripts is necessary for the monitoring of minimal residual disease (MRD) in these patients. Competitive RT-PCR and recently real-time RT-PCR are increasingly used for detection and quantification of leukemia specific fusion transcripts. For the direct comparison of both methods we cloned a 42 bp DNA fragment into the original AML1/MTG8 sequence. The resulting molecule was used as an internal competitor for our novel competitive nested RT-PCR for AML1/MTG8 and as an external standard for the generation of AML1/MTG8 standard curves in a real-time PCR assay. Using this standard molecule for both PCR techniques, we compared their sensitivity, linearity and reproducibility. Both methods were comparable with regard to all parameters tested irrespective of analyzing serial dilutions of plasmids, cell lines or samples from t(8;21) positive AML patients at different stages of the disease. Therefore, both techniques can be recommended for the monitoring of MRD in these particular AML patients. However, the automatization of the real-time PCR technique offers some technical advantages.

Computational Modeling and Treatment Identification in the Myelodysplastic Syndromes.

PubMed

Drusbosky, Leylah M; Cogle, Christopher R

2017-10-01

This review discusses the need for computational modeling in myelodysplastic syndromes (MDS) and early test results. As our evolving understanding of MDS reveals a molecularly complicated disease, the need for sophisticated computer analytics is required to keep track of the number and complex interplay among the molecular abnormalities. Computational modeling and digital drug simulations using whole exome sequencing data input have produced early results showing high accuracy in predicting treatment response to standard of care drugs. Furthermore, the computational MDS models serve as clinically relevant MDS cell lines for pre-clinical assays of investigational agents. MDS is an ideal disease for computational modeling and digital drug simulations. Current research is focused on establishing the prediction value of computational modeling. Future research will test the clinical advantage of computer-informed therapy in MDS.

Trend (1999-2009) in U.S. death rates from myelodysplastic syndromes: utility of multiple causes of death in surveillance.

PubMed

Polednak, Anthony P

2013-10-01

For myelodysplastic syndromes (MDS) (formerly known as preleukemia), a diverse group of myeloid neoplasms usually involving anemia in elderly persons, trends in U.S. death rates apparently have not been reported. Trends in annual age-standardized rates per 100,000 from 1999 to 2009 were examined for MDS using multiple causes vs. underlying cause alone, coded on death certificates for U.S. residents. The death rate (all ages combined) for MDS increased from 1999 to 2009, from 1.62 to 1.84 using underlying cause alone and from 2.89 to 3.27 using multiple causes. Rates using multiple causes were about 80% higher than those based on underlying cause alone. From 2001 to 2004 the rate for MDS using underlying cause alone (but not using multiple causes) declined, accompanied by an increase in the rate for deaths from leukemia as underlying cause with mention of MDS; this trend coincided with the advent of the 2001 World Health Organization's reclassification of certain MDS as leukemia. The MDS rate for age 65+ years increased after 2005, whereas the rate for age 25-64 years was low but declined from 2001 to 2003 and then stabilized. For deaths with MDS coded as other than underlying cause, rates did not decline for deaths from each of the two most common causes (i.e., cardiovascular diseases and leukemia). Evidence for decreases in MDS-related mortality rates was limited; the increase at age 65+ years is consistent with increases in incidence rates reported from cancer registries. Using multiple causes of death vs. only the underlying cause results in substantially higher MDS-related death rates, shows the impact of changes in the classification of myeloid neoplasms and emphasizes the importance of reducing cardiovascular disease mortality in MDS patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations.

PubMed

Pellagatti, Andrea; Armstrong, Richard N; Steeples, Violetta; Sharma, Eshita; Repapi, Emmanouela; Singh, Shalini; Sanchi, Andrea; Radujkovic, Aleksandar; Horn, Patrick; Dolatshad, Hamid; Roy, Swagata; Broxholme, John; Lockstone, Helen; Taylor, Stephen; Giagounidis, Aristoteles; Vyas, Paresh; Schuh, Anna; Hamblin, Angela; Papaemmanuil, Elli; Killick, Sally; Malcovati, Luca; Hennrich, Marco L; Gavin, Anne-Claude; Ho, Anthony D; Luft, Thomas; Hellström-Lindberg, Eva; Cazzola, Mario; Smith, Christopher W J; Smith, Stephen; Boultwood, Jacqueline

2018-06-21

SF3B1, SRSF2 and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the impact of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34 + cells of 84 MDS patients. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whilst several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms which independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the impact of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology. Copyright © 2018 American Society of Hematology.

Tumor Trp53 status and genotype affect the bone marrow microenvironment in acute myeloid leukemia

PubMed Central

Jacamo, Rodrigo; Davis, R. Eric; Ling, Xiaoyang; Sonnylal, Sonali; Wang, Zhiqiang; Ma, Wencai; Zhang, Min; Ruvolo, Peter; Ruvolo, Vivian; Wang, Rui-Yu; McQueen, Teresa; Lowe, Scott; Zuber, Johannes; Kornblau, Steven M.; Konopleva, Marina; Andreeff, Michael

2017-01-01

The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM-MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or nullgenetic backgrounds. We identified a set of genes whose expression in BM-MSC was modulated by all four AML genotypes tested. In addition, there were sets of differentially-expressed genes in AML-exposed BM-MSC that were unique to the particular AML genotype or Trp53 status. Our findings support the hypothesis that leukemia cells alter the transcriptome of surrounding BM stromal cells, in both common and genotype-specific ways. These changes are likely to be advantageous to AML cells, affecting disease progression and response to chemotherapy, and suggest opportunities for stroma-targeting therapy, including those based on AML genotype. PMID:29137349

Drug targeting of NR4A nuclear receptors for treatment of acute myeloid leukemia.

PubMed

Boudreaux, Seth P; Duren, Ryan P; Call, Steven G; Nguyen, Loc; Freire, Pablo R; Narayanan, Padmini; Redell, Michele S; Conneely, Orla M

2018-06-08

NR4As are AML tumor suppressors that are frequently silenced in human acute myeloid leukemia (AML). Despite their potential as novel targets for therapeutic intervention, mechanisms of NR4A silencing and strategies for their reactivation remain poorly defined. Here we show that NR4A silencing in AML occurs through blockade of transcriptional elongation rather than epigenetic promoter silencing. By intersection of NR4A-regulated gene signatures captured upon acute, exogenous expression of NR4As in human AML cells with in silico chemical genomics screening, we identify several FDA-approved drugs including dihydroergotamine (DHE) that reactivate NR4A expression and regulate NR4A-dependent gene signatures. We show that DHE induces NR4A expression via recruitment of the super elongation complex to enable elongation of NR4A promoter paused RNA polymerase II. Finally, DHE exhibits AML selective NR4A-dependent anti-leukemic activity in cytogenetically distinct human AML cells in vitro and delays AML progression in mice revealing its potential as a novel therapeutic agent in AML.

Global Cell Proteome Profiling, Phospho-signaling and Quantitative 
Proteomics for Identification of New Biomarkers in Acute Myeloid 
Leukemia Patients

PubMed Central

Aasebø, Elise; Forthun, Rakel B.; Berven, Frode; Selheim, Frode; Hernandez-Valladares, Maria

2016-01-01

The identification of protein biomarkers for acute myeloid leukemia (AML) that could find applications in AML diagnosis and prognosis, treatment and the selection for bone marrow transplant requires substantial comparative analyses of the proteomes from AML patients. In the past years, several studies have suggested some biomarkers for AML diagnosis or AML classification using methods for sample preparation with low proteome coverage and low resolution mass spectrometers. However, most of the studies did not follow up, confirm or validate their candidates with more patient samples. Current proteomics methods, new high resolution and fast mass spectrometers allow the identification and quantification of several thousands of proteins obtained from few tens of μg of AML cell lysate. Enrichment methods for posttranslational modifications (PTM), such as phosphorylation, can isolate several thousands of site-specific phosphorylated peptides from AML patient samples, which subsequently can be quantified with high confidence in new mass spectrometers. While recent reports aiming to propose proteomic or phosphoproteomic biomarkers on the studied AML patient samples have taken advantage of the technological progress, the access to large cohorts of AML patients to sample from and the availability of appropriate control samples still remain challenging. PMID:26306748

Phosphatidylserine index as a marker of the procoagulant phenotype of acute myelogenous leukemia cells

NASA Astrophysics Data System (ADS)

Tormoen, Garth W.; Recht, Olivia; Gruber, András; Levine, Ross L.; McCarty, Owen J. T.

2013-10-01

Patients with acute myelogenous leukemia (AML) are at risk for thrombotic complications. Risk to develop thrombosis is closely tied to leukemia subtype, and studies have shown an association between leukocytosis and thrombosis in AML M3. We evaluated the relative roles of cell count and the surface expression of tissue factor (TF) and phosphatidylserine (PS) in the procoagulant phenotype of AML cell lines. The TF-positive AML M3 cell lines, NB4 and HL60, and AML M2 cell line, AML14, exhibited both extrinsic tenase and prothrombinase activity in a purified system and promoted experimental thrombus formation. In contrast, the TF-negative AML cell line, HEL, exhibited only prothrombinase activity and did not affect the rate of occlusive thrombus formation. In plasma, NB4, HL60 and AML14 shortened clotting times in a cell-count, PS- and TF-dependent manner. Exposure of cultured NB4, HL60, and AML14 cells to the chemotherapeutic agent daunorubicin increased their extrinsic tenase activity and PS expression. Clot initiation time inversely correlated with logarithm of PS index, defined as the product of multiplying leukocyte count with cell surface PS exposure. We propose that leukemia cell PS index may serve as a biomarker for procoagulant activity.

Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia.

PubMed

Baron, Jeffrey; Wang, Eunice S

2018-06-11

Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. Despite the known clinical efficacy in relapsed/refractory acute myeloid leukemia (AML), GO was withdrawn from the market in 2010 due to increased early deaths witnessed in newly diagnosed AML patients receiving GO + intensive chemotherapy. In 2017, new data on the clinical efficacy and safety of GO administered on a fractionated-dosing schedule led to re-approval for newly diagnosed and relapsed/refractory AML. Areas covered: Addition of fractionated GO to chemotherapy significantly improved event-free survival of newly diagnosed AML patients with favorable and intermediate cytogenetic-risk disease. GO monotherapy also prolonged survival in newly diagnosed unfit patients and relapse-free survival in relapsed/refractory AML. This new dosing schedule was associated with decreased incidence of hepatotoxicity, veno-occlusive disease, and early mortality. Expert commentary: GO represents the first drug-antibody conjugate approved (twice) in the United States for AML. Its re-emergence adds a valuable agent back into the armamentarium for AML. The approval of GO as well as three other agents for AML in 2017 highlights the need for rapid cytogenetic and molecular characterization of AML and incorporation into new treatment algorithms.

The complexity of interpreting genomic data in patients with acute myeloid leukemia

PubMed Central

Nazha, A; Zarzour, A; Al-Issa, K; Radivoyevitch, T; Carraway, H E; Hirsch, C M; Przychodzen, B; Patel, B J; Clemente, M; Sanikommu, S R; Kalaycio, M; Maciejewski, J P; Sekeres, M A

2016-01-01

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML). Overall, mutations in FLT3, DNMT3A, NPM1 and IDH2 were more specific for pAML whereas UTAF1, STAG2, BCORL1, BCOR, EZH2, JAK2, CBL, PRPF8, SF3B1, ASXL1 and DHX29 were more specific for sAML. However, in multivariate analysis that included clinical variables, only FLT3 and DNMT3A remained specific for pAML and EZH2, BCOR, SF3B1 and ASXL1 for sAML. When the impact of mutations on OS was evaluated in the entire cohort, mutations in DNMT3A, PRPF8, ASXL1, CBL EZH2 and TP53 had a negative impact on OS; no mutation impacted OS favorably; however, in a cox multivariate analysis that included clinical data, mutations in DNMT3A, ASXL1, CBL, EZH2 and TP53 became significant. Thus, controlling for clinical variables is important when interpreting genomic data in AML. PMID:27983727

The complexity of interpreting genomic data in patients with acute myeloid leukemia.

PubMed

Nazha, A; Zarzour, A; Al-Issa, K; Radivoyevitch, T; Carraway, H E; Hirsch, C M; Przychodzen, B; Patel, B J; Clemente, M; Sanikommu, S R; Kalaycio, M; Maciejewski, J P; Sekeres, M A

2016-12-16

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML). Overall, mutations in FLT3, DNMT3A, NPM1 and IDH2 were more specific for pAML whereas UTAF1, STAG2, BCORL1, BCOR, EZH2, JAK2, CBL, PRPF8, SF3B1, ASXL1 and DHX29 were more specific for sAML. However, in multivariate analysis that included clinical variables, only FLT3 and DNMT3A remained specific for pAML and EZH2, BCOR, SF3B1 and ASXL1 for sAML. When the impact of mutations on OS was evaluated in the entire cohort, mutations in DNMT3A, PRPF8, ASXL1, CBL EZH2 and TP53 had a negative impact on OS; no mutation impacted OS favorably; however, in a cox multivariate analysis that included clinical data, mutations in DNMT3A, ASXL1, CBL, EZH2 and TP53 became significant. Thus, controlling for clinical variables is important when interpreting genomic data in AML.

Osteoblasts Protect AML Cells from SDF-1-Induced Apoptosis

PubMed Central

Kremer, Kimberly N.; Dudakovic, Amel; McGee-Lawrence, Meghan E.; Philips, Rachael L.; Hess, Allan D.; Smith, B. Douglas; van Wijnen, Andre J.; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; Hedin, Karen E.

2014-01-01

The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment. PMID:24851270

Fatty Acid Binding Protein FABP4 Mechanistically Links Obesity with Aggressive AML by Enhancing Aberrant DNA Methylation in AML Cells

PubMed Central

Yan, F; Shen, N; Pang, JX; Zhang, YW; Rao, EY; Bode, AM; Al-Kali, A; Zhang, DE; Litzow, MR; Li, B; Liu, SJ

2016-01-01

Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here, we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and IL-6 in sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and STAT3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15INK4B tumor suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity, and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia. PMID:27885273

Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells.

PubMed

Yan, F; Shen, N; Pang, J X; Zhang, Y W; Rao, E Y; Bode, A M; Al-Kali, A; Zhang, D E; Litzow, M R; Li, B; Liu, S J

2017-06-01

Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15 INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15 INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.

The biologic properties of recombinant human thrombopoietin in the proliferation and megakaryocytic differentiation of acute myeloblastic leukemia cells.

PubMed

Matsumura, I; Kanakura, Y; Kato, T; Ikeda, H; Horikawa, Y; Ishikawa, J; Kitayama, H; Nishiura, T; Tomiyama, Y; Miyazaki, H; Matsuzawa, Y

1996-10-15

Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis. However, the biologic effects of TPO on human acute myeloblastic leukemia (AML) cells are largely unknown. To determine if recombinant human (rh) TPO has proliferation-supporting and differentiation-inducing activities in AML cells, 15 cases of AML cells that were exclusively composed of undifferentiated leukemia cells and showed growth response to rhTPO in a short-term culture (72 hours) were subjected to long-term suspension culture with or without rhTPO. Of 15 cases, rhTPO supported proliferation of AML cells for 2 to 4 weeks in 4 cases whose French-American-British subtypes were M0, M2, M4, and M7, respectively. In addition to the proliferation-supporting activity, rhTPO was found to induce AML cells to progress to some degree of megakaryocytic differentiation at both morphologic and surface-phenotypic level in 2 AML cases with M0 and M7 subtypes. The treatment of AML cells with rhTPO resulted in rapid tyrosine phosphorylation of the TPO-receptor, c-mpl, and STAT3 in all of cases tested. By contrast, the expression of erythroid/megakaryocyte-specific transcription factors (GATA-1, GATA-2, and NF-E2) was markedly induced or enhanced in only 2 AML cases that showed megakaryocytic differentiation in response to rhTPO. These results suggested that, at least in a fraction of AML cases, TPO could not only support the proliferation of AML cells irrespective of AML subtypes, but could also induce megakaryocytic differentiation, possibly through activation of GATA-1, GATA-2, and NF-E2.

Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia

PubMed Central

De Luca, Luciana; Trino, Stefania; Laurenzana, Ilaria; Tagliaferri, Daniela; Falco, Geppino; Grieco, Vitina; Bianchino, Gabriella; Nozza, Filomena; Campia, Valentina; D'Alessio, Francesca; La Rocca, Francesco; Caivano, Antonella; Villani, Oreste; Cilloni, Daniela; Musto, Pellegrino; Del Vecchio, Luigi

2017-01-01

Lin28A is a highly conserved RNA-binding protein that concurs to control the balance between stemness and differentiation in several tissue lineages. Here, we report the role of miR-128a/Lin28A axis in blocking cell differentiation in acute myeloid leukemia (AML), a genetically heterogeneous disease characterized by abnormally controlled proliferation of myeloid progenitor cells accompanied by partial or total inability to undergo terminal differentiation. First, we found Lin28A underexpressed in blast cells from AML patients and AML cell lines as compared with CD34+ normal precursors. In vitro transfection of Lin28A in NPM1-mutated OCI-AML3 cell line significantly triggered cell-cycle arrest and myeloid differentiation, with increased expression of macrophage associate genes (EGR2, ZFP36 and ANXA1). Furthermore, miR-128a, a negative regulator of Lin28A, was found overexpressed in AML cells compared with normal precursors, especially in acute promyelocytic leukemia (APL) and in ‘AML with maturation’ (according to 2016 WHO classification of myeloid neoplasms and acute leukemia). Its forced overexpression by lentiviral infection in OCI-AML3 downregulated Lin28A with ensuing repression of macrophage-oriented differentiation. Finally, knockdown of miR-128a in OCI-AML3 and in APL/AML leukemic cells (by transfection and lentiviral infection, respectively) induced myeloid cell differentiation and increased expression of Lin28A, EGR2, ZFP36 and ANXA1, reverting myeloid differentiation blockage. In conclusion, our findings revealed a new mechanism for AML differentiation blockage, suggesting new strategies for AML therapy based upon miR-128a inhibition. PMID:28569789

Correlation between CD34 expression and chromosomal abnormalities but not clinical outcome in acute myeloid leukemia.

PubMed

Fruchart, C; Lenormand, B; Bastard, C; Boulet, D; Lesesve, J F; Callat, M P; Stamatoullas, A; Monconduit, M; Tilly, H

1996-11-01

The hemopoietic stem cell marker CD34 has been reported to be a useful predictor of treatment outcome in acute myeloid leukemia (AML). Previous data suggested that CD34 expression may be associated with other poor prognosis factors in AML such as undifferentiated leukemia, secondary AML (SAML), and clonal abnormalities involving chromosome 5 and 7. In order to analyze the correlations between the clinicopathologic features, cytogenetic and CD34 expression in AML, we retrospectively investigated 99 patients with newly diagnosed AML: 85 with de novo disease and 14 with secondary AML (SAML). Eighty-six patients who received the same induction chemotherapy were available for clinical outcome. Defining a case as positive when > or = 20% of bone marrow cells collected at diagnosis expressed the CD34 antigen, forty-five patients were included in the CD34 positive group. Ninety patients had adequate cytogenetic analysis. Thirty-two patients (72%) with CD34 positive AML exhibited an abnormal karyotype whereas 15 patients (28%) with CD34 negative AML had abnormal metaphases (P < 0.01). Monosomy 7/7q- or monosomy 5/5q- occurred in 10 patients and 8 of them expressed the CD34 antigen (P < 0.05). All patients with t(8;21) which is considered as a favorable factor in AML had levels of CD34 >/= 20% (P < 0.05). We did not find any association between CD34 expression and attainment of complete remission, overall survival, or disease-free survival. In conclusion, the variations of CD34 expression in AML are correlated with cytogenetic abnormalities associated both with poor and favorable outcome. The evaluation of the correlations between CD34 antigen and clinical outcome in AML should take into account the results of pretreatment karyotype.

The rarity of ALDH(+) cells is the key to separation of normal versus leukemia stem cells by ALDH activity in AML patients.

PubMed

Hoang, Van T; Buss, Eike C; Wang, Wenwen; Hoffmann, Isabel; Raffel, Simon; Zepeda-Moreno, Abraham; Baran, Natalia; Wuchter, Patrick; Eckstein, Volker; Trumpp, Andreas; Jauch, Anna; Ho, Anthony D; Lutz, Christoph

2015-08-01

To understand the precise disease driving mechanisms in acute myeloid leukemia (AML), comparison of patient matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. In this analysis, we have examined the value of aldehyde dehydrogenase (ALDH) activity in combination with CD34 expression for the separation of HSC from LSC in 104 patients with de novo AML. The majority of AML patients (80 out of 104) had low percentages of cells with high ALDH activity (ALDH(+) cells; <1.9%; ALDH-rare AML), whereas 24 patients had relatively numerous ALDH(+) cells (≥1.9%; ALDH-numerous AML). In patients with ALDH-rare AML, normal HSC could be separated by their CD34(+) ALDH(+) phenotype, whereas LSC were exclusively detected among CD34(+) ALDH(-) cells. For patients with ALDH-numerous AML, the CD34(+) ALDH(+) subset consisted mainly of LSC and separation from HSC was not feasible. Functional analyses further showed that ALDH(+) cells from ALDH-numerous AML were quiescent, refractory to ARA-C treatment and capable of leukemic engraftment in a xenogenic mouse transplantation model. Clinically, resistance to chemotherapy and poor long-term outcome were also characteristic for patients with ALDH-numerous AML providing an additional risk-stratification tool. The difference in spectrum and relevance of ALDH activity in the putative LSC populations demonstrates, in addition to phenotypic and genetic, also functional heterogeneity of leukemic cells and suggests divergent roles for ALDH activity in normal HSC versus LSC. By acknowledging these differences our study provides a new and useful tool for prospective identification of AML cases in which separation of HSC from LSC is possible. © 2014 UICC.

The TPO/c-MPL pathway in the bone marrow may protect leukemia cells from chemotherapy in AML Patients.

PubMed

Dong-Feng, Zeng; Ting, Liu; Yong, Zhang; Cheng, Chang; Xi, Zhang; Pei-Yan, Kong

2014-04-01

Accumulating evidence indicates that the interaction of human LSCs (leukemic stem cells) with the hematopoietic microenvironment, mediated by the thrombopoietin (TPO)/c-MPL pathway, may be an underlying mechanism for resistance to cell cycle-dependent cytotoxic chemotherapy. However, the role of TPO/c-MPL signaling in AML (acute myelogenous leukemia) chemotherapy resistance hasn't been fully understood. The c-MPL and TPO levels in different AML samples were measured by flow cytometry and ELISA. We also assessed the TPO levels in the osteoblasts derived from bone mesenchymal stem cells (BMSCs). The survival rate of an AML cell line that had been co-cultured with different BMSC-derived osteoblasts was measured to determine the IC50 of an AML chemotherapy drug daunorubicin (DNR). The levels of TPO/c-MPL in the initial and relapse AML patients were significantly higher than that in the control (P < 0.05). The osteoblasts derived from AML patients' BMSCs secreted more TPO than the osteoblasts derived from normal control BMSCs (P < 0.05). A strong positive correlation between the TPO level and c-MPL expression was found in the bone marrow mononuclear cells of the relapse AML patients. More importantly, the IC50 of DNR in the HEL + AML-derived osteoblasts was the highest among all co-culture systems. High level of TPO/c-MPL signaling may protect LSCs from chemotherapy in AML. The effects of inhibition of the TPO/c-MPL pathway on enhancing the chemotherapy sensitivity of AML cells, and on their downstream effector molecules that direct the interactions between patient-derived blasts and leukemia repopulating cells need to be further studied.

XPO1 Inhibition Using Selinexor Synergizes With Chemotherapy in Acute Myeloid Leukemia (AML) by Targeting DNA Repair and Restoring Topoisomerase IIα to the Nucleus

PubMed Central

Ranganathan, Parvathi; Kashyap, Trinayan; Yu, Xueyan; Meng, Xiaomei; Lai, Tzung-Huei; McNeil, Betina; Bhatnagar, Bhavana; Shacham, Sharon; Kauffman, Michael; Dorrance, Adrienne M.; Blum, William; Sampath, Deepa; Landesman, Yosef; Garzon, Ramiro

2016-01-01

Purpose Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore we asked whether adding already established effective drugs such as Topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML. Experimental Design The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML. Results Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared to each single therapy. Conclusions Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of AML patients that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression, and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. PMID:27358488

The significance of trilineage myelodysplasia in de novo acute myeloblastic leukemia: clinical and laboratory features.

PubMed

Lima, C S; Vassalo, J; Lorand-Metze, I; Bechelli, A P; Souza, C A

1997-01-01

A prospective study was undertaken to elucidate the clinical and laboratory differences between de novo acute myeloid leukemia (AML) and AML with trilineage myelodysplasia (AML-TMDS). One hundred and seven patients with AML were diagnosed at the University Hospital between January 1987 and July 1992, and were followed until July 1995. TMDS was identified in 17 of them (16%). With regard to age and sex distribution no difference was found between AML patients with and without TMDS (p = 0.43, p = 0.54, respectively). The duration of symptoms at presentation in AML-TMDS was similar to those observed in de novo AML (p = 0.29). Hemoglobin values and platelet counts were similar in both groups of patients (p = 0.45, p = 0.44, respectively). However, peripheral white blood cell and neutrophil counts, as well as blast counts in AML-TMDS patients were lower than those observed in AML without TMDS patients (p < 0.001 for all of them). Bone marrow blast counts in de novo AML were higher than the values observed in AML-TMDS patients (p < 0.001). TMDS occurred predominantly in M2 and M6 FAB types, and was absent in the M3 type. Bone marrow histology showed no particular feature that could be of diagnostic relevance. The remission rates were similar in both groups of patients (p = 0.55). The same was true for the probability of disease-free survival and overall survival during the period of study (p = 0.50, p = 0.33, respectively). These results suggest that: 1) in AML-TMDS patients, leukemia transformation occurs in a more undifferentiated pluripotent stem cell, leading to a dysplastic residual hemopoiesis besides the blast proliferation; 2) the incidence of TMDS in our group of patients did not influence the clinical outcome after treatment of the disease.

SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Li; Weng, Wei; Sun, Zhi-Xin

Previous studies have identified sphingosine kinase 1 (SphK1) as a potential drug target for treatment of acute myeloid leukemia (AML). In the current study, we investigated the potential anti-leukemic activity of a novel and specific SphK1 inhibitor, SKI-II. We demonstrated that SKI-II inhibited growth and survival of human AML cell lines (HL-60 and U937 cells). SKI-II was more efficient than two known SphK1 inhibitors SK1-I and FTY720 in inhibiting AML cells. Meanwhile, it induced dramatic apoptosis in above AML cells, and the cytotoxicity by SKI-II was almost reversed by the general caspase inhibitor z-VAD-fmk. SKI-II treatment inhibited SphK1 activation, andmore » concomitantly increased level of sphingosine-1-phosphate (S1P) precursor ceramide in AML cells. Conversely, exogenously-added S1P protected against SKI-II-induced cytotoxicity, while cell permeable short-chain ceramide (C6) aggravated SKI-II's lethality against AML cells. Notably, SKI-II induced potent apoptotic death in primary human AML cells, but was generally safe to the human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. In vivo, SKI-II administration suppressed growth of U937 leukemic xenograft tumors in severe combined immunodeficient (SCID) mice. These results suggest that SKI-II might be further investigated as a promising anti-AML agent. - Highlights: • SKI-II inhibits proliferation and survival of primary and transformed AML cells. • SKI-II induces apoptotic death of AML cells, but is safe to normal PBMCs. • SKI-II is more efficient than two known SphK1 inhibitors in inhibiting AML cells. • SKI-II inhibits SphK1 activity, while increasing ceramide production in AML cells. • SKI-II dose-dependently inhibits U937 xenograft growth in SCID mice.« less

Correlation between p65 and TNF-α in patients with acute myelocytic leukemia.

PubMed

Dong, Qiao-Mei; Ling, Chun; Zhu, Jun-Fang; Chen, Xuan; Tang, Yan; Zhao, L I

2015-11-01

The correlation between the expression levels of p65 and TNF-α in patients with acute myelocytic leukemia (AML) and AML cell lines were investigated. The bone marrow samples of 30 AML patients and 10 non-leukemia controls were studied. The mRNA expression levels of p65 and TNF-α were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Pearson's Correlation test was used to demonstrate the correlation between TNF-α and p65 expression levels in AML specimens. Receiver operating characteristic (ROC) curves were plotted to determine whether TNF-α and p65 expression levels could be used to differentiate AML samples from non-leukemia samples. MG132 and anti-TNF-α antibody were used to inhibit the expression of p65 and TNF-α in the AML cell line, HL-60. The expression of p65 and TNF-α were detected by RT-qPCR and western blot analysis. The mRNA expression levels of p65 and TNF-α were significantly increased in AML patients compared with non-leukemia control bone marrow samples by RT-qPCR, and the two molecules expression pattern's exhibited sufficient predictive power to distinguish AML patients from non-leukemia control samples. Pearson's correlation analysis demonstrated that TNF-α expression was strongly correlated with p65 expression in AML bone marrow samples. In HL-60 cells, inhibition of TNF-α reduced the expression of p65; in addition, inhibition of p65 reduced the expression of TNF-α as assessed by RT-qPCR and western blot analysis. p65 and TNF-α were highly expressed in AML patients, and these 2 molecules were strongly correlated. The present study indicates that p65 and TNF-α have potential as molecular markers to distinguish AML patients from non-leukemia control samples, and that these 2 molecules may be useful prognostic factor for patients with AML.

Comprehensive mutational profiling of core binding factor acute myeloid leukemia.

PubMed

Duployez, Nicolas; Marceau-Renaut, Alice; Boissel, Nicolas; Petit, Arnaud; Bucci, Maxime; Geffroy, Sandrine; Lapillonne, Hélène; Renneville, Aline; Ragu, Christine; Figeac, Martin; Celli-Lebras, Karine; Lacombe, Catherine; Micol, Jean-Baptiste; Abdel-Wahab, Omar; Cornillet, Pascale; Ifrah, Norbert; Dombret, Hervé; Leverger, Guy; Jourdan, Eric; Preudhomme, Claude

2016-05-19

Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group of diseases, and relapse incidence reaches up to 40%. Moreover, translocations involving CBFs are not sufficient to induce AML on its own and the full spectrum of mutations coexisting with CBF translocations has not been elucidated. To address these issues, we performed extensive mutational analysis by high-throughput sequencing in 215 patients with CBF-AML enrolled in the Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor Acute Myeloid Leukemia and Treating Patients with Childhood Acute Myeloid Leukemia with Interleukin-2 trials (age, 1-60 years). Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML. © 2016 by The American Society of Hematology.

Identification of Novel Genomic Aberrations in AML-M5 in a Level of Array CGH

PubMed Central

Zhang, Rui; Lee, Ji-Yun; Wang, Xianfu; Xu, Weihong; Hu, Xiaoxia; Lu, Xianglan; Niu, Yimeng; Tang, Rurong; Li, Shibo; Li, Yan

2014-01-01

To assess the possible existence of unbalanced chromosomal abnormalities and delineate the characterization of copy number alterations (CNAs) of acute myeloid leukemia-M5 (AML-M5), R-banding karyotype, oligonucelotide array CGH and FISH were performed in 24 patients with AML-M5. A total of 117 CNAs with size ranging from 0.004 to 146.263 Mb was recognized in 12 of 24 cases, involving all chromosomes other than chromosome 1, 4, X and Y. Cryptic CNAs with size less than 5 Mb accounted for 59.8% of all the CNAs. 12 recurrent chromosomal alterations were mapped. Seven out of them were described in the previous AML studies and five were new candidate AML-M5 associated CNAs, including gains of 3q26.2-qter and 13q31.3 as well as losses of 2q24.2, 8p12 and 14q32. Amplication of 3q26.2-qter was the sole large recurrent chromosomal anomaly and the pathogenic mechanism in AML-M5 was possibly different from the classical recurrent 3q21q26 abnormality in AML. As a tumor suppressor gene, FOXN3, was singled out from the small recurrent CNA of 14q32, however, it is proved that deletion of FOXN3 is a common marker of myeloid leukemia rather than a specific marker for AML-M5 subtype. Moreover, the concurrent amplication of MLL and deletion of CDKN2A were noted and it might be associated with AML-M5. The number of CNA did not show a significant association with clinico-biological parameters and CR number of the 22 patients received chemotherapy. This study provided the evidence that array CGH served as a complementary platform for routine cytogenetic analysis to identify those cryptic alterations in the patients with AML-M5. As a subtype of AML, AML-M5 carries both common recurrent CNAs and unique CNAs, which may harbor novel oncogenes or tumor suppressor genes. Clarifying the role of these genes will contribute to the understanding of leukemogenic network of AML-M5. PMID:24727659

Validation of the Italian version of the Movement Disorder Society--Unified Parkinson's Disease Rating Scale.

PubMed

Antonini, Angelo; Abbruzzese, Giovanni; Ferini-Strambi, Luigi; Tilley, Barbara; Huang, Jing; Stebbins, Glenn T; Goetz, Christopher G; Barone, Paolo; Bandettini di Poggio, Monica; Fabbrini, Giovanni; Di Stasio, Flavio; Tinazzi, Michele; Bovi, Tommaso; Ramat, Silvia; Meoni, Sara; Pezzoli, Gianni; Canesi, Margherita; Martinelli, Paolo; Maria Scaglione, Cesa Lorella; Rossi, Aroldo; Tambasco, Nicola; Santangelo, Gabriella; Picillo, Marina; Morgante, Letterio; Morgante, Francesca; Quatrale, Rocco; Sensi, MariaChiara; Pilleri, Manuela; Biundo, Roberta; Nordera, Giampietro; Caria, Antonella; Pacchetti, Claudio; Zangaglia, Roberta; Lopiano, Leonardo; Zibetti, Maurizio; Zappia, Mario; Nicoletti, Alessandra; Quattrone, Aldo; Salsone, Maria; Cossu, Gianni; Murgia, Daniela; Albanese, Alberto; Del Sorbo, Francesca

2013-05-01

The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an 'Official MDS translation,' the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Emerging biological therapies for the treatment of myelodysplastic syndromes.

PubMed

Zeidan, Amer M; Stahl, Maximilian; Komrokji, Rami

2016-09-01

No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure. This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche. Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.

Validating MDS Data about Risk Factors for Perineal Dermatitis by Comparing With Nursing Home Records

PubMed Central

Toth, Anna M.; Bliss, Donna Z.; Savik, Kay; Wyman, Jean F.

2011-01-01

Perineal dermatitis is one of the main complications of incontinence and increases the cost of health care. The Minimum Data Set (MDS) contains data about factors associated with perineal dermatitis identified in a published conceptual model of perineal dermatitis. The purpose of this study was to determine the validity of MDS data related to perineal dermatitis risk factors by comparing them with data in nursing home chart records. Findings indicate that MDS items defining factors associated with perineal dermatitis were valid and supported use of the MDS in further investigation of a significant, costly, and understudied health problem of nursing home residents. PMID:18512629

Cloning, expression and characterization of a novel human CAP10-like gene hCLP46 from CD34(+) stem/progenitor cells.

PubMed

Teng, Yun; Liu, Qiaohong; Ma, Jie; Liu, Feng; Han, Zeguang; Wang, Youxin; Wang, Wei

2006-04-12

A novel human gene, named as human CAP10-like protein 46 kDa (hCLP46), was isolated and identified from human acute myeloid leukemia transformed from myelodysplastic syndrome (MDS-AML) CD34(+) cells. hCLP46 (3q13.33) contains 11 exons encoding a putative protein of 392 amino acids, with a highly conserved CAP10 domain, a hydrophobic signal peptide at its N-terminus, and an endoplasmic reticulum (ER) retention signal motif KTEL at the C-terminus. The homologs of hCLP46 exist in different organisms from plants to animal kingdoms. Subcellular localization analysis showed that hCLP46 is an ER-resident protein. hCLP46 expressed in most human adult tissues at different intensities, with lengths of 3.5 kb and 1.9 kb. Transcript of hCLP46 was not detectable in colon, thymus, and small intestine, but was abundant in liver, indicating that hCLP46 may be involved in important physiological functions in the liver. hCLP46 over-expressed U937 cells had higher growth rate than the cells without exogenic hCLP46 protein expression, suggesting that hCLP46 protein possess the ability of promoting cell proliferation.

Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML.

PubMed

Hirabayashi, Shinsuke; Flotho, Christian; Moetter, Jessica; Heuser, Michael; Hasle, Henrik; Gruhn, Bernd; Klingebiel, Thomas; Thol, Felicitas; Schlegelberger, Brigitte; Baumann, Irith; Strahm, Brigitte; Stary, Jan; Locatelli, Franco; Zecca, Marco; Bergstraesser, Eva; Dworzak, Michael; van den Heuvel-Eibrink, Marry M; De Moerloose, Barbara; Ogawa, Seishi; Niemeyer, Charlotte M; Wlodarski, Marcin W

2012-03-15

Somatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We resequenced SF3B1, U2AF35, and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia. We found missense mutations in 2 juvenile myelomonocytic leukemia cases and in 1 child with systemic mastocytosis with MDS. In 1 juvenile myelomonocytic leukemia patient, the SRSF2 mutation that initially coexisted with an oncogenic NRAS mutation was absent at relapse, whereas the NRAS mutation persisted and a second, concomitant NRAS mutation later emerged. The patient with systemic mastocytosis and MDS carried both mutated U2AF35 and KIT in a single clone as confirmed by clonal sequencing. In the adult MDS patients sequenced for control purposes, we detected previously reported mutations in 7/30 and a novel SRSF2 deletion (c.284_307del) in 3 of 30 patients. These findings implicate that spliceosome mutations are rare in pediatric MDS and juvenile myelomonocytic leukemia and are unlikely to operate as driver mutations.

On-ground housing in “Mice Drawer System” (MDS) cage affects locomotor behaviour but not anxiety in male mice

NASA Astrophysics Data System (ADS)

Simone, Luciano; Bartolomucci, Alessandro; Palanza, Paola; Parmigiani, Stefano

2008-03-01

In the present study adult male mice were housed for 21 days in a housing modules of the Mice Drawer System (MDS). MDS is the facility that will support the research on board the International Space Station (ISS). Our investigation focused on: circadian rhythmicity of wide behavioural categories such as locomotor activity, food intake/drinking and resting; emotionality in the elevated plus maze (EPM); body weight. Housing in the MDS determined a strong up-regulation of activity and feeding behaviour and a concomitant decrease in inactivity. Importantly, housing in the MDS disrupted circadian rhythmicity in mice and also determined a decrease in body weight. Finally, when mice were tested in the EPM a clear hyperactivity (i.e. increased total transitions) was found, while no evidence for altered anxiety was detected. In conclusion, housing adult male mice in the MDS housing modules may affect their behaviour, circadian rhythmicity while having no effect on anxiety. It is suggested that to allow adaptation to the peculiar housing allowed by MDS a longer housing duration is needed.

Future prospects of therapeutic clinical trials in acute myeloid leukemia

PubMed Central

Khan, Maliha; Mansoor, Armaghan-e-Rehman; Kadia, Tapan M

2017-01-01

Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy that is most commonly seen in elderly adults. The response to current therapies to AML is quite variable, and very few new drugs have been recently approved for use in AML. This review aims to discuss the issues with current trial design for AML therapies, including trial end points, patient enrollment, cost of drug discovery and patient heterogeneity. We also discuss the future directions in AML therapeutics, including intensification of conventional therapy and new drug delivery mechanisms; targeted agents, including epigenetic therapies, cell cycle regulators, hypomethylating agents and chimeric antigen receptor T-cell therapy; and detail of the possible agents that may be incorporated into the treatment of AML in the future. PMID:27771959

An Analysis of microRNA Expression in the Myelodysplastic Syndromes Using Hematopoietic Stem Cells

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0082 TITLE: An Analysis of microRNA Expression in the Myelodysplastic Syndromes Using Hematopoietic Stem Cells ...syndromes (MDS) to identify microRNAs (miRNAs) dysregulated in MDS hematopoietic stem cells (MDS HSCs) as compared with normal HSCs. MiRNAs differentially...the age-related predisposition for the development of MDS. 15. SUBJECT TERMS MicroRNAs, the myelodysplastic syndromes, hematopoietic stem cells

An Analysis of MicroRNA Expression in the Myelodysplastic Syndromes Using Hematopoietic Stem Cells

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0082 TITLE: An Analysis of microRNA Expression in the Myelodysplastic Syndromes Using Hematopoietic Stem Cells ...syndromes (MDS) to identify microRNAs (miRNAs) dysregulated in MDS hematopoietic stem cells (MDS HSCs) as compared with normal HSCs. MiRNAs differentially...the age-related predisposition for the development of MDS. 15. SUBJECT TERMS MicroRNAs, the myelodysplastic syndromes, hematopoietic stem cells

Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload.

PubMed

Gattermann, Norbert

2008-07-01

Between 2002 and 2008, a number of consensus statements and guidelines were developed by various groups around the world to educate healthcare professionals on the treatment of myelodysplastic syndromes (MDS), including the management of transfusional iron overload with iron chelation therapy. Guidelines have been developed by The Italian Society of Hematology, The UK MDS Guidelines Group, The Nagasaki Group, The National Comprehensive Cancer Network, and The MDS Foundation. These guidelines show that the approaches to managing iron overload in patients with MDS are region specific, differing in their recommendations for when iron chelation therapy should be initiated and strategies for the ongoing management of iron overload. The guidelines all agree that red blood cell transfusions are clinically beneficial to treat the symptomatic anemia in MDS, and that patients with low-risk MDS receiving transfusions are the most likely to benefit from iron chelation therapy.

Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML.

PubMed

Liyanage, Sanduni U; Hurren, Rose; Voisin, Veronique; Bridon, Gaëlle; Wang, Xiaoming; Xu, ChangJiang; MacLean, Neil; Siriwardena, Thirushi P; Gronda, Marcela; Yehudai, Dana; Sriskanthadevan, Shrivani; Avizonis, Daina; Shamas-Din, Aisha; Minden, Mark D; Bader, Gary D; Laposa, Rebecca; Schimmer, Aaron D

2017-05-11

Mitochondrial DNA (mtDNA) biosynthesis requires replication factors and adequate nucleotide pools from the mitochondria and cytoplasm. We performed gene expression profiling analysis of 542 human acute myeloid leukemia (AML) samples and identified 55% with upregulated mtDNA biosynthesis pathway expression compared with normal hematopoietic cells. Genes that support mitochondrial nucleotide pools, including mitochondrial nucleotide transporters and a subset of cytoplasmic nucleoside kinases, were also increased in AML compared with normal hematopoietic samples. Knockdown of cytoplasmic nucleoside kinases reduced mtDNA levels in AML cells, demonstrating their contribution in maintaining mtDNA. To assess cytoplasmic nucleoside kinase pathway activity, we used a nucleoside analog 2'3'-dideoxycytidine (ddC), which is phosphorylated to the activated antimetabolite, 2'3'-dideoxycytidine triphosphate by cytoplasmic nucleoside kinases. ddC is a selective inhibitor of the mitochondrial DNA polymerase γ. ddC was preferentially activated in AML cells compared with normal hematopoietic progenitor cells. ddC treatment inhibited mtDNA replication, oxidative phosphorylation, and induced cytotoxicity in a panel of AML cell lines. Furthermore, ddC preferentially inhibited mtDNA replication in a subset of primary human leukemia cells and selectively targeted leukemia cells while sparing normal progenitor cells. In animal models of human AML, treatment with ddC decreased mtDNA, electron transport chain proteins, and induced tumor regression without toxicity. ddC also targeted leukemic stem cells in secondary AML xenotransplantation assays. Thus, AML cells have increased cytidine nucleoside kinase activity that regulates mtDNA biogenesis and can be leveraged to selectively target oxidative phosphorylation in AML. © 2017 by The American Society of Hematology.

Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML

PubMed Central

Liyanage, Sanduni U.; Hurren, Rose; Voisin, Veronique; Bridon, Gaëlle; Wang, Xiaoming; Xu, ChangJiang; MacLean, Neil; Siriwardena, Thirushi P.; Gronda, Marcela; Yehudai, Dana; Sriskanthadevan, Shrivani; Avizonis, Daina; Shamas-Din, Aisha; Minden, Mark D.; Bader, Gary D.; Laposa, Rebecca

2017-01-01

Mitochondrial DNA (mtDNA) biosynthesis requires replication factors and adequate nucleotide pools from the mitochondria and cytoplasm. We performed gene expression profiling analysis of 542 human acute myeloid leukemia (AML) samples and identified 55% with upregulated mtDNA biosynthesis pathway expression compared with normal hematopoietic cells. Genes that support mitochondrial nucleotide pools, including mitochondrial nucleotide transporters and a subset of cytoplasmic nucleoside kinases, were also increased in AML compared with normal hematopoietic samples. Knockdown of cytoplasmic nucleoside kinases reduced mtDNA levels in AML cells, demonstrating their contribution in maintaining mtDNA. To assess cytoplasmic nucleoside kinase pathway activity, we used a nucleoside analog 2′3′-dideoxycytidine (ddC), which is phosphorylated to the activated antimetabolite, 2′3′-dideoxycytidine triphosphate by cytoplasmic nucleoside kinases. ddC is a selective inhibitor of the mitochondrial DNA polymerase γ. ddC was preferentially activated in AML cells compared with normal hematopoietic progenitor cells. ddC treatment inhibited mtDNA replication, oxidative phosphorylation, and induced cytotoxicity in a panel of AML cell lines. Furthermore, ddC preferentially inhibited mtDNA replication in a subset of primary human leukemia cells and selectively targeted leukemia cells while sparing normal progenitor cells. In animal models of human AML, treatment with ddC decreased mtDNA, electron transport chain proteins, and induced tumor regression without toxicity. ddC also targeted leukemic stem cells in secondary AML xenotransplantation assays. Thus, AML cells have increased cytidine nucleoside kinase activity that regulates mtDNA biogenesis and can be leveraged to selectively target oxidative phosphorylation in AML. PMID:28283480

AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2

PubMed Central

Wang, Wei; Schwemmers, Sven; Hexner, Elizabeth O.

2010-01-01

The transcription factor NF-E2 is overexpressed in the majority of patients with polycythemia vera (PV). Concomitantly, 95% of these patients carry the JAK2V617F mutation. Although NF-E2 levels correlate with JAK2V671F allele burden in some PV cohorts, the molecular mechanism causing aberrant NF-E2 expression has not been described. Here we show that NF-E2 expression is also increased in patients with essential thrombocythemia and primary myelofibrosis independent of the presence of the JAK2V617F mutation. Characterization of the NF-E2 promoter revealed multiple functional binding sites for AML1/RUNX-1. Chromatin immunoprecipitation demonstrated AML1 binding to the NF-E2 promoter in vivo. Moreover, AML1 binding to the NF-E2 promoter was significantly increased in granulocytes from PV patients compared with healthy controls. AML1 mRNA expression was elevated in patients with PV, essential thrombocythemia, and primary myelofibrosis both in the presence and absence of JAK2V617F. In addition, AML1 and NF-E2 expression were highly correlated. RNAi-mediated suppression of either AML1 or of its binding partner CBF-β significantly decreased NF-E2 expression. Moreover, expression of the leukemic fusion protein AML/ETO drastically decreased NF-E2 protein levels. Our data identify NF-E2 as a novel AML1 target gene and delineate a role for aberrant AML1 expression in mediating elevated NF-E2 expression in MPN patients. PMID:20339092

Immunogenic apoptosis in human acute myeloid leukemia (AML): primary human AML cells expose calreticulin and release heat shock protein (HSP) 70 and HSP90 during apoptosis.

PubMed

Fredly, Hanne; Ersvær, Elisabeth; Gjertsen, Bjørn-Tore; Bruserud, Oystein

2011-06-01

Several previous studies have demonstrated that both conventional cytotoxic drugs as well as targeted therapeutics can induce apoptosis in primary human acute myelogenous leukemia (AML) cells. However, the apoptotic phenotype of dying AML cells has been less extensively characterized. Even though specific antileukemic immune reactivity is important in AML, especially for allotransplanted patients, it has not been investigated whether dying primary human AML cells show phenotypic characteristics consistent with immunogenic apoptosis [calreticulin exposure, heat shock protein (HSP) release]. We therefore investigated whether in vitro cultured primary human acute myeloid leukemia (AML) cells show calreticulin exposure and HSP70/HSP90 release during spontaneous (stress-induced) apoptosis when cultured in medium alone and when cultured in the presence of antileukemic drugs. Both surface exposure of calreticulin and release of HSP70 and HSP90 was detected but showed a wide variation between patients. This variation was also maintained when the AML cells were cultured in the presence of cytotoxic drugs (cytarabine, daunorubicin, mitomycin), all-trans retinoic acid (ATRA) and valproic acid. Finally, AML cells collected during in vivo ATRA therapy showed increased calreticulin exposure during spontaneous in vitro apoptosis, suggesting that in vivo pharmacotherapy can modulate the apoptotic phenotype. To conclude, apoptotic AML cells can show phenotypic characteristics consistent with immunogenic apoptosis, but there is a wide variation between patients and the level of calreticulin exposure/HSP release seems to depend on individual patient characteristics rather than the apoptosis-inducing agent.

IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.

PubMed

Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans-Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

2015-12-17

The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.

Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients.

PubMed

Ali, Mohamed A E; Naka, Kazuhito; Yoshida, Akiyo; Fuse, Kyoko; Kasada, Atsuo; Hoshii, Takayuki; Tadokoro, Yuko; Ueno, Masaya; Ohta, Kumiko; Kobayashi, Masahiko; Takahashi, Chiaki; Hirao, Atsushi

2014-07-18

Acute myeloid leukaemia (AML) is a heterogeneous neoplastic disorder in which a subset of cells function as leukaemia-initiating cells (LICs). In this study, we prospectively evaluated the leukaemia-initiating capacity of AML cells fractionated according to the expression of a nucleolar GTP binding protein, nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model in which green fluorescent protein (GFP) is expressed under the control of a region of the NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukaemia colonies in vitro, and exhibited the highest leukaemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukaemia-initiating capacity that we termed the 'leukaemia stem cell gene signature'. This gene signature stratified human AML patients into distinct clusters that reflected prognosis, demonstrating that the mouse leukaemia stem cell gene signature is significantly associated with the malignant properties of human AML. Further analyses of gene regulation in leukaemia stem cells could provide novel insights into diagnostic and therapeutic approaches to AML. Copyright © 2014 Elsevier Inc. All rights reserved.

Trib2 expression in granulocyte-monocyte progenitors drives a highly drug resistant acute myeloid leukaemia linked to elevated Bcl2

PubMed Central

O’Connor, Caitriona; Yalla, Krishna; Salomé, Mara; Moka, Hothri Ananyambica; Castañeda, Eduardo Gómez; Eyers, Patrick A.; Keeshan, Karen

2018-01-01

Trib2 pseudokinase has oncogenic and tumour suppressive functions depending on the cellular context. We investigated the ability of Trib2 to transform different haemopoietic stem and progenitor cells (HSPCs). Our study identified the granulocyte-macrophage progenitor (GMP) subpopulation as a potent leukaemia initiating cell of Trib2-driven AML in vivo. Trib2 transformed GMPs generated a fully penetrant and short latency AML. AML cells expressing elevated Trib2 led to a chemoresistant phenotype following chemotherapy treatment. We show that Trib2 overexpression results in an increase in BCL2 expression, and high Trib2 expressing cells are highly sensitive to cell killing by BCL2 inhibition (ABT199). Combined treatment with chemotherapeutic agents and BCL2 inhibition resulted in synergistic killing of Trib2+ AML cells. Trib2 transformed GMP AML cells showed more chemoresistance compared with HSPC derived Trib2 AML cells associated with higher Bcl2 expression. There is significant correlation of high TRIB2 and BCL2 expression in patient derived human AML cells. These data demonstrate that the cell of origin influences the leukaemic profile and chemotherapeutic response of Trib2+ AML. Combined TRIB2 and BCL2 expression in AML cells may have clinical utility relevant for monitoring drug resistance and disease relapse. PMID:29599919

Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and novel therapeutic target in acute myeloid leukemia

PubMed Central

Porter, Christopher C.; Kim, Jihye; Fosmire, Susan; Gearheart, Christy M.; van Linden, Annemie; Baturin, Dmitry; Zaberezhnyy, Vadym; Patel, Purvi R.; Gao, Dexiang; Tan, Aik Choon; DeGregori, James

2011-01-01

Acute myeloid leukemia (AML) remains a therapeutic challenge despite increasing knowledge about the molecular origins of the disease, as the mechanisms of AML cell escape from chemotherapy remain poorly defined. We hypothesized that AML cells are addicted to molecular pathways in the context of chemotherapy and used complementary approaches to identify these addictions. Using novel molecular and computational approaches, we performed genome-wide shRNA screens to identify proteins that mediate AML cell fate after cytarabine exposure, gene expression profiling of AML cells exposed to cytarabine to identify genes with induced expression in this context, and examination of existing gene expression data from primary patient samples. The integration of these independent analyses strongly implicates cell cycle checkpoint proteins, particularly WEE1, as critical mediators of AML cell survival after cytarabine exposure. Knockdown of WEE1 in a secondary screen confirmed its role in AML cell survival. Pharmacologic inhibition of WEE1 in AML cell lines and primary cells is synergistic with cytarabine. Further experiments demonstrate that inhibition of WEE1 prevents S-phase arrest induced by cytarabine, broadening the functions of WEE1 that may be exploited therapeutically. These data highlight the power of integrating functional and descriptive genomics, and identify WEE1 as potential therapeutic target in AML. PMID:22289989

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

PubMed

Morgado-Palacin, Isabel; Day, Amanda; Murga, Matilde; Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J; Hubbard, Chad; Armstrong, Scott A; Nussenzweig, André; Fernandez-Capetillo, Oscar

2016-09-13

Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias. Copyright © 2016, American Association for the Advancement of Science.

Falls documentation in nursing homes: agreement between the minimum data set and chart abstractions of medical and nursing documentation.

PubMed

Hill-Westmoreland, Elizabeth E; Gruber-Baldini, Ann L

2005-02-01

To assess the agreement between falls as recorded in the Minimum Data Set (MDS) and fall events abstracted from chart documentation of elderly nursing home (NH) residents. Secondary analysis of data from a longitudinal panel study. Fifty-six randomly selected NHs in Maryland stratified by facility size and geographic region. Four hundred sixty-two NH residents, aged 65 and older, in NHs for 1 year. Falls were abstracted from resident charts and compared with MDS fall variables. Fall events data obtained from other sources of chart documentation were matched for the corresponding periods of 30 and 180 days before the 1-year MDS assessment date. For a 30-day period, concordance between the MDS and chart abstractions of falls occurred in 65% of cases, with a kappa coefficient of 0.29 (P<.001), indicating fair agreement. Concordance occurred between the sources for 75% of cases for a 180-day period, with a kappa of 0.50 (P<.001), indicating moderate agreement. During the 180-day period, chart abstractions showed that 49% of the sample fell, whereas the MDS revealed that only 28% fell. An analysis of residents whose falls the MDS missed indicated that these residents had significantly more activity of daily living impairment and significantly less unsteady gait and cane/walker use. The MDS underreported falls. Nurses completing MDS assessments must carefully review residents' medical records for falls documentation. Future studies should use caution when employing MDS data as the only indicator of falls.

Cross-sectional study on the relationship between the Mediterranean Diet Score and blood lipids.

PubMed

Mertens, Evelien; Mullie, Patrick; Deforche, Benedicte; Lefevre, Johan; Charlier, Ruben; Huybrechts, Inge; Clarys, Peter

2014-09-04

Blood lipids are cardiovascular health indicators. High LDL cholesterol values and/or high total cholesterol (TC)/HDL cholesterol ratios are positively related with cardiovascular mortality. Evidence suggests that a Mediterranean diet can reduce the incidence of cardiovascular diseases. Adherence to the Mediterranean diet is often measured by the Mediterranean Diet Score (MDS). However, the association between the Mediterranean diet and blood lipid profiles seems still inconclusive. The aim of this study was to investigate the relationship between the MDS, its different components and blood lipid profiles. A sample of 506 women and 707 men (aged 18-75 years) was recruited. Three-day diet records were used to calculate the MDS. Blood samples were analyzed for serum TC, LDL and HDL cholesterol. ANOVA was used to analyze blood lipids across the MDS tertiles. A multivariate linear regression analysis was performed to investigate the associations between the MDS, its components and blood lipids, adjusted for several confounders. All analyses were stratified by gender. Few gender-specific associations were found between the MDS, its components and blood lipids. Only in men, the total MDS was negatively related with LDL cholesterol and the ratio TC/HDL cholesterol while positively with HDL cholesterol. In women, respectively two (MUFA/SFA and cereals) and in men three (fruits & nuts, meat and alcohol) of the nine MDS components were related with blood lipids. Analyses investigating the relationship between the MDS, its components and blood lipid profiles indicate only limited influence of the Mediterranean diet on blood lipids. More associations were detected in men compared to women.

When the good go bad: Mutant NPM1 in acute myeloid leukemia.

PubMed

Kunchala, Preethi; Kuravi, Sudhakiranmayi; Jensen, Roy; McGuirk, Joseph; Balusu, Ramesh

2018-05-01

Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. Acute myeloid leukemia (AML) is a heterogeneous disease, more than half of the AML cases exhibit normal karyotype (NK). Approximately 50-60 percent of patients with NK-AML carry NPM1 mutations which are characterized by cytoplasmic dislocation of the NPM1 protein. In AML, mutant NPM1 (NPM1c+) acts in a dominant negative fashion and also blocks the differentiation of myeloid cells through gain-of-function for the AML phenotype. Currently, there is limited knowledge on the gain-of-function mechanism of mutant NPM1. Here, we review the known mechanisms of mutant NPM1 in the pathogenesis of AML. We describe genetic abnormalities, the clinical significance of exon-12 mutations in the NPM1 gene, and chromosomal translocations including the recently discovered NPM1-TYK2, and NPM1-HAUS1. Also, we outline the possible therapeutic interventions for the treatment of AML by targeting NPM1. Overall, the review will summarize present knowledge on mutant NPM1 origin, pathogenesis, and therapy in AML. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

PubMed Central

Zaitseva, Lyubov; Murray, Megan Y.; Shafat, Manar S.; Lawes, Matthew J.; MacEwan, David J.; Bowles, Kristian M.; Rushworth, Stuart A.

2014-01-01

Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL. PMID:25294819

Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer?

PubMed Central

Grove, Carolyn S.; Vassiliou, George S.

2014-01-01

Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers. PMID:25056697

Granulocyte, monocyte and blast immunophenotype abnormalities in acute myeloid leukemia with myelodysplasia-related changes.

PubMed

Ayar, Sonali P; Ravula, Sreelakshmi; Polski, Jacek M

2014-01-01

Little literature exists regarding granulocyte and monocyte immunophenotype abnormalities in Acute Myeloid Leukemia (AML). We hypothesized that granulocyte and monocyte immunophenotype abnormalities are common in AML, and especially in AML with myelodysplasia-related changes (AMLMRC). Bone marrow or peripheral blood specimens from 48 cases of AML and 22 cases of control specimens were analyzed by flow cytometric immunophenotyping. Granulocyte, monocyte, and blast immunophenotype abnormalities were compared between cases of AML versus controls and AMLMRC versus AML without myelodysplasia. The results revealed that granulocyte, monocyte, and blast abnormalities were more common in AMLMRC than in AML without myelodysplasia or control cases. The difference reached statistical significance for abnormalities of granulocytes and abnormalities in all cells of interest. From the numerous individual abnormalities, only CD25 expression in blasts was significantly more prevalent in AMLMRC in this study. We conclude that detection of granulocyte, monocyte, and blast immunophenotype abnormalities can contribute to the diagnosis of AMLMRC.

Acute myeloid leukemia with leukemic pleural effusion.

PubMed

Chang, Hung

2013-10-01

Acute myeloid leukemia (AML) may be associated with extramedullary tumor growth, which is commonly known as myeloid sarcoma. Although AML with leukemic pleural effusion is considered rare, the true incidence is not clear. We report three cases of AML involving pleural effusion in this study. The cases were encountered in a single institute within two years, suggesting that leukemic effusion is more common than previously reported. Leukemic cells showed evidence of monocytic differentiation in all cases. Two patients presented with advanced AML. Both had concurrent myeloid sarcoma. Both were ineligible for intensive treatment and died soon after diagnosis of myeloid sarcoma. The third patient had pleural effusion upon diagnosis of AML. Remission was achieved and the effusion disappeared after treatment. We conclude leukemic effusion may become more common in an era of improved care and prolonged survival for AML patients. The prognostic impact is unclear and patients should be given standard AML treatment whenever possible. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Simultaneous Presentation of Giant Cell Arteritis and Myelodysplastic Syndrome in an Elderly Japanese Man.

PubMed

Senjo, Hajime; Higuchi, Takakazu; Morimoto, Masaya; Koyamada, Ryosuke; Yanaoka, Chisun; Okada, Sadamu

2018-05-18

An 81-year-old Japanese man presented with constitutional symptoms and anemia and was diagnosed with giant cell arteritis (GCA) and myelodysplastic syndrome (MDS) simultaneously. His symptoms and anemia improved promptly with steroids; however, the MDS rapidly progressed to overt leukemia. While MDS patients are at an increased risk of autoimmune diseases, an association with GCA has rarely been reported. This case illustrates the importance of considering GCA as a cause of anemia in elderly patients if MDS is already diagnosed, even in countries where the prevalence of GCA is very low. The simultaneous development of GCA and MDS suggests a common pathogenetic link between these two diseases.

Empirical Analysis of Using Erasure Coding in Outsourcing Data Storage With Provable Security

DTIC Science & Technology

2016-06-01

the fastest encoding performance among the four tested schemes. We expected to observe that Cauchy Reed-Solomonwould be faster than Reed- Solomon for all...providing recoverability for POR. We survey MDS codes and select Reed- Solomon and Cauchy Reed- Solomon MDS codes to be implemented into a prototype POR...tools providing recoverability for POR. We survey MDS codes and select Reed- Solomon and Cauchy Reed- Solomon MDS codes to be implemented into a

Assessing the Mechanisms of MDS and Its Transformation to Leukemia in a Novel Humanized Mouse

DTIC Science & Technology

2016-05-01

achievements N/A References N/A References: 1. Rongvaux, A., et al., Development and function of human innate immune cells in a...in cancer survivors. MDS is inherently difficult to study. MDS stem cells cannot be grown in culture and in vivo models are thus the gold standard...However, MDS stem cells are diseased and fail to efficiently engraft in current immunodeficient mouse models. We have optimized engraftment of

Combined methionine deprivation and chloroethylnitrosourea have time-dependent therapeutic synergy on melanoma tumors that NMR spectroscopy-based metabolomics explains by methionine and phospholipid metabolism reprogramming.

PubMed

Guénin, Samuel; Morvan, Daniel; Thivat, Emilie; Stepien, Georges; Demidem, Aicha

2009-01-01

Methionine (Met) deprivation stress (MDS) is proposed in association with chemotherapy in the treatment of some cancers. A synergistic effect of this combination is generally acknowledged. However, little is known on the mechanism of the response to this therapeutic strategy. A model of B16 melanoma tumor in vivo was treated by MDS alone and in combination with chloroethylnitrosourea (CENU). It was applied recent developments in proton-NMR spectroscopy-based metabolomics for providing information on the metabolic response of tumors to MDS and combination with chemotherapy. MDS inhibited tumor growth during the deprivation period and growth resumption thereafter. The combination of MDS with CENU induced an effective time-dependent synergy on growth inhibition. Metabolite profiling during MDS showed a decreased Met content (P < 0.01) despite the preservation of the protein content, disorders in sulfur-containing amino acids, glutamine/proline, and phospholipid metabolism [increase of glycerophosphorylcholine (P < 0.01), decrease in phosphocholine (P < 0.05)]. The metabolic profile of MDS combined with CENU and ANOVA analysis revealed the implication of Met and phospholipid metabolism in the observed synergy, which may be interpreted as a Met-sparing metabolic reprogramming of tumors. It follows that combination therapy of MDS with CENU seems to intensify adaptive processes, which may set limitations to this therapeutic strategy.

Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML.

PubMed

Wei, Andrew H; Tiong, Ing S

2017-12-07

In 2017, 4 drugs received US Food and Drug Administration marketing approval for acute myeloid leukemia (AML) treatment: targeted therapies for mutant FLT3 and IDH2 , a liposomal cytarabine-daunorubicin formulation for therapy-related AML and AML with myelodysplasia-related changes, and resurgence of an antibody-drug conjugate designed to target CD33. Promising results also emerged for the BCL-2 inhibitor venetoclax combined with low-intensity therapy in older patients unfit for intensive chemotherapy. This quintet of new drugs is likely to reshape the therapeutic landscape of AML. © 2017 by The American Society of Hematology.

INPP4B promotes cell survival via SGK3 activation in NPM1-mutated leukemia.

PubMed

Jin, Hongjun; Yang, Liyuan; Wang, Lu; Yang, Zailin; Zhan, Qian; Tao, Yao; Zou, Qin; Tang, Yuting; Xian, Jingrong; Zhang, Shuaishuai; Jing, Yipei; Zhang, Ling

2018-01-17

Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been recognized as a distinct leukemia entity in the 2016 World Health Organization (WHO) classification. The genetic events underlying oncogenesis in NPM1-mutated AML that is characterized by a normal karyotype remain unclear. Inositol polyphosphate 4-phosphatase type II (INPP4B), a new factor in the phosphoinositide-3 kinase (PI3K) pathway-associated cancers, has been recently found a clinically relevant role in AML. However, little is known about the specific mechanistic function of INPP4B in NPM1-mutated AML. The INPP4B expression levels in NPM1-mutated AML primary blasts and AML OCI-AML3 cell lines were determined by qRT-PCR and western blotting. The effect of INPP4B knockdown on OCI-AML3 leukemia cell proliferation was evaluated, using the Cell Counting Kit-8 and colony formation assay. After INPP4B overexpression or knockdown, the activation of serum and glucocorticoid-regulated kinase 3 (SGK3) and AKT was assessed. The effects of PI3K signaling pathway inhibitors on the levels of p-SGK3 in OCI-AML3 cells were tested. The mass of PI (3,4) P 2 and PI (3) P was analyzed by ELISA upon INPP4B overexpression. Knockdown of SGK3 by RNA interference and a rescue assay were performed to confirm the critical role of SGK3 in INPP4B-mediated cell survival. In addition, the molecular mechanism underlying INPP4B expression in NPM1-mutated leukemia cells was explored. Finally, Kaplan-Meier survival analysis was conducted on the NPM1-mutated AML cohort stratified into quartiles for INPP4B expression in The Cancer Genome Atlas (TCGA) dataset. High expression of INPP4B was observed in NPM1-mutated AML. Knockdown of INPP4B repressed cell proliferation in OCI-AML3 cells, whereas recovered INPP4B rescued this inhibitory effect in vitro. Mechanically, INPP4B enhanced phosphorylated SGK3 (p-SGK3) status, but did not affect AKT activation. SGK3 was required for INPP4B-induced cell proliferation in OCI-AML3 cells. High levels of INPP4B were at least partially caused by the NPM1 mutant via ERK/Ets-1 signaling. Finally, high expression of INPP4B showed a trend towards lower overall survival and event-free survival in NPM1-mutated AML patients. Our results indicate that INPP4B promotes leukemia cell survival via SGK3 activation, and INPP4B might be a potential target in the treatment of NPM1-mutated AML.

Missing the Benefit of Metformin in Acute Myeloid Leukemia: A Problem of Contrast?

PubMed

Ceacareanu, Alice C; Nimako, George K; Wintrob, Zachary A P

2017-01-01

To evaluate whether metformin's cancer-related benefits reported in patients with solid tumors (ST) are also present in acute myeloid leukemia (AML) patients. Baseline demographic and clinical history for all diabetes mellitus patients newly diagnosed with AML or cancer of the breast, ovary, prostate, gastrointestinal tract, lung, or kidney at Roswell Park Cancer Institute in Buffalo, NY (January 2003-December 2010, n = 924) was collected. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan-Meier (KM) analysis and Cox proportional hazards regression (hazard ratio [HR]). Baseline metformin use provided significant OS and DFS benefit in ST but not in AML (KM: P ST-OS = 0.003; P ST-DFS = 0.002; P AML-OS = 0.961; P AML-DFS = 0.943). AML median survival was slightly better with metformin use, but users derived no relapse benefit. In ST, metformin nonusers had shorter median survival, 57.7 versus 86 months, and poorer outcomes (HR ST-OS = 1.33; P ST-OS = 0.002; HR ST-DFS = 1.32; P ST-DFS = 0.002). These findings remained significant in age-adjusted models (HR ST-OS = 1.21; P ST-OS = 0.039; HR ST-DFS = 1.23; P ST-DFS = 0.02) but not fully adjusted models (HR ST-OS = 0.96; P ST-OS = 0.688; HR ST-DFS = 1.0; P ST-DFS = 0.94). Higher mortality was noted in AML patients taking insulin versus oral diabetes pharmacotherapy at baseline (HR AML-OS = 2.03; P AML-OS = 0.04). Lack of metformin benefit in AML could be due to advanced age at cancer diagnosis. Metformin substitution with insulin before computed tomography scans with contrast - a frequent AML assessment practice - may also explain the lack of subsequent benefit despite taking metformin at baseline. A temporary metformin substitution is recommended by the package insert due to a possible drug interaction with the contrast dye. Our data suggest that metformin substitution was permanent in many patients. Nonetheless, the observed benefit in other malignancies warrants further investigation of metformin use in AML.

Disease-related costs of care and survival among Medicare-enrolled patients with myelodysplastic syndromes.

PubMed

Zeidan, Amer M; Wang, Rong; Davidoff, Amy J; Ma, Shuangge; Zhao, Yinjun; Gore, Steven D; Gross, Cary P; Ma, Xiaomei

2016-05-15

Although newer treatments for myelodysplastic syndromes (MDS), particularly hypomethylating agents (HMAs), are expensive, it is unclear whether MDS-related costs of care are associated with overall survival. This study evaluated the relation between MDS-related costs and survival among Medicare beneficiaries with MDS. Eligible patients were identified from the Surveillance, Epidemiology, and End Results-Medicare database with codes for MDS from International Classification of Diseases for Oncology, 3rd edition. The patients were diagnosed between January 1, 2005 and December 31, 2011, were 66 years old or older, and were followed through death or the end of study (December 31, 2012). Medicare payments were used to estimate costs. Cumulative costs in a propensity score-matched group of cancer-free Medicare beneficiaries were subtracted from costs in the MDS cohort in each registry to estimate MDS-related costs. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from multivariate Cox proportional hazards models adjusted for patient and disease characteristics. There were 8580 eligible patients, and 1,267 (14.7%) received HMAs. The overall 2-year survival rate was 48.7%, and the 2-year registry-specific MDS-related cost per patient ranged from $40,793 to $78,156 across 16 registries. The 2-year MDS-related cost was not associated with survival in the overall study population (first tertile, reference; second tertile, HR, 0.96; 95% CI, 0.89-1.04; P = .29; third tertile, HR, 0.98; 95% CI, 0.91-1.06; P = .64) or in subgroups of patients who did or did not receive HMAs. Medicare expenditures for elderly patients with MDS varied across registries but were not associated with survival. A lack of an association between costs and outcomes warrants additional research because it may help to identify potential areas for cost-saving interventions without compromising patient outcomes. Cancer 2016;122:1598-607. © 2016 American Cancer Society. © 2016 American Cancer Society.

Impairment in immuno-modulatory function of Flk1(+)CD31(-)CD34(-) MSCs from MDS-RA patients.

PubMed

Han, Qin; Sun, Zhao; Liu, Lihui; Chen, Bin; Cao, Ying; Li, Kanghua; Zhao, Robert Chunhua

2007-11-01

Myelodysplastic syndromes are a group of hematopoietic disorders characterized by hematopoietic stem cell dysregulation and abnormalities in the immune system. Mesenchymal stem cells (MSCs) and their derived stromal cells constitute a bone marrow microenvironment, which is the niche for hematopoiesis and a key compartment for immune development and regulation. Existing evidence has shown that MSCs from MDS patients have impaired capacity in supporting hematopoiesis. Here, we conducted an investigation to determine whether the immuno-modulatory function of MSCs is also impaired in MDS-RA (refractory anemia) patients. Flk1(+)CD31(-)CD34(-) MSCs were isolated from 15 MDS-RA patients and cultured for testing biological and immunological characteristics. MDS-RA patient-derived Flk1(+)CD31(-)CD34(-) MSCs showed normal morphology, phenotype and karyotype but appeared impaired in immuno-modulatory function. The capacity of patient Flk1(+)CD31(-)CD34(-) MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. In conclusion, MDS-RA patient-derived MSCs have impaired immuno-modulatory functions, suggesting that the dysregulation of hematopoiesis and immune response may originate from MSCs rather than HSCs. MSCs might be a potential target for developing efficacious cures for MDS.

Abandoned Mine Lands: Revitalization and Reuse

EPA Pesticide Factsheets

EPA recognizes that reuse opportunities at AMLs may provide the critical impetus to expedite environmental cleanup. EPA’s AML Team is dedicated to providing tools and resources to support the reuse of AMLs.

A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets.

PubMed

Adamia, Sophia; Haibe-Kains, Benjamin; Pilarski, Patrick M; Bar-Natan, Michal; Pevzner, Samuel; Avet-Loiseau, Herve; Lode, Laurence; Verselis, Sigitas; Fox, Edward A; Burke, John; Galinsky, Ilene; Dagogo-Jack, Ibiayi; Wadleigh, Martha; Steensma, David P; Motyckova, Gabriela; Deangelo, Daniel J; Quackenbush, John; Stone, Richard; Griffin, James D

2014-03-01

Despite new treatments, acute myeloid leukemia (AML) remains an incurable disease. More effective drug design requires an expanded view of the molecular complexity that underlies AML. Alternative splicing of RNA is used by normal cells to generate protein diversity. Growing evidence indicates that aberrant splicing of genes plays a key role in cancer. We investigated genome-wide splicing abnormalities in AML and based on these abnormalities, we aimed to identify novel potential biomarkers and therapeutic targets. We used genome-wide alternative splicing screening to investigate alternative splicing abnormalities in two independent AML patient cohorts [Dana-Farber Cancer Institute (DFCI) (Boston, MA) and University Hospital de Nantes (UHN) (Nantes, France)] and normal donors. Selected splicing events were confirmed through cloning and sequencing analysis, and than validated in 193 patients with AML. Our results show that approximately 29% of expressed genes genome-wide were differentially and recurrently spliced in patients with AML compared with normal donors bone marrow CD34(+) cells. Results were reproducible in two independent AML cohorts. In both cohorts, annotation analyses indicated similar proportions of differentially spliced genes encoding several oncogenes, tumor suppressor proteins, splicing factors, and heterogeneous-nuclear-ribonucleoproteins, proteins involved in apoptosis, cell proliferation, and spliceosome assembly. Our findings are consistent with reports for other malignances and indicate that AML-specific aberrations in splicing mechanisms are a hallmark of AML pathogenesis. Overall, our results suggest that aberrant splicing is a common characteristic for AML. Our findings also suggest that splice variant transcripts that are the result of splicing aberrations create novel disease markers and provide potential targets for small molecules or antibody therapeutics for this disease. ©2013 AACR

Hyperforin inhibits Akt1 kinase activity and promotes caspase-mediated apoptosis involving Bad and Noxa activation in human myeloid tumor cells.

PubMed

Merhi, Faten; Tang, Ruoping; Piedfer, Marion; Mathieu, Julie; Bombarda, Isabelle; Zaher, Murhaf; Kolb, Jean-Pierre; Billard, Christian; Bauvois, Brigitte

2011-01-01

The natural phloroglucinol hyperforin HF displays anti-inflammatory and anti-tumoral properties of potential pharmacological interest. Acute myeloid leukemia (AML) cells abnormally proliferate and escape apoptosis. Herein, the effects and mechanisms of purified HF on AML cell dysfunction were investigated in AML cell lines defining distinct AML subfamilies and primary AML cells cultured ex vivo. HF inhibited in a time- and concentration-dependent manner the growth of AML cell lines (U937, OCI-AML3, NB4, HL-60) by inducing apoptosis as evidenced by accumulation of sub-G1 population, phosphatidylserine externalization and DNA fragmentation. HF also induced apoptosis in primary AML blasts, whereas normal blood cells were not affected. The apoptotic process in U937 cells was accompanied by downregulation of anti-apoptotic Bcl-2, upregulation of pro-apoptotic Noxa, mitochondrial membrane depolarization, activation of procaspases and cleavage of the caspase substrate PARP-1. The general caspase inhibitor Z-VAD-fmk and the caspase-9- and -3-specific inhibitors, but not caspase-8 inhibitor, significantly attenuated apoptosis. HF-mediated apoptosis was associated with dephosphorylation of active Akt1 (at Ser(473)) and Akt1 substrate Bad (at Ser(136)) which activates Bad pro-apoptotic function. HF supppressed the kinase activity of Akt1, and combined treatment with the allosteric Akt1 inhibitor Akt-I-VIII significantly enhanced apoptosis of U937 cells. Our data provide new evidence that HF's pro-apoptotic effect in AML cells involved inhibition of Akt1 signaling, mitochondria and Bcl-2 members dysfunctions, and activation of procaspases -9/-3. Combined interruption of mitochondrial and Akt1 pathways by HF may have implications for AML treatment.

Hyperforin Inhibits Akt1 Kinase Activity and Promotes Caspase-Mediated Apoptosis Involving Bad and Noxa Activation in Human Myeloid Tumor Cells

PubMed Central

Merhi, Faten; Tang, Ruoping; Piedfer, Marion; Mathieu, Julie; Bombarda, Isabelle; Zaher, Murhaf; Kolb, Jean-Pierre; Billard, Christian; Bauvois, Brigitte

2011-01-01

Background The natural phloroglucinol hyperforin HF displays anti-inflammatory and anti-tumoral properties of potential pharmacological interest. Acute myeloid leukemia (AML) cells abnormally proliferate and escape apoptosis. Herein, the effects and mechanisms of purified HF on AML cell dysfunction were investigated in AML cell lines defining distinct AML subfamilies and primary AML cells cultured ex vivo. Methodology and Results HF inhibited in a time- and concentration-dependent manner the growth of AML cell lines (U937, OCI-AML3, NB4, HL-60) by inducing apoptosis as evidenced by accumulation of sub-G1 population, phosphatidylserine externalization and DNA fragmentation. HF also induced apoptosis in primary AML blasts, whereas normal blood cells were not affected. The apoptotic process in U937 cells was accompanied by downregulation of anti-apoptotic Bcl-2, upregulation of pro-apoptotic Noxa, mitochondrial membrane depolarization, activation of procaspases and cleavage of the caspase substrate PARP-1. The general caspase inhibitor Z-VAD-fmk and the caspase-9- and -3-specific inhibitors, but not caspase-8 inhibitor, significantly attenuated apoptosis. HF-mediated apoptosis was associated with dephosphorylation of active Akt1 (at Ser473) and Akt1 substrate Bad (at Ser136) which activates Bad pro-apoptotic function. HF supppressed the kinase activity of Akt1, and combined treatment with the allosteric Akt1 inhibitor Akt-I-VIII significantly enhanced apoptosis of U937 cells. Significance Our data provide new evidence that HF's pro-apoptotic effect in AML cells involved inhibition of Akt1 signaling, mitochondria and Bcl-2 members dysfunctions, and activation of procaspases -9/-3. Combined interruption of mitochondrial and Akt1 pathways by HF may have implications for AML treatment. PMID:21998731

Clonal Architecture of Secondary Acute Myeloid Leukemia

PubMed Central

Walter, Matthew J.; Shen, Dong; Ding, Li; Shao, Jin; Koboldt, Daniel C.; Chen, Ken; Larson, David E.; McLellan, Michael D.; Dooling, David; Abbott, Rachel; Fulton, Robert; Magrini, Vincent; Schmidt, Heather; Kalicki-Veizer, Joelle; O’Laughlin, Michelle; Fan, Xian; Grillot, Marcus; Witowski, Sarah; Heath, Sharon; Frater, John L.; Eades, William; Tomasson, Michael; Westervelt, Peter; DiPersio, John F.; Link, Daniel C.; Mardis, Elaine R.; Ley, Timothy J.; Wilson, Richard K.; Graubert, Timothy A.

2012-01-01

BACKGROUND The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. METHODS We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. RESULTS Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene. CONCLUSIONS Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.) PMID:22417201

Waveform modeling of the seismic response of a mid-ocean ridge axial melt sill

NASA Astrophysics Data System (ADS)

Xu, Min; Stephen, R. A.; Canales, J. Pablo

2017-12-01

Seismic reflections from axial magma lens (AML) are commonly observed along many mid-ocean ridges, and are thought to arise from the negative impedance contrast between a solid, high-speed lid and the underlying low-speed, molten or partially molten (mush) sill. The polarity of the AML reflection ( P AML P) at vertical incidence and the amplitude vs offset (AVO) behavior of the AML reflections (e.g., P AML P and S-converted P AML S waves) are often used as a diagnostic tool for the nature of the low-speed sill. Time-domain finite difference calculations for two-dimensional laterally homogeneous models show some scenarios make the interpretation of melt content from partial-offset stacks of P- and S-waves difficult. Laterally heterogeneous model calculations indicate diffractions from the edges of the finite-width AML reducing the amplitude of the AML reflections. Rough seafloor and/or a rough AML surface can also greatly reduce the amplitude of peg-leg multiples because of scattering and destructive interference. Mid-crustal seismic reflection events are observed in the three-dimensional multi-channel seismic dataset acquired over the RIDGE-2000 Integrated Study Site at East Pacific Rise (EPR, cruise MGL0812). Modeling indicates that the mid-crustal seismic reflection reflections are unlikely to arise from peg-leg multiples of the AML reflections, P-to- S converted phases, or scattering due to rough topography, but could probably arise from deeper multiple magma sills. Our results support the identification of Marjanović et al. (Nat Geosci 7(11):825-829, 2014) that a multi-level complex of melt lenses is present beneath the axis of the EPR.

Effects of triple combination therapy with azilsartan/amlodipine/hydrochlorothiazide on office/home blood pressure: a randomized-controlled trial in Japanese essential hypertensive patients.

PubMed

Rakugi, Hiromi; Shimizu, Kohei; Sano, Yuhei; Nishiyama, Yuya; Kinugawa, Yoshinobu; Terashio, Souhei

2018-04-01

The efficacy and safety of triple therapy with azilsartan (AZI), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) compared with dual therapy with AZI/AML or HCTZ monotherapy were evaluated in Japanese essential hypertensive patients in a double-blinded manner. A total of 353 patients with office blood pressure (BP) of at least 150/95 mmHg were randomized to a 10-week treatment with AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, AZI/AML 20/5 mg, HCTZ 12.5 mg, or HCTZ 6.25 mg. The mean change from baseline in office diastolic/systolic BPs at week 10 was -25.9/-41.4, -24.9/-38.6, and -22.4/-34.5 mmHg in the AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, and AZI/AML 20/5 mg groups, respectively. AZI/AML/HCTZ 20/5/12.5 mg led to a significantly greater reduction in diastolic and systolic BP than the dual therapy. In addition, the change in home diastolic BP measured with telemetry devices showed a significant difference between the two triple therapy groups. The incidences of adverse events except dizziness postural were similar among the treatment groups in the triple therapy groups. Triple therapy with AZI/AML/HCTZ 20/5/12.5 mg shows a greater antihypertensive effect than the dual therapy and has acceptable safety profiles for Japanese essential hypertensive patients. It was also observed that home BP measurement by automated telemetry could detect changes in BP that were not detected in office BP measurement, although further investigation is needed.

Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner.

PubMed

Nabissi, Massimo; Morelli, Maria Beatrice; Amantini, Consuelo; Liberati, Sonia; Santoni, Matteo; Ricci-Vitiani, Lucia; Pallini, Roberto; Santoni, Giorgio

2015-10-15

Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differentiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differentiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Altogether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs. © 2015 UICC.

Inhibition of poly(ADP-ribose) polymerase 1 protects against acute myeloid leukemia by suppressing the myeloproliferative leukemia virus oncogene

PubMed Central

Wang, Lingbo; Cai, Weili; Zhang, Wei; Chen, Xueying; Dong, Wenqian; Tang, Dongqi; Zhang, Yun; Ji, Chunyan; Zhang, Mingxiang

2015-01-01

An abnormal expression of poly(ADP-ribose) polymerase 1 (PARP-1) has been described in many tumors. PARP-1 promotes tumorigenesis and cancer progression by acting on different molecular pathways. PARP-1 inhibitors can be used with radiotherapy or chemotherapy to enhance the susceptibility of tumor cells to the treatment. However, the specific mechanism of PARP-1 in acute myeloid leukemia (AML) remains unknown. Our study showed that expression of PARP-1 was upregulated in AML patients. PARP-1 inhibition slowed AML cell proliferation, arrested the cell cycle, induced apoptosis in vitro and improved AML prognosis in vivo. Mechanistically, microarray assay of AML cells with loss of PARP-1 function revealed that the myeloproliferative leukemia virus oncogene (MPL) was significantly downregulated. In human AML samples, MPL expression was increased, and gain-of-function and loss-of-function analysis demonstrated that MPL promoted cell growth. Moreover, PARP-1 and MPL expression were positively correlated in AML samples, and their overexpression was associated with an unfavorable prognosis. Furthermore, PARP-1 and MPL consistently acted on Akt and ERK1/2 pathways, and the anti-proliferative and pro-apoptotic function observed with PARP-1 inhibition were reversed in part via MPL activation upon thrombopoietin stimulation or gene overexpression. These data highlight the important function of PARP-1 in the progression of AML, which suggest PARP-1 as a potential target for AML treatment. PMID:26314963

Is Acute Myeloid Leukemia a Liquid Tumor?

PubMed Central

Ohanian, Maro; Faderl, Stefan; Ravandi, Farhad; Pemmaraju, Naveen; Garcia-Manero, Guillermo; Cortes, Jorge; Estrov, Zeev

2014-01-01

Extramedullary manifestations of acute myeloid leukemia (AML) were described as early as the 19th century. However, the incidence, clinical significance, and pathobiology of extramedullary AML remain ill defined. We reviewed case reports, retrospective case series, pilot studies, and imaging studies of extramedullary leukemia (EML) to determine its frequency, characteristics, clinical presentation, and significance. EML precedes or accompanies development of AML and occurs during or following treatment, even during remission. Although imaging studies are rarely conducted and the true incidence of EML has yet to be verified, authors have reported several estimates based on retrospective and autopsy studies. The incidence of EML in patients with AML of all ages is estimated to be about 9% and EML in children with AML was detected in 40% of patients at diagnosis. The combination of positron emission tomography and computed tomography were the most sensitive and reliable techniques of detecting and monitoring EML. Based on our literature review, the frequency of EML is likely underreported. The well-documented nature of EML in AML patients suggests that AML can manifest as a solid tumor. The extent to which EML accompanies AML and whether EML is derived from bone marrow are unknown. Furthermore, questions remain regarding the role of the microenvironment, which may or may not facilitate the survival and proliferation of EML, and the implications of these interactions with regard to minimal residual disease, tumor cell quiescence, and relapse. Therefore, prospective studies of detection and characterization of EML in AML patients are warranted. PMID:23280377

Is acute myeloid leukemia a liquid tumor?

PubMed

Ohanian, Maro; Faderl, Stefan; Ravandi, Farhad; Pemmaraju, Naveen; Garcia-Manero, Guillermo; Cortes, Jorge; Estrov, Zeev

2013-08-01

Extramedullary manifestations of acute myeloid leukemia (AML) were described as early as the 19th century. However, the incidence, clinical significance and pathobiology of extramedullary AML remain ill defined. We reviewed case reports, retrospective case series, pilot studies and imaging studies of extramedullary leukemia (EML) to determine its frequency, characteristics, clinical presentation and significance. EML precedes or accompanies development of AML and occurs during or following treatment, even during remission. Although imaging studies are rarely conducted and the true incidence of EML has yet to be verified, authors have reported several estimates based on retrospective and autopsy studies. The incidence of EML in patients with AML of all ages is estimated to be about 9% and EML in children with AML was detected in 40% of patients at diagnosis. The combination of positron emission tomography and computed tomography were the most sensitive and reliable techniques of detecting and monitoring EML. Based on our literature review, the frequency of EML is likely underreported. The well-documented nature of EML in patients with AML suggests that AML can manifest as a solid tumor. The extent to which EML accompanies AML and whether EML is derived from bone marrow are unknown. Furthermore, questions remain regarding the role of the microenvironment, which may or may not facilitate the survival and proliferation of EML, and the implications of these interactions with regard to minimal residual disease, tumor cell quiescence and relapse. Therefore, prospective studies of detection and characterization of EML in patients with AML are warranted. Copyright © 2013 UICC.

Autophagy is dispensable for Kmt2a/Mll-Mllt3/Af9 AML maintenance and anti-leukemic effect of chloroquine.

PubMed

Chen, Xiaoyi; Clark, Jason; Wunderlich, Mark; Fan, Cuiqing; Davis, Ashley; Chen, Song; Guan, Jun-Lin; Mulloy, James C; Kumar, Ashish; Zheng, Yi

2017-05-04

Recently, macroautophagy/autophagy has emerged as a promising target in various types of solid tumor treatment. However, the impact of autophagy on acute myeloid leukemia (AML) maintenance and the validity of autophagy as a viable target in AML therapy remain unclear. Here we show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared with normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent phagophore (the autophagosome precursor) membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo. Mechanistically, neither Atg5 nor Rb1cc1 disruption impairs endolysosome formation or survival signaling pathways. The autophagy inhibitor chloroquine shows autophagy-independent anti-leukemic effects in vitro but has no efficacy in vivo likely due to limited achievable drug efficacy in blood. Further, vesicular exocytosis appears to mediate chloroquine resistance in AML cells, and exocytotic inhibition significantly enhances the anti-leukemic effect of chloroquine. Thus, chloroquine can induce leukemia cell death in vitro in an autophagy-independent manner but with inadequate efficacy in vivo, and vesicular exocytosis is a possible mechanism of chloroquine resistance in MA9-AML. This study also reveals that autophagy-specific targeting is unlikely to benefit MA9-AML therapy.

Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia.

PubMed

Chen, Lisa S; Redkar, Sanjeev; Taverna, Pietro; Cortes, Jorge E; Gandhi, Varsha

2011-07-21

Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-x(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment.

Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia

PubMed Central

Chen, Lisa S.; Redkar, Sanjeev; Taverna, Pietro; Cortes, Jorge E.

2011-01-01

Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment. PMID:21628411

Validation of the Hebrew version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

PubMed

Zitser, Jennifer; Peretz, Chava; Ber David, Aya; Shabtai, Herzl; Ezra, Adi; Kestenbaum, Meir; Brozgol, Marina; Rosenberg, Alina; Herman, Talia; Balash, Yakov; Gadoth, Avi; Thaler, Avner; Stebbins, Glenn T; Goetz, Christopher G; Tilley, Barbara C; Luo, Sheng T; Liu, Yuanyuan; Giladi, Nir; Gurevich, Tanya

2017-12-01

The Movement Disorders Society (MDS) published the English new Unified Parkinson's Disease Rating Scale (MDS-UPDRS) as the official benchmark scale for Parkinson's disease (PD) in 2008. We aimed to validate the Hebrew version of the MDS-UPDRS, explore its dimensionality and compare it to the original English one. The MDS-UPDRS questionnaire was translated to Hebrew and was tested on 389 patients with PD, treated at the Movement Disorders Unit at Tel-Aviv Medical Center. The MDS-UPDRS is made up of four sections. The higher the score, the worst the clinical situation of the patient is. Confirmatory and explanatory factor analysis were applied to determine if the factor structure of the English version could be confirmed in the Hebrew version. The Hebrew version of the MDS-UPDRS showed satisfactory clinimetric properties. The internal consistency of the Hebrew-version was satisfactory, with Cronbach's alpha values 0.79, 0.90, 0.93, 0.80, for parts 1 to 4 respectively. In the confirmatory factor analysis, all four parts had high (greater than 0.90) comparative fit index (CFI) in comparison to the original English MDS-UPDRS with high factor structure (0.96, 0.99, 0.94, 1.00, respectively), thus confirming the pre-specified English factor structure. Explanatory factor analysis yielded that the Hebrew responses differed from the English one within an acceptable range: in isolated item differences in factor structure and in the findings of few items having cross loading on multiple factors. The Hebrew version of the MDS-UPDRS meets the requirements to be designated as the Official Hebrew Version of the MDS-UPDRS. Copyright © 2017 Elsevier Ltd. All rights reserved.

An improved resource management model based on MDS

NASA Astrophysics Data System (ADS)

Yuan, Man; Sun, Changying; Li, Pengfei; Sun, Yongdong; He, Rui

2005-11-01

GRID technology provides a kind of convenient method for managing GRID resources. This service is so-called monitoring, discovering service. This method is proposed by Globus Alliance, in this GRID environment, all kinds of resources, such as computational resources, storage resources and other resources can be organized by MDS specifications. However, this MDS is a theory framework, particularly, in a small world intranet, in the case of limit of resources, the MDS has its own limitation. Based on MDS, an improved light method for managing corporation computational resources and storage resources is proposed in intranet(IMDS). Firstly, in MDS, all kinds of resource description information is stored in LDAP, it is well known although LDAP is a light directory access protocol, in practice, programmers rarely master how to access and store resource information into LDAP store, in such way, it limits MDS to be used. So, in intranet, these resources' description information can be stored in RDBMS, programmers and users can access this information by standard SQL. Secondly, in MDS, how to monitor all kinds of resources in GRID is not transparent for programmers and users. In such way, it limits its application scope, in general, resource monitoring method base on SNMP is widely employed in intranet, therefore, a kind of resource monitoring method based on SNMP is integrated into MDS. Finally, all kinds of resources in the intranet can be described by XML, and all kinds of resources' description information is stored in RDBMS, such as MySql, and retrieved by standard SQL, dynamic information for all kinds of resources can be sent to resource storage by SNMP, A prototype resource description, monitoring is designed and implemented in intranet.

Inter-observer variance with the diagnosis of myelodysplastic syndromes (MDS) following the 2008 WHO classification.

PubMed

Font, P; Loscertales, J; Benavente, C; Bermejo, A; Callejas, M; Garcia-Alonso, L; Garcia-Marcilla, A; Gil, S; Lopez-Rubio, M; Martin, E; Muñoz, C; Ricard, P; Soto, C; Balsalobre, P; Villegas, A

2013-01-01

Morphology is the basis of the diagnosis of myelodysplastic syndromes (MDS). The WHO classification offers prognostic information and helps with the treatment decisions. However, morphological changes are subject to potential inter-observer variance. The aim of our study was to explore the reliability of the 2008 WHO classification of MDS, reviewing 100 samples previously diagnosed with MDS using the 2001 WHO criteria. Specimens were collected from 10 hospitals and were evaluated by 10 morphologists, working in five pairs. Each observer evaluated 20 samples, and each sample was analyzed independently by two morphologists. The second observer was blinded to the clinical and laboratory data, except for the peripheral blood (PB) counts. Nineteen cases were considered as unclassified MDS (MDS-U) by the 2001 WHO classification, but only three remained as MDS-U by the 2008 WHO proposal. Discordance was observed in 26 of the 95 samples considered suitable (27 %). Although there were a high number of observers taking part, the rate of discordance was quite similar among the five pairs. The inter-observer concordance was very good regarding refractory anemia with excess blasts type 1 (RAEB-1) (10 of 12 cases, 84 %), RAEB-2 (nine of 10 cases, 90 %), and also good regarding refractory cytopenia with multilineage dysplasia (37 of 50 cases, 74 %). However, the categories with unilineage dysplasia were not reproducible in most of the cases. The rate of concordance with refractory cytopenia with unilineage dysplasia was 40 % (two of five cases) and 25 % with RA with ring sideroblasts (two of eight). Our results show that the 2008 WHO classification gives a more accurate stratification of MDS but also illustrates the difficulty in diagnosing MDS with unilineage dysplasia.

Detecting significant change in stream benthic macroinvertebrate communities in wilderness areas

USGS Publications Warehouse

Milner, Alexander M.; Woodward, Andrea; Freilich, Jerome E.; Black, Robert W.; Resh, Vincent H.

2016-01-01

Within a region, both MDS analyses typically identified similar years as exceeding reference condition variation, illustrating the utility of the approach for identifying wider spatial scale effects that influence more than one stream. MDS responded to both simulated water temperature stress and a pollutant event, and generally outlying years on MDS plots could be explained by environmental variables, particularly higher precipitation. Multivariate control charts successfully identified whether shifts in community structure identified by MDS were significant and whether the shift represented a press disturbance (long-term change) or a pulse disturbance. We consider a combination of TD and MDS with control charts to be a potentially powerful tool for determining years significantly outside of a reference condition variation.

Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism

PubMed Central

Rotin, Lianne E.; Gronda, Marcela; MacLean, Neil; Hurren, Rose; Wang, XiaoMing; Lin, Feng-Hsu; Wrana, Jeff; Datti, Alessandro; Barber, Dwayne L.; Minden, Mark D.; Slassi, Malik; Schimmer, Aaron D.

2016-01-01

Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease. PMID:26624983

Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia.

PubMed

Narayan, N; Morenos, L; Phipson, B; Willis, S N; Brumatti, G; Eggers, S; Lalaoui, N; Brown, L M; Kosasih, H J; Bartolo, R C; Zhou, L; Catchpoole, D; Saffery, R; Oshlack, A; Goodall, G J; Ekert, P G

2017-04-01

Enforced expression of microRNA-155 (miR-155) in myeloid cells has been shown to have both oncogenic or tumour-suppressor functions in acute myeloid leukaemia (AML). We sought to resolve these contrasting effects of miR-155 overexpression using murine models of AML and human paediatric AML data sets. We show that the highest miR-155 expression levels inhibited proliferation in murine AML models. Over time, enforced miR-155 expression in AML in vitro and in vivo, however, favours selection of intermediate miR-155 expression levels that results in increased tumour burden in mice, without accelerating the onset of disease. Strikingly, we show that intermediate and high miR-155 expression also regulate very different subsets of miR-155 targets and have contrasting downstream effects on the transcriptional environments of AML cells, including genes involved in haematopoiesis and leukaemia. Furthermore, we show that elevated miR-155 expression detected in paediatric AML correlates with intermediate and not high miR-155 expression identified in our experimental models. These findings collectively describe a novel dose-dependent role for miR-155 in the regulation of AML, which may have important therapeutic implications.

Small Molecule Inhibition of cAMP Response Element Binding Protein in Human Acute Myeloid Leukemia Cells

PubMed Central

Mitton, Bryan; Chae, Hee-Don; Hsu, Katie; Dutta, Ritika; Aldana-Masangkay, Grace; Ferrari, Roberto; Davis, Kara; Tiu, Bruce C.; Kaul, Arya; Lacayo, Norman; Dahl, Gary; Xie, Fuchun; Li, Bingbing X.; Breese, Marcus R.; Landaw, Elliot M.; Nolan, Garry; Pellegrini, Matteo; Romanov, Sergei; Xiao, Xiangshu; Sakamoto, Kathleen M.

2016-01-01

The transcription factor CREB (cAMP Response Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro. In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML. To test this concept, a small molecule inhibitor of CREB, XX-650-23, was developed. This molecule blocks a critical interaction between CREB and its required co-activator CBP (CREB Binding Protein), leading to disruption of CREB-driven gene expression. Inhibition of CBP-CREB interaction induced apoptosis and cell cycle arrest in AML cells, and prolonged survival in vivo in mice injected with human AML cells. XX-650-23 had little toxicity on normal human hematopoietic cells and tissues in mice. To understand the mechanism of XX-650-23, we performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells. Our results demonstrate that small molecule inhibition of CBP-CREB interaction mostly affects apoptotic, cell cycle, and survival pathways, which may represent a novel approach for AML therapy. PMID:27211267

Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism.

PubMed

Rotin, Lianne E; Gronda, Marcela; MacLean, Neil; Hurren, Rose; Wang, XiaoMing; Lin, Feng-Hsu; Wrana, Jeff; Datti, Alessandro; Barber, Dwayne L; Minden, Mark D; Slassi, Malik; Schimmer, Aaron D

2016-01-19

Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease.

Impaired health-related quality of life in acute myeloid leukemia survivors: a single-center study.

PubMed

Leunis, Annemieke; Redekop, William K; Uyl-de Groot, Carin A; Löwenberg, Bob

2014-09-01

The purpose of this study was to assess the impact of acute myeloid leukemia (AML) and its treatment on health-related quality of life (HRQOL) by comparing the HRQOL of AML survivors with the HRQOL in the general population. Two HRQOL questionnaires (EQ-5D and QLQ-C30) were sent to patients diagnosed with AML between 1999 and 2011 at a single academic hospital and still alive in 2012. HRQOL in AML survivors was compared with general population reference values. Multivariate analysis was used to identify factors associated with HRQOL in AML survivors. Questionnaires were returned by 92 of the 103 patients (89%). AML survivors reported significantly worse functioning, more fatigue, pain, dyspnea, appetite loss, and financial difficulties and lower EQ-VAS scores than the general population (P < 0.05). Impaired HRQOL in AML survivors was mainly found in survivors without a paid job. Other factors associated with a poor HRQOL were allogeneic hematopoietic stem cell transplantation and the absence of social support. This single-center study showed that the HRQOL in AML survivors is worse than the HRQOL in the general population. HRQOL in these patients can be improved by adequately treating and preventing fatigue, pain, dyspnea, and appetite loss. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML.

PubMed

Wong, Terrence N; Miller, Christopher A; Klco, Jeffery M; Petti, Allegra; Demeter, Ryan; Helton, Nichole M; Li, Tiandao; Fulton, Robert S; Heath, Sharon E; Mardis, Elaine R; Westervelt, Peter; DiPersio, John F; Walter, Matthew J; Welch, John S; Graubert, Timothy A; Wilson, Richard K; Ley, Timothy J; Link, Daniel C

2016-02-18

There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population. Here, we report that 5 of 15 patients with genetic clearance of their founding AML clone after induction chemotherapy had a concomitant expansion of a hematopoietic population unrelated to the initial AML. These populations frequently harbored somatic mutations in genes recurrently mutated in AML or myelodysplastic syndromes and were detectable at very low frequencies at the time of AML diagnosis. These results suggest that nonleukemic hematopoietic stem and progenitor cells, harboring specific aging-acquired mutations, may have a competitive fitness advantage after induction chemotherapy, expand, and persist long after the completion of chemotherapy. Although the clinical importance of these "rising" clones remains to be determined, it will be important to distinguish them from leukemia-related populations when assessing for molecular responses to induction chemotherapy. © 2016 by The American Society of Hematology.

Proteogenomics approaches for studying cancer biology and their potential in the identification of acute myeloid leukemia biomarkers.

PubMed

Hernandez-Valladares, Maria; Vaudel, Marc; Selheim, Frode; Berven, Frode; Bruserud, Øystein

2017-08-01

Mass spectrometry (MS)-based proteomics has become an indispensable tool for the characterization of the proteome and its post-translational modifications (PTM). In addition to standard protein sequence databases, proteogenomics strategies search the spectral data against the theoretical spectra obtained from customized protein sequence databases. Up to date, there are no published proteogenomics studies on acute myeloid leukemia (AML) samples. Areas covered: Proteogenomics involves the understanding of genomic and proteomic data. The intersection of both datatypes requires advanced bioinformatics skills. A standard proteogenomics workflow that could be used for the study of AML samples is described. The generation of customized protein sequence databases as well as bioinformatics tools and pipelines commonly used in proteogenomics are discussed in detail. Expert commentary: Drawing on evidence from recent cancer proteogenomics studies and taking into account the public availability of AML genomic data, the interpretation of present and future MS-based AML proteomic data using AML-specific protein sequence databases could discover new biological mechanisms and targets in AML. However, proteogenomics workflows including bioinformatics guidelines can be challenging for the wide AML research community. It is expected that further automation and simplification of the bioinformatics procedures might attract AML investigators to adopt the proteogenomics strategy.

[Two Kinds of HLA-mismatched Allogeneic Hematopoictic Stem Cell Transplantation for Treatment of Hematologic Malignancies].

PubMed

Li, Wei-Da; Gao, Zhi-Yong; Yu, Xin-Jian; Lu, Da-Yu; Lu, Dao-Pei

2016-04-01

To investigate the safety and effectiveness of HLA-mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with related haploidentical bone marrow infusion for treatment of hematologic malignancies and to explore the mathod for reduction of aGVHD incidence and clinical significance. A total of 30 patients with hematologic malignancies (8 cases of AML, 17 AML, 2 MDS and 3 Mix-AL) received related haploidentical and unrelated HLA-mismatched allo-HSCT combined with related haploidentical bone marrow infusion. Among them 20 cases received related haploidentical transplantation of the first donor, 10 cases received unrelated HLA-mismatched treaplantation. The new conditioning regimen for the patients underwent allo-HSCT consisted of fludarabine, busulfan, Me-CCNU and cyclophosphamide. The drugs for GVHD prophylaxis included cyclosporine A and methotrexate, while mycophenolate mofetil and rabbit anti-T-lymphocyte globulin (ATG) were used. All the patients achieved full engraftment. The median time for neutrophils to reach over 0.5 × 10(9)/L was 14 days (8-26 days), while the median time for platelets to reach over 20 × 10(9)/L was 11.5days (10-24 days). The incidence of I-II grade of aGVHD at 100 d was 22.28% (95% CI 9.9%-34.7%), the incidences of II-IV and III-IV grade of aGVHD were 22.7% (95% CI, 10%-35.4%) and 12.7% (95% CI 6.9%-15.5%) respectively. The incidences of I-II and III-IV cGVHD were 13.3% (95% CI, 1.4%- 26.8%) and 3.3 % (95% CI, 0%-12.2%), one case (3.3%) was in extensive cGVHD. DFS and OS of 2 years were 81.1% (95% CI, 66.0%-96.2%) and 68.2% (95% CI 51.0%-85.4%). These data suggest that the incidence of grade II-IV grade of aGVHD in recipients of 2 partially HLA-matched units was lower, co-infusion of haplo-BM and partially matched units in allogeneic transplantation is safe and effective for reducing the incidence of aGVHD and improving the survival in DFS.

Physician's assistants in primary care practices: delegation of tasks and physician supervision.

PubMed

Ekwo, E; Dusdieker, L B; Fethke, C; Daniels, M

1979-01-01

Little information is available on factors influencing physicians (MDs) to delegate health care tasks to physician's assistants (PAs). Information about assignment of tasks to PAs was sought from 19 MDs engaged in practice in primary care settings in Iowa. These MDs employed 28 PAs. Tasks assigned to PAs appeared to be those that MDs judged to require little or no supervision. Tasks that could be performed efficiently by other non-MD personnel were not asigned to PAs. However, PAs were observed at the practice sites to perform tasks which the MDs had indicated could be appropriately assigned to PAs, as well as some tasks that could be performed by other non-MD personnel. The MDs provided health care to 126 (13.6 percent) of the 925 patients seen by PAs for whom the sequences of patient-provider contact were recorded. In these settings, the PAs functioned with a high degree of autonomy in providing health care. These findings have implications for educators and potential employers of PAs.

Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation?

PubMed

Zeidan, Amer M; Gore, Steven D

2013-10-01

Myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies characterized by dysplastic changes, ineffective hematopoiesis and variable risk of leukemic progression. At diagnosis, 86% of MDS patients are ≥60 years. Azacitidine, the only drug that prolongs life in high-risk (HR)-MDS patients, adds a median of only 9.5 months to life. Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative approach. Despite recent improvements including use of reduced intensity conditioning (RIC) that decrease transplant-related mortality, alloSCT continues to be used rarely in elderly MDS. There is paucity of data regarding outcomes of RIC alloSCT in elderly MDS patients, especially in direct comparison with azanucleosides. In this paper, the authors discuss the recent Markov decision analysis by Koreth et al. in which investigators demonstrated superior survival of patients with HR-MDS aged 60-70 years who underwent RIC alloSCT in comparison with those who were treated with azanucleosides.

Acute myeloid leukemia (AML) - children

MedlinePlus

Acute myeloid leukemia is a cancer of the blood and bone marrow. Bone marrow is the soft tissue inside ... develops quickly. Both adults and children can get acute myeloid leukemia ( AML ). This article is about AML in children.

DNA methylation and targeted sequencing of methyltransferases family genes in canine acute myeloid leukaemia, modelling human myeloid leukaemia.

PubMed

Bronzini, I; Aresu, L; Paganin, M; Marchioretto, L; Comazzi, S; Cian, F; Riondato, F; Marconato, L; Martini, V; Te Kronnie, G

2017-09-01

Tumours shows aberrant DNA methylation patterns, being hypermethylated or hypomethylated compared with normal tissues. In human acute myeloid leukaemia (hAML) mutations in DNA methyltransferase (DNMT3A) are associated to a more aggressive tumour behaviour. As AML is lethal in dogs, we defined global DNA methylation content, and screened the C-terminal domain of DNMT3 family of genes for sequence variants in 39 canine acute myeloid leukaemia (cAML) cases. A heterogeneous pattern of DNA methylation was found among cAML samples, with subsets of cases being hypermethylated or hypomethylated compared with healthy controls; four recurrent single nucleotide variations (SNVs) were found in DNMT3L gene. Although SNVs were not directly correlated to whole genome DNA methylation levels, all hypomethylated cAML cases were homozygous for the deleterious mutation at p.Arg222Trp. This study contributes to understand genetic modifications of cAML, leading up to studies that will elucidate the role of methylome alterations in the pathogenesis of AML in dogs. © 2016 John Wiley & Sons Ltd.

Novel agents in acute myeloid leukemia.

PubMed

Ungewickell, Alexander; Medeiros, Bruno C

2012-08-01

Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, long-term survivors represent only 10-15 % of all AML patients older than 60 years of age and <10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

Study of the S427G polymorphism and of MYBL2 variants in patients with acute myeloid leukemia.

PubMed

Dolz, Sandra; García, Paloma; Llop, Marta; Fuster, Óscar; Luna, Irene; Ibáñez, Mariam; Gómez, Inés; López, María; Such, Esperanza; Cervera, José; Sanz, Miguel A; De Juan, Inmaculada; Palanca, Sarai; Murria, Rosa; Bolufer, Pascual; Barragán, Eva

2015-06-19

Dysregulation of MYBL2 has been associated to tumorigenesis and the S427G polymorphism could induce partial inactivation of MYBL2, associating it with cancer risk. It has previously been shown that MYBL2 was over-expressed in some acute myeloid leukemias (AML), portending poor prognosis. However, to date no studies have investigated the S427G or other genetic variants of MYBL2 in AML. This study analyzed the S427G in 197 AML patients and 179 controls and screened the MYBL2 sequence in patients. In contrast to other studies in solid tumors, the S427G was not associated with the incidence of AML. This study detected four unannotated genetic alterations, of which the Q67X could be involved in MYBL2 dysfunction. Eight polymorphisms were identified, among which the rs73116571, located in a splicing region, was associated with higher incidence in AML and weaker MYBL2 expression, suggesting pre-disposition to AML. Additional functional studies should be performed to verify these genetic variations as possible targets in AML.

Proteasome inhibition enhances the efficacy of volasertib-induced mitotic arrest in AML in vitro and prolongs survival in vivo.

PubMed

Schnerch, Dominik; Schüler, Julia; Follo, Marie; Felthaus, Julia; Wider, Dagmar; Klingner, Kathrin; Greil, Christine; Duyster, Justus; Engelhardt, Monika; Wäsch, Ralph

2017-03-28

Elderly and frail patients, diagnosed with acute myeloid leukemia (AML) and ineligible to undergo intensive treatment, have a dismal prognosis. The small molecule inhibitor volasertib induces a mitotic block via inhibition of polo-like kinase 1 and has shown remarkable anti-leukemic activity when combined with low-dose cytarabine. We have demonstrated that AML cells are highly vulnerable to cell death in mitosis yet manage to escape a mitotic block through mitotic slippage by sustained proteasome-dependent slow degradation of cyclin B. Therefore, we tested whether interfering with mitotic slippage through proteasome inhibition arrests and kills AML cells more efficiently during mitosis. We show that therapeutic doses of bortezomib block the slow degradation of cyclin B during a volasertib-induced mitotic arrest in AML cell lines and patient-derived primary AML cells. In a xenotransplant mouse model of human AML, mice receiving volasertib in combination with bortezomib showed superior disease control compared to mice receiving volasertib alone, highlighting the potential therapeutic impact of this drug combination.

Expression of microRNA-181 determines response to treatment with azacitidine and predicts survival in elderly patients with acute myeloid leukaemia.

PubMed

Butrym, Aleksandra; Rybka, Justyna; Baczyńska, Dagmara; Poręba, Rafał; Mazur, Grzegorz; Kuliczkowski, Kazimierz

2016-10-01

MicroRNAs (miRs) are small non-coding RNAs that play important roles in cell differentiation and survival. Abnormal expression of miRs has been demonstrated in numerous types of cancer, including acute myeloid leukaemia (AML). The aim of the present study was to evaluate miR-181 expression at diagnosis and following the completion of chemotherapy in AML patients, with regard to clinical response and outcome, particularly in patients treated with azacitidine. miR-181 expression was analysed using reverse transcription-quantitative polymerase chain reaction in 95 bone marrow specimens from newly diagnosed AML patients and in 20 healthy subjects for comparison. The results revealed upregulated miR-181 expression in the total cohort of AML patients, which was correlated with longer survival. However, in a subset of older AML patients treated with azacitidine, low miR-181 expression at diagnosis was a predictor for complete remission and prolonged survival. The findings indicated that miR-181 has an important role in AML and determines response to azacitidine treatment in older AML patients.

Expression of microRNA-181 determines response to treatment with azacitidine and predicts survival in elderly patients with acute myeloid leukaemia

PubMed Central

Butrym, Aleksandra; Rybka, Justyna; Baczyńska, Dagmara; Poręba, Rafał; Mazur, Grzegorz; Kuliczkowski, Kazimierz

2016-01-01

MicroRNAs (miRs) are small non-coding RNAs that play important roles in cell differentiation and survival. Abnormal expression of miRs has been demonstrated in numerous types of cancer, including acute myeloid leukaemia (AML). The aim of the present study was to evaluate miR-181 expression at diagnosis and following the completion of chemotherapy in AML patients, with regard to clinical response and outcome, particularly in patients treated with azacitidine. miR-181 expression was analysed using reverse transcription-quantitative polymerase chain reaction in 95 bone marrow specimens from newly diagnosed AML patients and in 20 healthy subjects for comparison. The results revealed upregulated miR-181 expression in the total cohort of AML patients, which was correlated with longer survival. However, in a subset of older AML patients treated with azacitidine, low miR-181 expression at diagnosis was a predictor for complete remission and prolonged survival. The findings indicated that miR-181 has an important role in AML and determines response to azacitidine treatment in older AML patients. PMID:27698792

Age and comorbidities deeply impact on clinical outcome of patients with myelodysplastic syndromes.

PubMed

Balleari, E; Salvetti, C; Del Corso, L; Filiberti, R; Bacigalupo, A; Bellodi, A; Beltrami, G; Bergamaschi, M; Berisso, G; Calzamiglia, T; Carella, A M; Cavalleri, M; Da Col, A; Favorini, S; Forni, G L; Goretti, R; Miglino, M; Mitscheuning, L; Molinari, E; Racchi, O; Scudeletti, M; Tassara, R; Gobbi, M; Lemoli, R; Clavio, M

2015-08-01

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders, with very different prognosis in given individuals; age and comorbidities are emerging as relevant patient-related factors influencing clinical outcome in MDS. Our aim was to evaluate the impact of age, comorbidities and disease severity (IPSS and IPSS-R prognostic scores) in a "real-life" series of MDS patients. 318 patients with available assessment of comorbidities at diagnosis and consecutively registered into the Registro Ligure delle Mielodisplasie were analyzed. Comorbidities were evaluated according to HCT-CI and MDS-CI comorbidity indexes. Overall survival (OS) and the probability of death among patients who did not develop acute myeloid leukemia (NLD cumulative incidence) were analyzed. Comorbidities were seen in 177 (55.7%) patients. An older age (>75 y) had a significant negative impact on OS (p=0.008). HCT-CI was not associated with OS. MDS-CI was of prognostic significance (p=0.001), but the association was limited to pts with IPSS or IPSS-R "lower-risk". In multivariate analysis, MDS-CI remained an independent factor associated with OS and with an increased risk of NLD both when controlling for IPSS (p=0.019 and p=0.001, respectively) and for IPSS-R (p=0.048 and p=0.002, respectively). Evaluation of age and comorbidities according to a tailored tool such is MDS-CI helps to predict survival in patients with MDS and should be incorporated to current prognostic scores. Copyright © 2015 Elsevier Ltd. All rights reserved.

Azelaic Acid Exerts Antileukemic Activity in Acute Myeloid Leukemia

PubMed Central

Pan, Yunbao; Liu, Dong; Wei, Yongchang; Su, Dan; Lu, Chenyang; Hu, Yanchao; Zhou, Fuling

2017-01-01

Acute myeloid leukemia (AML) is an acute leukemia common in most adults; its prevalence intensifies with age. The overall survival of AML is very poor because of therapeutic resistance. Azelaic acid (AZA) is non-toxic, non-teratogenic, and non-mutagenic and its antitumor effect on various tumor cells is well established; Nonetheless, its therapeutic effects in AML cells are largely unknown. In this study, it was shown that AZA significantly inhibits the cell viability and induces apoptosis in AML cells in a dose-dependent manner. Additionally, AZA suppressed the expression of phosphorylated Akt, Jab1 and Trx, and this suppression was enhanced by treatment with Jab1 siRNA. Furthermore, AZA sensitized AML cells to Ara-c chemotherapy. The suppressive effect of AZA on tumor growth was examined in vivo by subcutaneously inoculated AML cells in a tumor model using nude mice. These findings indicate that AZA is useful as an effective ingredient in antineoplastic activity. PMID:28659796

Azelaic Acid Exerts Antileukemic Activity in Acute Myeloid Leukemia.

PubMed

Pan, Yunbao; Liu, Dong; Wei, Yongchang; Su, Dan; Lu, Chenyang; Hu, Yanchao; Zhou, Fuling

2017-01-01

Acute myeloid leukemia (AML) is an acute leukemia common in most adults; its prevalence intensifies with age. The overall survival of AML is very poor because of therapeutic resistance. Azelaic acid (AZA) is non-toxic, non-teratogenic, and non-mutagenic and its antitumor effect on various tumor cells is well established; Nonetheless, its therapeutic effects in AML cells are largely unknown. In this study, it was shown that AZA significantly inhibits the cell viability and induces apoptosis in AML cells in a dose-dependent manner. Additionally, AZA suppressed the expression of phosphorylated Akt, Jab1 and Trx, and this suppression was enhanced by treatment with Jab1 siRNA. Furthermore, AZA sensitized AML cells to Ara-c chemotherapy. The suppressive effect of AZA on tumor growth was examined in vivo by subcutaneously inoculated AML cells in a tumor model using nude mice. These findings indicate that AZA is useful as an effective ingredient in antineoplastic activity.

[Detection of heterogeneity and evolution of subclones in t(8;21) AML by QM-FISH].

PubMed

Wang, Ying-chan; Hu, Lin-ping; Lin, Dong; Li, Cheng-wen; Yuan, Tian; Jia, Yu-jiao; Tian, Zheng; Tang, Ke-jing; Wang, Min; Wang, Jian-xiang

2013-10-01

To explore the heterogeneous subclones in acute myeloid leukemia (AML) with t(8;21) by quantitative multicolor- fluorescence in situ hybridization (QM-FISH), and to figure out whether there is putative ancestral relationship among different subclones. Bacterial artificial chromosomes (BAC) clones that contain the targeted genes including AML1, ETO, WT1, p27 and c-kit were searched in the data base UCSC Genome Bioinformatics. Multicolor FISH probes were prepared by linking fluorescein labeled dUTP or dCTP to targeted genes by nick translation. Bone marrow mononuclear cells from t (8;21) AML patients are dropped on to the wet surface of glass slides after hypotonic treatment and fixation. After hybridization, the fluorescence signals were captured by Zeiss fluorescence microscope. The copy number of AML1, ETO, WT1, p27, c- kit and the AML1-ETO fusion gene in AML1-ETO positive cells was counted. The cells with same signals were defined as a subclone. Various subclones were recorded and their proportions were calculated, and their evolutionary relationship was deduced. The subclones in matched primary and relapsed samples were compared, the evolution of dominant clones were figured out and the genomic abnormality that is associated with relapse and drug resistance were speculated. In this study, 36 primary AML with t(8;21) cases and 1 relapsed case paired with the primary case were detected. In these 36 primary cases, 4 cases (11.1%) acquired additional AML1-ETO fusion signal, 3(8.3%) had additional AML1 signal, 4(11.1%) had additional ETO signal, 20(55.6%) had additional WT1 signal, 15(41.7%) had additional p27 signal and 14(38.9%) had additional c-kit signal. In addition, 10(27.8%) displayed AML1 signal deletion, and such an aberration represents statistic significance in male patients. It seems that male patients usually accompany AML1 signal deletion. Of 36 cases, 28(77.8 %) harbored at least 2 subclones (ranged from 2 to 10). According to the genetic signature of subclones, we can assemble a putative ancestral tree, and the genetic architecture is linear or branching. In particular, the clonal architecture of the relapsed sample exhibited significant clonal evolution compared to its paired sample at diagnosis, including proportion changes in dominant clone, subclone disappearance and appearance of new dominant clones. Genomic abnormality is very diverse in t(8;21) AML. Subclones have linear or complex branching evolutionary histories, and clonal architecture is dynamic.

[Renal angiomyolipomas without fat component: tomodensitometric and histologic characteristics, clinical course].

PubMed

Negre, T; Faure, A; Andre, M; Daniel, L; Coulange, C; Lechevallier, E

2011-11-01

Angiomyolipoma is the most frequent benign renal solid tumor. Because of the lack of fat component on the CT scan, diagnosis of this tumor is hard and can require percutaneous biopsy of unknown renal tumor. The follow-up of the poor fat CT scan component AML (PFCT AML) is uncertain. Five hundred percutaneous renal biopsy under tomodenstitometry have been realised between 1998 and 2008. There was 41 PFCT AML on the 500 biopsy. By definition, a PFCT AML is an AML where the diagnosis is done on a percutaneous biopsy but where there was no fat component on the first CT scan. We studied and compared clinical, tomodensitometric and histologic parameters of these 41 patients (mean age: 56, 9±11.04; sexe rate M/F: 6/35) where renal AML was diagnosed on percutaneous renal biopsy but without fat component on CT scan. Average size was 26.44±14.68mm. We phone-called 16 patients for the long-term follow-up. Average follow-up was 41±28.3 months. For four patients on 16, initial diagnosis was done in front of local symptoms, for one of the 16 diagnosis was done in front of general symptoms, for one of the diagnosis was done during Bourneville tuberous sclerosis evolution and 10 of the 16 was done fortuitously. After review of the initial CT scan, fat density was found on 24% of them. Ten percent was epithelioid angiomyolipoma. Four renal biopsy on 41 (10%) was epithelioid AML. No epithelioid AML had fat component after the second look of the CT scan. Among the 16 patients who were phone-called, three (19%) underwent a complication. Two had abdominal pain and was treated medically. Initial sizes were 26 and 30mm. Only one patient must be operated by radical nephrectomy for acute hemorrhage. Initial size was 45mm. No neoplasic degeneration was identified for those 16 patients. In our study, the PFCT AML rate was 8.2%. In 25% cases, CT scan read-through shown a fat component and could help for the diagnosis. PFCT AML evolution seems to be the same as a classic AML. Conservative treatment had a good covering because there was no death and no malignant evolution. However, we found 10% of epithelioid angiomyolipoma in which malignant risk is high. PFCT AML diagnosed on renal percutaneous biopsy of unknown renal tumor requires the same management than the classic AML. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Direct and indirect targeting of MYC to treat acute myeloid leukemia.

PubMed

Brondfield, Sam; Umesh, Sushma; Corella, Alexandra; Zuber, Johannes; Rappaport, Amy R; Gaillard, Coline; Lowe, Scott W; Goga, Andrei; Kogan, Scott C

2015-07-01

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is often resistant to conventional therapies. The MYC oncogene is commonly overexpressed in AML but has remained an elusive target. We aimed to examine the consequences of targeting MYC both directly and indirectly in AML overexpressing MYC/Myc due to trisomy 8/15 (human/mouse), FLT3-ITD mutation, or gene amplification. We performed in vivo knockdown of Myc (shRNAs) and both in vitro and in vivo experiments using four drugs with indirect anti-MYC activity: VX-680, GDC-0941, artemisinin, and JQ1. shRNA knockdown of Myc in mice prolonged survival, regardless of the mechanism underlying MYC overexpression. VX-680, an aurora kinase inhibitor, demonstrated in vitro efficacy against human MYC-overexpressing AMLs regardless of the mechanism of MYC overexpression, but was weakest against a MYC-amplified cell line. GDC-0941, a PI3-kinase inhibitor, demonstrated efficacy against several MYC-overexpressing AMLs, although only in vitro. Artemisinin, an antimalarial, did not demonstrate consistent efficacy against any of the human AMLs tested. JQ1, a bromodomain and extra-terminal bromodomain inhibitor, demonstrated both in vitro and in vivo efficacy against several MYC-overexpressing AMLs. We also confirmed a decrease in MYC levels at growth inhibitory doses for JQ1, and importantly, sensitivity of AML cell lines to JQ1 appeared independent of the mechanism of MYC overexpression. Our data support growing evidence that JQ1 and related compounds may have clinical efficacy in AML treatment regardless of the genetic abnormalities underlying MYC deregulation.

Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult acute myeloid leukaemia.

PubMed

Khan, N; Hills, R K; Virgo, P; Couzens, S; Clark, N; Gilkes, A; Richardson, P; Knapper, S; Grimwade, D; Russell, N H; Burnett, A K; Freeman, S D

2017-05-01

It remains unclear in adult acute myeloid leukaemia (AML) whether leukaemic expression of CD33, the target antigen for gemtuzumab ozogamicin (GO), adds prognostic information on GO effectiveness at different doses. CD33 expression quantified in 1583 patients recruited to UK-NCRI-AML17 (younger adults) and UK-NCRI-AML16 (older adults) trials was correlated with clinical outcomes and benefit from GO including a dose randomisation. CD33 expression associated with genetic subgroups, including lower levels in both adverse karyotype and core-binding factor (CBF)-AML, but was not independently prognostic. When comparing GO versus no GO (n=393, CBF-AMLs excluded) by stratified subgroup-adjusted analysis, patients with lowest quartile (Q1) %CD33-positivity had no benefit from GO (relapse risk, HR 2.41 (1.27-4.56), P=0.009 for trend; overall survival, HR 1.52 (0.92-2.52)). However, from the dose randomisation (NCRI-AML17, n=464, CBF-AMLs included), 6 mg/m 2 GO only had a relapse benefit without increased early mortality in CD33-low (Q1) patients (relapse risk HR 0.64 (0.36-1.12) versus 1.70 (0.99-2.92) for CD33-high, P=0.007 for trend). Thus CD33 expression is a predictive factor for GO effect in adult AML; although GO does not appear to benefit the non-CBF AML patients with lowest CD33 expression a higher GO dose may be more effective for CD33-low but not CD33-high younger adults.

Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia.

PubMed

Müller-Tidow, Carsten; Klein, Hans-Ulrich; Hascher, Antje; Isken, Fabienne; Tickenbrock, Lara; Thoennissen, Nils; Agrawal-Singh, Shuchi; Tschanter, Petra; Disselhoff, Christine; Wang, Yipeng; Becker, Anke; Thiede, Christian; Ehninger, Gerhard; zur Stadt, Udo; Koschmieder, Steffen; Seidl, Matthias; Müller, Frank U; Schmitz, Wilhelm; Schlenke, Peter; McClelland, Michael; Berdel, Wolfgang E; Dugas, Martin; Serve, Hubert

2010-11-04

Acute myeloid leukemia (AML) is commonly associated with alterations in transcription factors because of altered expression or gene mutations. These changes might induce leukemia-specific patterns of histone modifications. We used chromatin-immunoprecipitation on microarray to analyze histone 3 lysine 9 trimethylation (H3K9me3) patterns in primary AML (n = 108), acute lymphoid leukemia (n = 28), CD34(+) cells (n = 21) and white blood cells (n = 15) specimens. Hundreds of promoter regions in AML showed significant alterations in H3K9me3 levels. H3K9me3 deregulation in AML occurred preferentially as a decrease in H3K9me3 levels at core promoter regions. The altered genomic regions showed an overrepresentation of cis-binding sites for ETS and cyclic adenosine monophosphate response elements (CREs) for transcription factors of the CREB/CREM/ATF1 family. The decrease in H3K9me3 levels at CREs was associated with increased CRE-driven promoter activity in AML blasts in vivo. AML-specific H3K9me3 patterns were not associated with known cytogenetic abnormalities. But a signature derived from H3K9me3 patterns predicted event-free survival in AML patients. When the H3K9me3 signature was combined with established clinical prognostic markers, it outperformed prognosis prediction based on clinical parameters alone. These findings demonstrate widespread changes of H3K9me3 levels at gene promoters in AML. Signatures of histone modification patterns are associated with patient prognosis in AML.

p53−/− synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia

PubMed Central

Kong, Guangyao; Rajagopalan, Adhithi; Lu, Li; Song, Jingming; Hussaini, Mohamed; Zhang, Xinmin; Ranheim, Erik A.; Liu, Yangang; Wang, Jinyong; Gao, Xin; Chang, Yuan-I; Johnson, Kirby D.; Zhou, Yun; Yang, David; Bhatnagar, Bhavana; Lucas, David M.; Bresnick, Emery H.; Zhong, Xuehua; Padron, Eric

2017-01-01

Somatic mutations in TP53 and NRAS are associated with transformation of human chronic myeloid diseases to acute myeloid leukemia (AML). Here, we report that concurrent RAS pathway and TP53 mutations are identified in a subset of AML patients and confer an inferior overall survival. To further investigate the genetic interaction between p53 loss and endogenous NrasG12D/+ in AML, we generated conditional NrasG12D/+p53−/− mice. Consistent with the clinical data, recipient mice transplanted with NrasG12D/+p53−/− bone marrow cells rapidly develop a highly penetrant AML. We find that p53−/− cooperates with NrasG12D/+ to promote increased quiescence in megakaryocyte-erythroid progenitors (MEPs). NrasG12D/+p53−/− MEPs are transformed to self-renewing AML-initiating cells and are capable of inducing AML in serially transplanted recipients. RNA sequencing analysis revealed that transformed MEPs gain a partial hematopoietic stem cell signature and largely retain an MEP signature. Their distinct transcriptomes suggests a potential regulation by p53 loss. In addition, we show that during AML development, transformed MEPs acquire overexpression of oncogenic Nras, leading to hyperactivation of ERK1/2 signaling. Our results demonstrate that p53−/− synergizes with enhanced oncogenic Nras signaling to transform MEPs and drive AML development. This model may serve as a platform to test candidate therapeutics in this aggressive subset of AML. PMID:27815262

Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors*

PubMed Central

Altman, Jessica K.; Sassano, Antonella; Kaur, Surinder; Glaser, Heather; Kroczynska, Barbara; Redig, Amanda J.; Russo, Suzanne; Barr, Sharon; Platanias, Leonidas C.

2011-01-01

Purpose To determine whether mTORC2 and RI-mTORC1 complexes are present in AML cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors. Experimental Design Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor colony formation. Results mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. Rapamycin insensitive (RI) mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027, blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro. Conclusions Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin. PMID:21415215

lncRNA co-expression network model for the prognostic analysis of acute myeloid leukemia

PubMed Central

Pan, Jia-Qi; Zhang, Yan-Qing; Wang, Jing-Hua; Xu, Ping; Wang, Wei

2017-01-01

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy with great variability of prognostic behaviors. Previous studies have reported that long non-coding RNAs (lncRNAs) play an important role in AML and may thus be used as potential prognostic biomarkers. However, thus use of lncRNAs as prognostic biomarkers in AML and their detailed mechanisms of action in this disease have not yet been well characterized. For this purpose, in the present study, the expression levels of lncRNAs and mRNAs were calculated using the RNA-seq V2 data for AML, following which a lncRNA-lncRNA co-expression network (LLCN) was constructed. This revealed a total of 8 AML prognosis-related lncRNA modules were identified, which displayed a significant correlation with patient survival (p≤0.05). Subsequently, a prognosis-related lncRNA module pathway network was constructed to interpret the functional mechanism of the prognostic modules in AML. The results indicated that these prognostic modules were involved in the AML pathway, chemokine signaling pathway and WNT signaling pathway, all of which play important roles in AML. Furthermore, the investigation of lncRNAs in these prognostic modules suggested that an lncRNA (ZNF571-AS1) may be involved in AML via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway by regulating KIT and STAT5. The results of the present study not only provide potential lncRNA modules as prognostic biomarkers, but also provide further insight into the molecular mechanisms of action of lncRNAs. PMID:28204819

Using Multidimensional Scaling To Assess the Dimensionality of Dichotomous Item Data.

ERIC Educational Resources Information Center

Meara, Kevin; Robin, Frederic; Sireci, Stephen G.

2000-01-01

Investigated the usefulness of multidimensional scaling (MDS) for assessing the dimensionality of dichotomous test data. Focused on two MDS proximity measures, one based on the PC statistic (T. Chen and M. Davidson, 1996) and other, on interitem Euclidean distances. Simulation results show that both MDS procedures correctly identify…

75 FR 5796 - Danaher Corporation and MDS, Inc.; Analysis of Agreement Containing Consent Orders to Aid Public...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-04

..., Ontario, MDS is a life sciences company that operates three core businesses, MDS Analytical Technologies... life sciences company that manufactures and sells scientific research equipment that it distributes... devices and associated reagent products, to Life Technologies Corp. (``Life Technologies'') within 10 days...

Regulation and Function of TIFAB in Myelodysplastic Syndrome

DTIC Science & Technology

2013-06-01

genomic alteration in MDS is deletion of chromosome 5q (del(5q)). MDS patients with an isolated del(5q) presenting with anemia, neutropenia , and...is deletion of chromosome 5q (del(5q)). MDS patients with an isolated del(5q) presenting with anemia, neutropenia , and elevated platelets associated

MDS MIC Catalog Inputs

NASA Technical Reports Server (NTRS)

Johnson-Throop, Kathy A.; Vowell, C. W.; Smith, Byron; Darcy, Jeannette

2006-01-01

This viewgraph presentation reviews the inputs to the MDS Medical Information Communique (MIC) catalog. The purpose of the group is to provide input for updating the MDS MIC Catalog and to request that MMOP assign Action Item to other working groups and FSs to support the MITWG Process for developing MIC-DDs.

Decision points in the treatment of transfusional iron overload in patients with myelodysplastic syndromes: why, when, and how to chelate.

PubMed

Imran, Farhan; Phatak, Pradyumna

2017-01-01

Patients with myelodysplastic syndromes (MDS) differ from those with other transfusion-dependent conditions (eg, thalassemia) as they are typically older, have comorbid conditions, and a generally shorter life expectancy. The underlying disease process in MDS and frequent use of red blood cell transfusions lead to iron accumulation and ultimately organ damage. Whether iron-reducing interventions such as chelation therapy can improve outcomes in this population is currently under investigation. Areas covered: We reviewed published English-language articles from PubMed on the topic of iron overload (IO) in MDS, and the use of iron chelation therapies (ICTs) to alleviate iron burden. Expert commentary: Data on IO-associated complications in MDS are derived largely from retrospective studies and there are limited data to guide clinicians on major treatment decisions. Although effective and well-tolerated oral ICTs are available, and general recommendations may be made regarding usage in MDS, guidance is not yet based on prospective data. The clinical endpoints and assessments for MDS may differ substantively from those used in patients with thalassemia, as an older population may have competing causes for morbidity. We expect that emergent data from clinical trials currently underway will define more appropriate endpoints/assessments for the MDS population in clinical trials.

New Insight Into the Biology, Risk Stratification, and Targeted Treatment of Myelodysplastic Syndromes.

PubMed

Haider, Mintallah; Duncavage, Eric J; Afaneh, Khalid F; Bejar, Rafael; List, Alan F

2017-01-01

In myelodysplastic syndromes (MDS), somatic mutations occur in five major categories: RNA splicing, DNA methylation, activated cell signaling, myeloid transcription factors, and chromatin modifiers. Although many MDS cases harbor more than one somatic mutation, in general, there is mutual exclusivity of mutated genes within a class. In addition to the prognostic significance of individual somatic mutations, more somatic mutations in MDS have been associated with poor prognosis. Prognostic assessment remains a critical component of the personalization of care for patient with MDS because treatment is highly risk adapted. Multiple methods for risk stratification are available with the revised International Prognostic Scoring System (IPSS-R), currently considered the gold standard. Increasing access to myeloid gene panels and greater evidence for the diagnostic and predictive value of somatic mutations will soon make sequencing part of the standard evaluation of patients with MDS. In the absence of formal guidelines for their prognostic use, well-validated mutations can still refine estimates of risk made with the IPSS-R. Not only are somatic gene mutations advantageous in understanding the biology of MDS and prognosis, they also offer potential as biomarkers and targets for the treatment of patients with MDS. Examples include deletion 5q, spliceosome complex gene mutations, and TP53 mutations.

Expression profile analysis of long non-coding RNA in acute myeloid leukemia by microarray and bioinformatics.

PubMed

Feng, Yuandong; Shen, Ying; Chen, Hongli; Wang, Xiaman; Zhang, Ru; Peng, Yue; Lei, Xiaoru; Liu, Tian; Liu, Jing; Gu, Liufang; Wang, Fangxia; Yang, Yun; Bai, Ju; Wang, Jianli; Zhao, Wanhong; He, Aili

2018-02-01

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt that are involved in tumorigenesis and play a key role in cancer progression. To determine whether lncRNAs are involved in acute myeloid leukemia (AML), we analyzed the expression profile of lncRNAs and mRNAs in AML. Five pairs of AML patients and iron deficiency anemia (IDA) controls were screened by microarray. Through coexpression analysis, differently expressed transcripts were divided into modules, and lncRNAs were functionally annotated. We further analyzed the clinical significance of crucial lncRNAs from modules in public data. Finally, the expression of three lncRNAs, RP11-222K16.2, AC092580.4, and RP11-305O.6, were validated in newly diagnosed AML, AML relapse, and IDA patient groups by quantitative RT-PCR, which may be associated with AML patients' overall survival. Further analysis showed that RP11-222K16.2 might affect the differentiation of natural killer cells, and promote the immunized evasion of AML by regulating Eomesodermin expression. Analysis of this study revealed that dysregulated lncRNAs and mRNAs in AML vs IDA controls could affect the immune system and hematopoietic cell differentiation. The biological functions of those lncRNAs need to be further validated. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML.

PubMed

Knapper, Steven; Russell, Nigel; Gilkes, Amanda; Hills, Robert K; Gale, Rosemary E; Cavenagh, James D; Jones, Gail; Kjeldsen, Lars; Grunwald, Michael R; Thomas, Ian; Konig, Heiko; Levis, Mark J; Burnett, Alan K

2017-03-02

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3 -internal tandem duplication mutations, 23% FLT3 -tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3 -mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively. © 2017 by The American Society of Hematology.

Concurrent targeting Akt and sphingosine kinase 1 by A-674563 in acute myeloid leukemia cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Lin; Shaoyang Central Hospital, Hunan Province; Zhang, Yanan

Akt signaling plays a pivotal role in acute myeloid leukemia (AML) development and progression. In the present study, we evaluated the potential anti-AML activity by a novel Akt kinase inhibitor A-674563. Our results showed that A-674563 dose-dependently inhibited survival and proliferation of U937 AML cells and six lines of human AML progenitor cells, yet sparing human peripheral blood mononuclear leukocytes (PBMCs). A-674563 activated caspase-3/9 and apoptosis in the AML cells. Reversely, the pan-caspase inhibitor z-VAD-CHO dramatically alleviated A-674563-induced AML cell apoptosis and cytotoxicity. For the molecular study, we showed that A-674563 blocked Akt activation in U937 cells and human AMLmore » progenitor cells. Further, A-674563 decreased sphingosine kinase 1 (SphK1) activity in above AML cells to deplete pro-survival sphingosine-1-phosphate (S1P) and boost pro-apoptotic ceramide production. Such an effect on SphK1 signaling by A-674563 appeared independent of Akt blockage. Significantly, K6PC-5, a novel SphK1 activator, or supplement with S1P attenuated A-674563-induced ceramide production, and subsequent U937 cell death and apoptosis. Importantly, intraperitoneal injection of A-674563 at well-tolerated doses suppressed U937 leukemic xenograft tumor growth in nude mice, whiling significantly improving the animal survival. The results of the current study demonstrate that A-674563 exerts potent anti-leukemic activity in vitro and in vivo, possibly via concurrent targeting Akt and SphK1 signalings. - Highlights: • A-674563 is cytotoxic and anti-proliferative in U937 and AML progenitor cells. • A-674563 activates caspase-3/9 and apoptosis in U937 and AML progenitor cells. • Whiling blocking Akt, A-674563 manipulates other signalings in AML cells. • A-674563 inhibits SphK1 activity in AML cells, independent of Akt blockage. • A-674563 injection inhibits U937 xenograft in vivo growth, and improves mice survival.« less

IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication.

PubMed

Paschka, Peter; Schlenk, Richard F; Gaidzik, Verena I; Habdank, Marianne; Krönke, Jan; Bullinger, Lars; Späth, Daniela; Kayser, Sabine; Zucknick, Manuela; Götze, Katharina; Horst, Heinz-A; Germing, Ulrich; Döhner, Hartmut; Döhner, Konstanze

2010-08-01

To analyze the frequency and prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in acute myeloid leukemia (AML). We studied 805 adults (age range, 16 to 60 years) with AML enrolled on German-Austrian AML Study Group (AMLSG) treatment trials AML HD98A and APL HD95 for mutations in exon 4 of IDH1 and IDH2. Patients were also studied for NPM1, FLT3, MLL, and CEBPA mutations. The median follow-up for survival was 6.3 years. IDH mutations were found in 129 patients (16.0%) -IDH1 in 61 patients (7.6%), and IDH2 in 70 patients (8.7%). Two patients had both IDH1 and IDH2 mutations. All but one IDH1 mutation caused substitutions of residue R132; IDH2 mutations caused changes of R140 (n = 48) or R172 (n = 22). IDH mutations were associated with older age (P < .001; effect conferred by IDH2 only); lower WBC (P = .04); higher platelets (P < .001); cytogenetically normal (CN) -AML (P< .001); and NPM1 mutations, in particular with the genotype of mutated NPM1 without FLT3 internal tandem duplication (ITD; P < .001). In patients with CN-AML with the latter genotype, IDH mutations adversely impacted relapse-free survival (RFS; P = .02) and overall survival (P = .03), whereas outcome was not affected in patients with CN-AML who lacked this genotype. In CN-AML, multivariable analyses revealed a significant interaction between IDH mutation and the genotype of mutated NPM1 without FLT3-ITD (ie, the adverse impact of IDH mutation [RFS]; P = .046 was restricted to this patient subset). IDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset.

Myelodysplastic syndromes in Chernobyl clean-up workers.

PubMed

Gluzman, Daniil F; Sklyarenko, Lilia M; Koval, Stella V; Rodionova, Nataliia K; Zavelevich, Michael P; Ivanivskaya, Tetiana S; Poludnenko, Liudmyla Yu; Ukrainskaya, Nataliia I

2015-10-01

The studies of the recent decades posed the question of the association between radiation exposure and myelodysplastic syndromes (MDS). This association has been proved in secondary MDS originating upon exposure to chemotherapeutics and/or radiation therapy. The long-term study in Japanese atomic (A)-bomb survivors demonstrated the significant linear dose-response for MDS confirming the link between radiation exposure and this form of hematopoietic malignancies. All these findings provide the strong basis for studying MDS in the persons exposed to radiation following the Chernobyl disaster, especially those in the cohort of Chernobyl clean-up workers of 1986-1987. The data on MDS among Chernobyl clean-up workers (1986-1987) diagnosed in 1996-2012 at the reference laboratory of RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology are summarized. MDS cases were diagnosed in 23 persons (21 males and 2 females) having been exposed to radiation as clean-up workers of 1986-1987. Refractory anemia (RA) has been detected in 13, refractory anemia with ring sideroblasts (RARS)-in 2, and refractory anemia with excess blasts (RAEB)-in 8 patients. The median age of those MDS patients was 62.0 years. In addition, 5 cases of chronic myelomonocytic leukemia (CMML) were recorded in the group of Chernobyl clean-up workers with the median time of 14.8 years from 1986-1987 to diagnosis. The association between radiation exposure and MDS is discussed. The suggested life-long risk for myelodysplastic syndromes among A-bomb survivors in Japan highlights the importance of the continuing follow-up studies in the affected populations in the post-Chernobyl period.

Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplastic syndrome patients.

PubMed

Feng, Xiaomin; Shikama, Yayoi; Shichishima, Tsutomu; Noji, Hideyoshi; Ikeda, Kazuhiko; Ogawa, Kazuei; Kimura, Hideo; Takeishi, Yasuchika; Kimura, Junko

2013-01-01

Although quantitative and qualitative granulocyte defects have been described in myelodysplastic syndromes (MDS), the underlying molecular basis of granulocyte dysfunction in MDS is largely unknown. We recently found that FOS mRNA elevation under translation-inhibiting stimuli was significantly smaller in granulocytes from MDS patients than in healthy individuals. The aim of this study is to clarify the cause of the impaired FOS induction in MDS. We first examined the mechanisms of FOS mRNA elevation using granulocytes from healthy donors cultured with the translation inhibitor emetine. Emetine increased both transcription and mRNA stability of FOS. p38 MAPK inhibition abolished the emetine-induced increase of FOS transcription but did not affect FOS mRNA stabilization. The binding of an AU-rich element (ARE)-binding protein HuR to FOS mRNA containing an ARE in 3'UTR was increased by emetine, and the knockdown of HuR reduced the FOS mRNA stabilizing effect of emetine. We next compared the emetine-induced transcription and mRNA stabilization of FOS between MDS patients and healthy controls. Increased rates of FOS transcription by emetine were similar in MDS and controls. In the absence of emetine, FOS mRNA decayed to nearly 17% of initial levels in 45 min in both groups. In the presence of emetine, however, 76.7±19.8% of FOS mRNA remained after 45 min in healthy controls, versus 37.9±25.5% in MDS (P<0.01). To our knowledge, this is the first report demonstrating attenuation of stress-induced FOS mRNA stabilization in MDS granulocytes.

Polymorphisms of Interlukin-1β rs16944 confer susceptibility to myelodysplastic syndromes.

PubMed

Yin, Congcong; He, Na; Li, Peng; Zhang, Chen; Yu, Jie; Hua, Mingqiang; Ji, Chunyan; Ma, Daoxin

2016-11-15

Genetic factors have been shown to be associated with Myelodysplastic syndromes (MDS) susceptibility. In recent years, the role of inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. But the relationship between polymorphisms in NOD-like receptor protein 3 (NLRP3) inflammasome and MDS is rarely reported. Thus, we conducted a case-control study, and genotyped five single nucleotide polymorphisms (SNPs) (NLRP3, IL-1β, IL-18, CARD8, and NF-κB) in MDS patients and healthy controls. The association of different genotypes with patient characteristics was analyzed. Comparing MDS patients with controls, GG genotype of IL-1β (rs16944) was observed to be associated with a significantly increased risk of MDS 78/166 (48.8%) vs 26/96 (27.0%), OR=2.1, CI (1.0-4.4). No significant association was identified regarding the rest of investigated polymorphisms and MDS susceptibility. Complex karyotypes were more frequent in patients with GG genotype of IL-1β (rs16944). Patients with IL-1β polymorphisms (rs16944) GG and GA had lower hemoglobin than those without. Patients with IL-1β polymorphisms (rs16944) GG had higher IPSS scores than those without IL-1β polymorphisms. In conclusion, our present data shows that the IL-1β polymorphisms (rs16944) GG were frequently occurred in MDS. IL-1β (rs16944) GG genotype might serve as a novel biomarker and potential targets for MDS. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of a modified through-mask drinking system (MDS) on fluid intake during exercise in chemical protective gear. Report for January-May 1989

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szlyk, P.C.; Sils, I.V.; Tharion, W.J.

This study was designed to evaluate the effects of a modified through-mask drinking system (MDS) on voluntary fluid consumption. Eighteen male volunteers walked on a treadmill (4.02 km/hr, 0 deg. grade, 50 min/hr for 6 hr) in a climatic chamber (dry bulb=32.6 deg C, wet bulb=17.5 deg C, 20.4% relative humidity, and windspeed=8.05 km/hr, producing a WBGT of 22.1 deg C). Subjects wore chemical protective gear (trousers, jacket, boots, gloves, and M17A1 protective mask) and were randomly assigned one of two through-mask and were randomly assigned one of two through-mask drinking systems: CS (n=9), the current gravity fed system ormore » MDS (n=9), a prototype hand-pump drinking system. Because decontamination of the mask and drinking connections was performed prior to drinking, the overall use of the CS was rated significantly more difficult during both work and rest than the MDS. Failure to decontaminate connections prior to drinking was noted early in the trial in 2 soldiers using the CS suggesting an increase risk of accidental contamination associated with this system. Drinking with the MDS had no measurable adverse effect on hydration status of the test subjects: water intake rate, 0.36 L/hr (CS) and 0.42 L/hr (MDS); sweat rate, 0.63 L/hr (CS) and 0.67 L/hr (MDS); body weight loss, 0.32 %/hr (CS) and 0.31 %/hr (MDS).« less

The MDS-UPDRS tracks motor and non-motor improvement due to subthalamic nucleus deep brain stimulation in Parkinson disease.

PubMed

Chou, Kelvin L; Taylor, Jennifer L; Patil, Parag G

2013-11-01

The Movement Disorders Society revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) improves upon the original UPDRS by adding more non-motor items, making it a more robust tool to evaluate the severity of motor and non-motor symptoms of Parkinson disease. Previous studies on deep brain stimulation have not used the MDS-UPDRS. To determine if the MDS-UPDRS could detect improvement in both motor and non-motor symptoms after bilateral subthalamic nucleus deep brain stimulation for Parkinson disease. We compared scores on the entire MDS-UPDRS prior to surgery (baseline) and approximately six months following the initial programming visit in twenty subjects (12M/8F) with Parkinson disease undergoing bilateral subthalamic nucleus deep brain stimulation. STN DBS significantly improved the scores for every section of the MDS-UPDRS at the 6 month follow-up. Part I improved by 3.1 points (22%), Part II by 5.3 points (29%), Part III by 13.1 points (29%) with stimulation alone, and Part IV by 7.1 points (74%). Individual non-motor items in Part I that improved significantly were constipation, light-headedness, and fatigue. Both motor and non-motor symptoms, as assessed by the MDS-UPDRS, improve with bilateral subthalamic nucleus stimulation six months after the stimulator is turned on. We recommend that the MDS-UPDRS be utilized in future deep brain stimulation studies because of the advantage of detecting change in non-motor symptoms. Copyright © 2013 Elsevier Ltd. All rights reserved.

Linear dependence between the wavefront gradient and the masked intensity for the point source with a CCD sensor

NASA Astrophysics Data System (ADS)

Yang, Huizhen; Ma, Liang; Wang, Bin

2018-01-01

In contrast to the conventional adaptive optics (AO) system, the wavefront sensorless (WFSless) AO system doesn't need a WFS to measure the wavefront aberrations. It is simpler than the conventional AO in system architecture and can be applied to the complex conditions. The model-based WFSless system has a great potential in real-time correction applications because of its fast convergence. The control algorithm of the model-based WFSless system is based on an important theory result that is the linear relation between the Mean-Square Gradient (MSG) magnitude of the wavefront aberration and the second moment of the masked intensity distribution in the focal plane (also called as Masked Detector Signal-MDS). The linear dependence between MSG and MDS for the point source imaging with a CCD sensor will be discussed from theory and simulation in this paper. The theory relationship between MSG and MDS is given based on our previous work. To verify the linear relation for the point source, we set up an imaging model under atmospheric turbulence. Additionally, the value of MDS will be deviate from that of theory because of the noise of detector and further the deviation will affect the correction effect. The theory results under noise will be obtained through theoretical derivation and then the linear relation between MDS and MDS under noise will be discussed through the imaging model. Results show the linear relation between MDS and MDS under noise is also maintained well, which provides a theoretical support to applications of the model-based WFSless system.

Mediators of the Association of Major Depressive Syndrome and Anxiety Syndrome with Postpartum Smoking Relapse

PubMed Central

Correa-Fernández, Virmarie; Ji, Lingyun; Castro, Yessenia; Heppner, Whitney L.; Vidrine, Jennifer Irvin; Costello, Tracy J.; Mullen, Patricia Dolan; Cofta-Woerpel, Ludmila; Velasquez, Mary M.; Greisinger, Anthony; Cinciripini, Paul M.; Wetter, David W.

2012-01-01

Objective Based on conceptual models of addiction and affect regulation, this study examined the mechanisms linking current major depressive syndrome (MDS) and anxiety syndrome (AS) to postpartum smoking relapse. Method Data were collected in a randomized clinical trial from 251 women who quit smoking during pregnancy. Simple and multiple mediation models of the relations of MDS and AS with postpartum relapse were examined using linear regression, continuation ratio logit models, and a Bootstrapping procedure to test the indirect effects. Results Both MDS and AS significantly predicted postpartum smoking relapse. After adjusting for MDS, AS significantly predicted relapse. However, after adjusting for AS, MDS no longer predicted relapse. Situationally-based self-efficacy, expectancies of controlling negative affect by means other than smoking, and various dimensions of primary and secondary tobacco dependence individually mediated the effect of both MDS and AS on relapse. In multiple mediation models, self-efficacy in negative/affective situations significantly mediated the effect of MDS and AS on relapse. Conclusion The findings underscore the negative impact of depression and anxiety on postpartum smoking relapse, and suggest that the effects of MDS on postpartum relapse may be largely explained by comorbid AS. The current investigation provided mixed support for affect regulation models of addiction. Cognitive and tobacco dependence-related aspects of negative and positive reinforcement significantly mediated the relationship of depression and anxiety with relapse, while affect and stress did not. The findings emphasize the unique role of low agency with respect to abstaining from smoking in negative affective situations as a key predictor of postpartum smoking relapse. PMID:22390410

Mediators of the association of major depressive syndrome and anxiety syndrome with postpartum smoking relapse.

PubMed

Correa-Fernández, Virmarie; Ji, Lingyun; Castro, Yessenia; Heppner, Whitney L; Vidrine, Jennifer Irvin; Costello, Tracy J; Mullen, Patricia Dolan; Cofta-Woerpel, Ludmila; Velasquez, Mary M; Greisinger, Anthony; Cinciripini, Paul M; Wetter, David W

2012-08-01

Based on conceptual models of addiction and affect regulation, this study examined the mechanisms linking current major depressive syndrome (MDS) and anxiety syndrome (AS) to postpartum smoking relapse. Data were collected in a randomized clinical trial from 251 women who quit smoking during pregnancy. Simple and multiple mediation models of the relations of MDS and AS with postpartum relapse were examined using linear regression, continuation ratio logit models, and a bootstrapping procedure to test the indirect effects. Both MDS and AS significantly predicted postpartum smoking relapse. After adjusting for MDS, AS significantly predicted relapse. However, after adjusting for AS, MDS no longer predicted relapse. Situationally based self-efficacy, expectancies of controlling negative affect by means other than smoking, and various dimensions of primary and secondary tobacco dependence individually mediated the effect of both MDS and AS on relapse. In multiple mediation models, self-efficacy in negative/affective situations significantly mediated the effect of MDS and AS on relapse. The findings underscore the negative impact of depression and anxiety on postpartum smoking relapse and suggest that the effects of MDS on postpartum relapse may be largely explained by comorbid AS. The current investigation provided mixed support for affect regulation models of addiction. Cognitive and tobacco dependence-related aspects of negative and positive reinforcement significantly mediated the relationship of depression and anxiety with relapse, whereas affect and stress did not. The findings emphasize the unique role of low agency with respect to abstaining from smoking in negative affective situations as a key predictor of postpartum smoking relapse. © 2012 American Psychological Association

Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML

PubMed Central

Mahmud, Hasan; Scherpen, Frank J.G.; de Boer, Tiny Meeuwsen; Lourens, Harm-Jan; Schoenherr, Caroline; Eder, Matthias; Scherr, Michaela; Guryev, Victor; De Bont, Eveline S.

2017-01-01

The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our previous peptide microarray. PLC-γ1 is known to play a role in cancer progression, however, the impact of PLC-γ1 in AML is currently unknown. Therefore, we aimed to study the functional role of PLC-γ1 by investigating the cellular growth, survival and its underlying mechanism in t(8;21) AML. In this study, PLC-γ1 expression was significantly higher in t(8;21) AML compared to other karyotypes. The PLC-γ1 protein expression was suppressed in AML1-ETO knock down cells indicating that it might induce kasumi-1 cell death. ShRNA-mediated PLC-γ1 knockdown in kasumi-1 cells significantly blocked cell growth, induced apoptosis and cell cycle arrest which was explained by the increased activation of apoptotic related and cell cycle regulatory protein expressions. Gene expression array analysis showed the up-regulation of apoptotic and DNA damage response genes together with the downregulation of cell growth, proliferation and differentiation genes in the PLC-γ1 suppressed kasumi-1 cells, consistent with the observed phenotypic effects. Importantly, PLC-γ1 suppressed kasumi-1 cells showed higher chemosensitivity to the chemotherapeutic drug treatments and lower cell proliferation upon hypoxic stress. Taken together, these in vitro finding strongly support an important role for PLC-γ1 in the survival of t(8;21) AML mimicking kasumi-1 cells and identify PLC-γ1 as a potential therapeutic target for t(8;21) AML treatment. PMID:28978037

Exosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia (AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis*

PubMed Central

Wojtuszkiewicz, Anna; Schuurhuis, Gerrit J.; Kessler, Floortje L.; Piersma, Sander R.; Knol, Jaco C.; Pham, Thang V.; Jansen, Gerrit; Musters, René J. P.; van Meerloo, Johan; Assaraf, Yehuda G.; Kaspers, Gertjan J. L.; Zweegman, Sonja; Cloos, Jacqueline; Jimenez, Connie R.

2016-01-01

Expression of apoptosis-regulating proteins (B-cell CLL/lymphoma 2 - BCL-2, Myeloid Cell Leukemia 1 - MCL-1, BCL-2 like 1 - BCL-X and BCL-2-associated X protein - BAX) in acute myeloid leukemia (AML) blasts at diagnosis is associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. Herein, we further explored this aspect of dynamic apoptosis regulation in AML. First, we showed that the intraindividual ex vivo apoptosis-related profiles of normal lymphocytes and AML blasts within the bone marrow of AML patients were highly correlated. The expression values of apoptosis-regulating proteins were far beyond healthy control lymphocytes, which implicates the influence of microenvironmental factors. Second, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p = 0.0067 and p = 1.0, respectively). Using secretome proteomics, we identified novel proteins possibly engaged in apoptosis regulation. Intriguingly, this analysis revealed that major functional protein clusters engaged in global gene regulation, including mRNA splicing, protein translation, and chromatin remodeling, were more abundant (p = 4.01E-06) in secretomes of apoptosis-resistant AML. These findings were confirmed by subsequent extracellular vesicle proteomics. Finally, confocal-microscopy-based colocalization studies show that splicing factors-containing vesicles secreted by high AAI cells are taken up by low AAI cells. The current results constitute the first comprehensive analysis of proteins released by apoptosis-resistant and sensitive primary AML cells. Together, the data point to vesicle-mediated release of global gene regulatory protein clusters as a plausible novel mechanism of induction of apoptosis resistance. Deciphering the modes of communication between apoptosis-resistant blasts may in perspective lead to the discovery of prognostic tools and development of novel therapeutic interventions, aimed at limiting or overcoming therapy resistance. PMID:26801919

Feasibility of the AML profiler (Skyline™ Array) for patient risk stratification in a multicentre trial: a preliminary comparison with the conventional approach.

PubMed

Nomdedéu, Josep F; Puigdecanet, Eulalia; Bussaglia, Elena; Hernández, Juan José; Carricondo, Maite; Estivill, Camino; Martí-Tutusaus, Josep Maria; Tormo, Mar; Zamora, Lurdes; Serrano, Elena; Perea, Granada; de Llano, Maria Paz Queipo; García, Antoni; Sánchez-Ortega, Isabel; Ribera, Josep Maria; Nonell, Lara; Aventin, Anna; Solé, Francesc; Brunet, Maria Salut; Sierra, Jorge

2017-12-01

Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline™ Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL-PTD, FLT3-ITD and TKD, NPM1 and CEBPAdm mutations. Purified RNA was used to assess RUNX1-RUNX1T1, PML-RARα and CBFβ-MYH11 rearrangements. RNA remnants underwent gene expression profiling analysis using the AML profiler, which detects chromosomal aberrations: t(8;21), t(15;17), inv(16), mutations (CEBPAdm, ABD-NPM1) and BAALC and EVI1 expression. Thirty cases were successfully analysed with both methods. Five cases had FLT3-ITD. In one case, a t(8;21) was correctly detected by both methods. Four cases had inv(16); in one, the RNA quality was unsatisfactory and it was not hybridized, and in the other three, the AML profiler detected the genetic lesion - this being a rare type I translocation in one case. Two cases with acute promyelocytic leukaemia were diagnosed by both methods. Results for NPM1 mutations were concordant in all but two cases (2/11, non-ABD mutations). Analysis of costs and turnaround times showed that the AML profiler was no more expensive than the conventional molecular approach. These results suggest that the AML profiler could be useful in multicentre trials to rapidly identify patients with AML with a good prognosis. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Acute myeloid leukemia in children: Current status and future directions.

PubMed

Taga, Takashi; Tomizawa, Daisuke; Takahashi, Hiroyuki; Adachi, Souichi

2016-02-01

Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML-DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all-trans retinoic acid (ATRA)-combined regimen with an 80-90% OS. Children with ML-DS are treated with a less intensive regimen compared with non-DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high-risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials. © 2015 Japan Pediatric Society.

Homoharringtonine combined with aclarubicin and cytarabine synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase-3-mediated cleavage of the AML1-ETO oncoprotein.

PubMed

Cao, Jiang; Feng, Hao; Ding, Ning-Ning; Wu, Qing-Yun; Chen, Chong; Niu, Ming-Shan; Chen, Wei; Qiu, Ting-Ting; Zhu, Hong-Hu; Xu, Kai-Lin

2016-11-01

Homoharringtonine combined with aclarubicin and cytarabine (HAA) is a highly effective treatment for acute myeloid leukemia (AML), especially for t(8;21) AML. However, the underlying mechanisms by which HAA kills t(8;21) AML cells remain unclear. In this study, SKNO-1 and Kasumi-1 cells with t(8;21) were used. Compared with individual or pairwise administration of homoharringtonine, aclarubicin, or cytarabine, HAA showed the strongest inhibition of growth and induction of apoptosis in SKNO-1 and Kasumi-1 cells. HAA caused cleavage of the AML1-ETO (AE) oncoprotein to form truncated AE (ΔAE). Pretreatment with the caspase-3 inhibitor caspase-3 inhibitor Q-DEVD-OPh (QDO) not only suppressed HAA-induced apoptosis but also abrogated the cleavage of AE and generation of ΔAE. These results suggest that HAA synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase-3-mediated cleavage of the AML1-ETO oncoprotein, thus providing direct evidence for the strong activity of HAA toward t(8;21) AML. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia

PubMed Central

Will, Britta; Vogler, Thomas O.; Narayanagari, Swathi; Bartholdy, Boris; Todorova, Tihomira I.; da Silva Ferreira, Mariana; Chen, Jiahao; Yu, Yiting; Mayer, Jillian; Barreyro, Laura; Carvajal, Luis; Ben Neriah, Daniela; Roth, Michael; van Oers, Johanna; Schaetzlein, Sonja; McMahon, Christine; Edelmann, Winfried; Verma, Amit; Steidl, Ulrich

2016-01-01

Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reduction of PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in 35% reduction of PU.1 expression, was sufficient to induce myeloid biased preleukemic stem cells and subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1 cooperating transcription factor, Irf8. Strikingly, we found significant molecular similarities with human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor that commonly occurs in human disease is sufficient to initiate cancer development and provides mechanistic insight into the formation and progression of preleukemic stem cells in AML. PMID:26343801

SAMPLING DISTRIBUTIONS OF ERROR IN MULTIDIMENSIONAL SCALING.

ERIC Educational Resources Information Center

STAKE, ROBERT E.; AND OTHERS

AN EMPIRICAL STUDY WAS MADE OF THE ERROR FACTORS IN MULTIDIMENSIONAL SCALING (MDS) TO REFINE THE USE OF MDS FOR MORE EXPERT MANIPULATION OF SCALES USED IN EDUCATIONAL MEASUREMENT. THE PURPOSE OF THE RESEARCH WAS TO GENERATE TABLES OF THE SAMPLING DISTRIBUTIONS THAT ARE NECESSARY FOR DISCRIMINATING BETWEEN ERROR AND NONERROR MDS DIMENSIONS. THE…

New q-ary quantum MDS codes with distances bigger than q/2

NASA Astrophysics Data System (ADS)

He, Xianmang; Xu, Liqing; Chen, Hao

2016-07-01

The construction of quantum MDS codes has been studied by many authors. We refer to the table in page 1482 of (IEEE Trans Inf Theory 61(3):1474-1484, 2015) for known constructions. However, there have been constructed only a few q-ary quantum MDS [[n,n-2d+2,d

BMDS: A Collection of R Functions for Bayesian Multidimensional Scaling

ERIC Educational Resources Information Center

Okada, Kensuke; Shigemasu, Kazuo

2009-01-01

Bayesian multidimensional scaling (MDS) has attracted a great deal of attention because: (1) it provides a better fit than do classical MDS and ALSCAL; (2) it provides estimation errors of the distances; and (3) the Bayesian dimension selection criterion, MDSIC, provides a direct indication of optimal dimensionality. However, Bayesian MDS is not…

Trisomy 8, a Cytogenetic Abnormality in Myelodysplastic Syndromes, Is Constitutional or Not?

PubMed Central

Saumell, Sílvia; Solé, Francesc; Arenillas, Leonor; Montoro, Julia; Valcárcel, David; Pedro, Carme; Sanzo, Carmen; Luño, Elisa; Giménez, Teresa; Arnan, Montserrat; Pomares, Helena; De Paz, Raquel; Arrizabalaga, Beatriz; Jerez, Andrés; Martínez, Ana B.; Sánchez-Castro, Judith; Rodríguez-Gambarte, Juan D.; Raya, José M.; Ríos, Eduardo; Rodríguez-Rivera, María; Espinet, Blanca; Florensa, Lourdes

2015-01-01

Isolated trisomy 8 is not considered presumptive evidence of myelodysplastic syndrome (MDS) in cases without minimal morphological criteria. One reason given is that trisomy 8 (+8) can be found as a constitutional mosaicism (cT8M). We tried to clarify the incidence of cT8M in myeloid neoplasms, specifically in MDS, and the diagnostic value of isolated +8 in MDS. Twenty-two MDS and 10 other myeloid neoplasms carrying +8 were studied. Trisomy 8 was determined in peripheral blood by conventional cytogenetics (CC) and on granulocytes, CD3+ lymphocytes and oral mucosa cells by fluorescence in situ hybridization (FISH). In peripheral blood CC, +8 was seen in 4/32 patients. By FISH, only one patient with chronic myelomonocytic leukemia showed +8 in all cell samples and was interpreted as a cT8M. In our series +8 was acquired in all MDS. Probably, once discarded cT8M by FISH from CD3+ lymphocytes and non-hematological cells, +8 should be considered with enough evidence to MDS. PMID:26066831

Myelodysplastic syndromes and the role of iron overload.

PubMed

Harvey, R Donald

2010-04-01

The epidemiology of myelodysplastic syndromes (MDS) and iron overload, recent clinical findings that highlight the importance of actively managing iron overload, and recommendations for initiating and maintaining iron chelation therapy (ICT) are summarized. MDS are a variety of hematological disorders with differing time courses. Disease morbidities are primarily due to cytopenias and evolution to acute myeloid leukemia. Iron overload is a serious complication in patients with MDS due to the long-term use of red blood cell transfusions in patients with symptomatic anemia. Clinical consequences of iron overload include end-organ damage and dysfunction, an increased frequency of transplant-related complications, and reduced survival rates. To prevent these complications, recommendations for initiating and maintaining ICT should be followed by clinicians caring for patients with MDS and iron overload. As current therapeutic options for patients with MDS do not always reduce the transfusion burden, many patients will still need long-term transfusion therapy. Strategies for the management of iron overload in MDS should be considered early in the disease course and in appropriate patients in order to prevent negative clinical outcomes associated with excessive iron accumulation.

Trisomy 8, a Cytogenetic Abnormality in Myelodysplastic Syndromes, Is Constitutional or Not?

PubMed

Saumell, Sílvia; Solé, Francesc; Arenillas, Leonor; Montoro, Julia; Valcárcel, David; Pedro, Carme; Sanzo, Carmen; Luño, Elisa; Giménez, Teresa; Arnan, Montserrat; Pomares, Helena; De Paz, Raquel; Arrizabalaga, Beatriz; Jerez, Andrés; Martínez, Ana B; Sánchez-Castro, Judith; Rodríguez-Gambarte, Juan D; Raya, José M; Ríos, Eduardo; Rodríguez-Rivera, María; Espinet, Blanca; Florensa, Lourdes

2015-01-01

Isolated trisomy 8 is not considered presumptive evidence of myelodysplastic syndrome (MDS) in cases without minimal morphological criteria. One reason given is that trisomy 8 (+8) can be found as a constitutional mosaicism (cT8M). We tried to clarify the incidence of cT8M in myeloid neoplasms, specifically in MDS, and the diagnostic value of isolated +8 in MDS. Twenty-two MDS and 10 other myeloid neoplasms carrying +8 were studied. Trisomy 8 was determined in peripheral blood by conventional cytogenetics (CC) and on granulocytes, CD3+ lymphocytes and oral mucosa cells by fluorescence in situ hybridization (FISH). In peripheral blood CC, +8 was seen in 4/32 patients. By FISH, only one patient with chronic myelomonocytic leukemia showed +8 in all cell samples and was interpreted as a cT8M. In our series +8 was acquired in all MDS. Probably, once discarded cT8M by FISH from CD3+ lymphocytes and non-hematological cells, +8 should be considered with enough evidence to MDS.

Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Münster AML-study group

PubMed Central

Coenen, Eva A.; Zwaan, C. Michel; Reinhardt, Dirk; Harrison, Christine J.; Haas, Oskar A.; de Haas, Valerie; Mihál, Vladimir; De Moerloose, Barbara; Jeison, Marta; Rubnitz, Jeffrey E.; Tomizawa, Daisuke; Johnston, Donna; Alonzo, Todd A.; Hasle, Henrik; Auvrignon, Anne; Dworzak, Michael; Pession, Andrea; van der Velden, Vincent H. J.; Swansbury, John; Wong, Kit-fai; Terui, Kiminori; Savasan, Sureyya; Winstanley, Mark; Vaitkeviciene, Goda; Zimmermann, Martin; Pieters, Rob; van den Heuvel-Eibrink, Marry M.

2013-01-01

In pediatric acute myeloid leukemia (AML), cytogenetic abnormalities are strong indicators of prognosis. Some recurrent cytogenetic abnormalities, such as t(8;16)(p11;p13), are so rare that collaborative studies are required to define their prognostic impact. We collected the clinical characteristics, morphology, and immunophenotypes of 62 pediatric AML patients with t(8;16)(p11;p13) from 18 countries participating in the International Berlin-Frankfurt-Münster (I-BFM) AML study group. We used the AML-BFM cohort diagnosed from 1995-2005 (n = 543) as a reference cohort. Median age of the pediatric t(8;16)(p11;p13) AML patients was significantly lower (1.2 years). The majority (97%) had M4-M5 French-American-British type, significantly different from the reference cohort. Erythrophagocytosis (70%), leukemia cutis (58%), and disseminated intravascular coagulation (39%) occurred frequently. Strikingly, spontaneous remissions occurred in 7 neonates with t(8;16)(p11;p13), of whom 3 remain in continuous remission. The 5-year overall survival of patients diagnosed after 1993 was 59%, similar to the reference cohort (P = .14). Gene expression profiles of t(8;16)(p11;p13) pediatric AML cases clustered close to, but distinct from, MLL-rearranged AML. Highly expressed genes included HOXA11, HOXA10, RET, PERP, and GGA2. In conclusion, pediatric t(8;16)(p11;p13) AML is a rare entity defined by a unique gene expression signature and distinct clinical features in whom spontaneous remissions occur in a subset of neonatal cases. PMID:23974201

Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia.

PubMed

Jamalpour, Maria; Li, Xiujuan; Cavelier, Lucia; Gustafsson, Karin; Mostoslavsky, Gustavo; Höglund, Martin; Welsh, Michael

2017-10-01

The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines. Despite a low frequency of SHB gene mutations, many tumors overexpressed SHB mRNA compared with normal myeloid blood cells. AML patients with tumors expressing low SHB mRNA displayed longer survival times. A subgroup of AML exhibiting a favorable prognosis, acute promyelocytic leukemia (APL) with a PMLRARA translocation, expressed less SHB mRNA than AML tumors in general. When examining genes co-expressed with SHB in AML tumors, four other genes ( PAX5, HDAC7, BCORL1, TET1) related to leukemia were identified. A network consisting of these genes plus SHB was identified that relates to certain phenotypic characteristics, such as immune cell, vascular and apoptotic features. SHB knockdown in the APL PMLRARA cell line NB4 and the monocyte/macrophage cell line MM6 adversely affected proliferation, linking SHB gene expression to tumor cell expansion and consequently to patient survival. It is concluded that tumor SHB gene expression relates to AML survival and its subgroup APL. Moreover, this gene is included in a network of genes that plays a role for an AML phenotype exhibiting certain immune cell, vascular and apoptotic characteristics.

Jab1/Csn5-thioredoxin signaling in relapsed acute monocytic leukemia under oxidative stress

PubMed Central

Zhou, Fuling; Pan, Yunbao; Wei, Yongchang; Zhang, Ronghua; Bai, Gaigai; Shen, Qiuju; Meng, Shan; Le, Xiao-Feng; Andreeff, Michael; Claret, Francois X.

2018-01-01

Purpose High levels of ROS and ineffective antioxidant systems contribute to oxidative stress, which affects the function of hematopoietic cells in acute myeloid leukemia (AML); however, the mechanisms by which ROS lead to malignant transformation in relapsed AML-M5 are not completely understood. We hypothesized that alterations in intracellular ROS would trigger AML-M5 relapse by activating the intrinsic pathway. Experimental Design We studied ROS levels and conducted JAB1/COPS5 and TRX gene expression analyses with blood samples obtained from 60 matched AML-M5 patients at diagnosis and relapse and conducted mechanism studies of Jab1’s regulation of Trx in leukemia cell lines. Results Our data showed that increased production of ROS and a low capacity of antioxidant enzymes were characteristics of AML-M5, both at diagnosis and at relapse. Consistently, increased gene expression levels of thioredoxin (TRX) and c-Jun activation domain-binding protein-1 (JAB1/COPS5) were associated with low overall survival rates in patients with AML-M5. In addition, stimulating AML-M5 cells with low concentrations of hydrogen peroxide led to increased Jab1 and Trx expression. Consistently, transfection of ectopic Jab1 into leukemia cells increased Trx expression, whereas silencing of Jab1 in leukemia cells reduced Trx expression. Mechanistically, Jab1 interacted with Trx and stabilized Trx protein. Moreover, Jab1 transcriptionally regulated Trx. Furthermore, depletion of Jab1 inhibited leukemia cell growth both in vitro and in vivo. Conclusions We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of AML-M5. Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5. PMID:28270496

Genetic analysis of leukemic transformation of chronic myeloproliferative neoplasms

PubMed Central

Abdel-Wahab, Omar; Manshouri, Taghi; Patel, Jay; Harris, Kelly; Yao, JinJuan; Hedvat, Cyrus; Heguy, Adriana; Bueso-Ramos, Carlos; Kantarjian, Hagop; Levine, Ross L.; Verstovsek, Srdan

2009-01-01

The genetic events which contribute to transformation of myeloproliferative neoplasms (MPN) to acute myeloid leukemia (AML) are not well characterized. We investigated the role of JAK2, TET2, ASXL1, and IDH1 mutations in leukemic transformation of MPNs through mutational analysis of 63 patients with AML secondary to a preexisting MPN (sAML). We identified frequent TET2 (26.3%), ASXL1 (19.3%), IDH1 (9.5%), and JAK2 (36.8%) mutations in sAML; all possible mutational combinations of these genes were observed. Analysis of 14 patients for which paired samples from MPN and sAML were available demonstrated TET2 mutations were frequently acquired at leukemic transformation (6/14=43%). In contrast, ASXL1 mutations were almost always detected in both the MPN and AML clones from individual patients. A case was also observed where TET2 and ASXL1 mutations were found before the patient acquired a JAK2 mutation or developed clinical evidence of MPN. We conclude that mutations in TET2, ASXL1, and IDH1 are common in sAML derived from a pre-existing MPN. Although TET2/ASXL1 mutations may precede acquisition of JAK2 mutations by the MPN clone, mutations in TET2, but not ASXL1, are commonly acquired at the time of leukemic transformation. These data suggest the mutational order of events in MPN and sAML varies in different patients, and that TET2 and ASXL1 mutations have distinct roles in MPN pathogenesis and leukemic transformation. The presence of sAML with no pre-existing JAK2/TET2/ASXL1/IDH1 mutations indicates the existence of other mutations necessary for leukemic transformation. PMID:20068184

The TEL-AML1 fusion protein of acute lymphoblastic leukemia modulates IRF3 activity during early B-cell differentiation.

PubMed

de Laurentiis, A; Hiscott, J; Alcalay, M

2015-12-03

The t(12;21) translocation is the most common genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) and gives rise to the TEL-AML1 fusion gene. Many studies on TEL-AML1 describe specific properties of the fusion protein, but a thorough understanding of its function is lacking. We exploited a pluripotent hematopoietic stem/progenitor cell line, EML1, and generated a cell line (EML-TA) stably expressing the TEL-AML1 fusion protein. EML1 cells differentiate to mature B-cells following treatment with IL7; whereas EML-TA display an impaired differentiation capacity and remain blocked at an early stage of maturation. Global gene expression profiling of EML1 cells at different stages of B-lymphoid differentiation, compared with EML-TA, identified the interferon (IFN)α/β pathway as a primary target of repression by TEL-AML1. In particular, expression and phosphorylation of interferon-regulatory factor 3 (IRF3) was decreased in EML-TA cells; strikingly, stable expression of IRF3 restored the capacity of EML-TA cells to differentiate into mature B-cells. Similarly, IRF3 silencing in EML1 cells by siRNA was sufficient to block B-lymphoid differentiation. The ability of TEL-AML1 to block B-cell differentiation and downregulate the IRF3-IFNα/β pathway was confirmed in mouse and human primary hematopoietic precursor cells (Lin- and CD34+ cells, respectively), and in a patient-derived cell line expressing TEL-AML1 (REH). Furthermore, treatment of TEL-AML1 expressing cells with IFNα/β was sufficient to overcome the maturation block. Our data provide new insight on TEL-AML1 function and may offer a new therapeutic opportunity for B-ALL.

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts*

PubMed Central

Kremer, Kimberly N.; Dudakovic, Amel; Hess, Allan D.; Smith, B. Douglas; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; van Wijnen, Andre J.; Hedin, Karen E.

2015-01-01

Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently up-regulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1α (PP1α) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1α or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1α-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis. PMID:26491017

Superior long-term outcome with idarubicin compared with high-dose daunorubicin in patients with acute myeloid leukemia age 50 years and older.

PubMed

Gardin, Claude; Chevret, Sylvie; Pautas, Cécile; Turlure, Pascal; Raffoux, Emmanuel; Thomas, Xavier; Quesnel, Bruno; de Revel, Thierry; de Botton, Stéphane; Gachard, Nathalie; Renneville, Aline; Boissel, Nicolas; Preudhomme, Claude; Terré, Christine; Fenaux, Pierre; Bordessoule, Dominique; Celli-Lebras, Karine; Castaigne, Sylvie; Dombret, Hervé

2013-01-20

Although standard chemotherapy remains associated with a poor outcome in older patients with acute myeloid leukemia (AML), it is unclear which patients can survive long enough to be considered as cured. This study aimed to identify factors influencing the long-term outcome in these patients. The study included 727 older patients with AML (median age, 67 years) treated in two idarubicin (IDA) versus daunorubicin (DNR) Acute Leukemia French Association trials. Prognostic analysis was based on standard univariate and multivariate models and also included a cure fraction model to focus on long-term outcome. Age, WBC count, secondary AML, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adverse-risk and favorable-risk AML subsets (European LeukemiaNet classification) all influenced complete remission (CR) rate and overall survival (OS). IDA random assignment was associated with higher CR rate, but not with longer OS (P = .13). The overall cure rate was 13.3%. Older age and ECOG-PS more than 1 negatively influenced cure rate, which was higher in patients with favorable-risk AML (39.1% v 8.0% in adverse-risk AML; P < .001) and those treated with IDA (16.6% v 9.8% with DNR; P = .018). The long-term impact of IDA was still observed in patients younger than age 65 years, although all of the younger patients in the DNR control arm received high DNR doses (cure rate, 27.4% for IDA v 15.9% for DNR; P = .049). In multivariate analysis, IDA random assignment remained associated with a higher cure rate (P = .04), together with younger age and favorable-risk AML, despite not influencing OS (P = .11). In older patients with AML, younger age, favorable-risk AML, and IDA treatment predict a better long-term outcome.

Niclosamide suppresses acute myeloid leukemia cell proliferation through inhibition of CREB-dependent signaling pathways

PubMed Central

Chae, Hee-Don; Cox, Nick; Dahl, Gary V.; Lacayo, Norman J.; Davis, Kara L.; Capolicchio, Samanta; Smith, Mark; Sakamoto, Kathleen M.

2018-01-01

CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells. Niclosamide significantly inhibited CREB function and CREB-mediated gene expression in cells, leading to apoptosis and G1/S cell cycle arrest with reduced phosphorylated CREB levels. CREB knockdown protected cells from niclosamide treatment-mediated cytotoxic effects. Furthermore, treatment with a combination of niclosamide and CREB inhibitor XX-650-23 showed an additive anti-proliferative effect, consistent with the hypothesis that niclosamide and XX-650-23 regulate the same targets or pathways to inhibit proliferation and survival of AML cells. Niclosamide significantly inhibited the progression of disease in AML patient-derived xenograft (PDX) mice, and prolonged survival of PDX mice. Niclosamide also showed synergistic effects with chemotherapy drugs to inhibit AML cell proliferation. While chemotherapy antagonized the cytotoxic potential of niclosamide, pretreatment with niclosamide sensitized cells to chemotherapeutic drugs, cytarabine, daunorubicin, and vincristine. Therefore, our results demonstrate niclosamide as a potential drug to treat AML by inducing apoptosis and cell cycle arrest through inhibition of CREB-dependent pathways in AML cells. PMID:29435104

Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia

PubMed Central

Klein, Hans-Ulrich; Hascher, Antje; Isken, Fabienne; Tickenbrock, Lara; Thoennissen, Nils; Agrawal-Singh, Shuchi; Tschanter, Petra; Disselhoff, Christine; Wang, Yipeng; Becker, Anke; Thiede, Christian; Ehninger, Gerhard; zur Stadt, Udo; Koschmieder, Steffen; Seidl, Matthias; Müller, Frank U.; Schmitz, Wilhelm; Schlenke, Peter; McClelland, Michael; Berdel, Wolfgang E.; Dugas, Martin; Serve, Hubert

2010-01-01

Acute myeloid leukemia (AML) is commonly associated with alterations in transcription factors because of altered expression or gene mutations. These changes might induce leukemia-specific patterns of histone modifications. We used chromatin-immunoprecipitation on microarray to analyze histone 3 lysine 9 trimethylation (H3K9me3) patterns in primary AML (n = 108), acute lymphoid leukemia (n = 28), CD34+ cells (n = 21) and white blood cells (n = 15) specimens. Hundreds of promoter regions in AML showed significant alterations in H3K9me3 levels. H3K9me3 deregulation in AML occurred preferentially as a decrease in H3K9me3 levels at core promoter regions. The altered genomic regions showed an overrepresentation of cis-binding sites for ETS and cyclic adenosine monophosphate response elements (CREs) for transcription factors of the CREB/CREM/ATF1 family. The decrease in H3K9me3 levels at CREs was associated with increased CRE-driven promoter activity in AML blasts in vivo. AML-specific H3K9me3 patterns were not associated with known cytogenetic abnormalities. But a signature derived from H3K9me3 patterns predicted event-free survival in AML patients. When the H3K9me3 signature was combined with established clinical prognostic markers, it outperformed prognosis prediction based on clinical parameters alone. These findings demonstrate widespread changes of H3K9me3 levels at gene promoters in AML. Signatures of histone modification patterns are associated with patient prognosis in AML. PMID:20498303

Relationship between the non-motor items of the MDS-UPDRS and Quality of Life in patients with Parkinson's disease.

PubMed

Skorvanek, Matej; Rosenberger, Jaroslav; Minar, Michal; Grofik, Milan; Han, Vladimir; Groothoff, Johan W; Valkovic, Peter; Gdovinova, Zuzana; van Dijk, Jitse P

2015-01-01

The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed comprehensive tool to assess Parkinson's disease (PD), which covers a wider range of non-motor PD manifestations than the original UPDRS scale. The aim of this study was to assess the relationship between the MDS-UPDRS and Quality of Life (QoL) and to analyze the relationship between individual MDS-UPDRS non-motor items and QoL. A total of 291 PD patients were examined in a multicenter Slovak study. Patients were assessed by the MDS-UPDRS, HY scale and PDQ39. Data were analyzed using the multiple regression analyses. The mean participant age was 68.0 ± 9.0 years, 53.5% were men, mean disease duration was 8.3 ± 5.3 years and mean HY was 2.7 ± 1.0. In a multiple regression analysis model the PDQ39 summary index was related to MDS-UPDRS parts II, I and IV respectively, but not to part III. Individual MDS-UPDRS non-motor items related to the PDQ39 summary index in the summary group and in the non-fluctuating patients subgroup were pain, fatigue and features of dopamine dysregulation syndrome (DDS). In the fluctuating PD patient subgroup, PDQ39 was related to pain and Depressed mood items. Other MDS-UPDRS non-motor items e.g. Anxious mood, Apathy, Cognitive impairment, Hallucinations and psychosis, Sleep problems, Daytime sleepiness and Urinary problems were related to some PDQ39 domains. The overall burden of NMS in PD is more important in terms of QoL than motor symptoms. Individual MDS-UPDRS non-motor items related to worse QoL are especially pain and other sensations, fatigue and features of DDS. Copyright © 2015 Elsevier B.V. All rights reserved.

Considering Bone Marrow Blasts From Nonerythroid Cellularity Improves the Prognostic Evaluation of Myelodysplastic Syndromes.

PubMed

Arenillas, Leonor; Calvo, Xavier; Luño, Elisa; Senent, Leonor; Alonso, Esther; Ramos, Fernando; Ardanaz, María Teresa; Pedro, Carme; Tormo, Mar; Marco, Víctor; Montoro, Julia; Díez-Campelo, María; Brunet, Salut; Arrizabalaga, Beatriz; Xicoy, Blanca; Andreu, Rafael; Bonanad, Santiago; Jerez, Andrés; Nomdedeu, Benet; Ferrer, Ana; Sanz, Guillermo F; Florensa, Lourdes

2016-09-20

WHO classification of myeloid malignancies is based mainly on the percentage of bone marrow (BM) blasts. This is considered from total nucleated cells (TNCs), unless there is erythroid-hyperplasia (erythroblasts ≥ 50%), calculated from nonerythroid cells (NECs). In these instances, when BM blasts are ≥ 20%, the disorder is classified as erythroleukemia, and when BM blasts are < 20%, as myelodysplastic syndrome (MDS). In the latter, the percentage of blasts is considered from TNCs. We assessed the percentage of BM blasts from TNCs and NECs in 3,692 patients with MDS from the Grupo Español de Síndromes Mielodisplásicos, 465 patients with erythroid hyperplasia (MDS-E) and 3,227 patients without erythroid hyperplasia. We evaluated the relevance of both quantifications on classification and prognostication. By enumerating blasts systematically from NECs, 22% of patients with MDS-E and 12% with MDS from the whole series diagnosed within WHO categories with < 5% BM blasts, were reclassified into higher-risk categories and showed a poorer overall survival than did those who remained in initial categories (P = .006 and P = .001, respectively). Following WHO recommendations, refractory anemia with excess blasts (RAEB)-2 diagnosis is not possible in MDS-E, as patients with 10% to < 20% BM blasts from TNCs fulfill erythroleukemia criteria; however, by considering blasts from NECs, 72 patients were recoded as RAEB-2 and showed an inferior overall survival than did patients with RAEB-1 without erythroid hyperplasia. Recalculating the International Prognostic Scoring System by enumerating blasts from NECs in MDS-E and in the overall MDS population reclassified approximately 9% of lower-risk patients into higher-risk categories, which indicated the survival expected for higher-risk patients. Regardless of the presence of erythroid hyperplasia, calculating the percentage of BM blasts from NECs improves prognostic assessment of MDS. This fact should be considered in future WHO classification reviews. © 2016 by American Society of Clinical Oncology.

Receptor tyrosine kinase alterations in AML - biology and therapy.

PubMed

Stirewalt, Derek L; Meshinchi, Soheil

2010-01-01

Acute myeloid leukemia (AML) is the most common form of leukemia in adults, and despite some recent progress in understanding the biology of the disease, AML remains the leading cause of leukemia-related deaths in adults and children. AML is a complex and heterogeneous disease, often involving multiple genetic defects that promote leukemic transformation and drug resistance. The cooperativity model suggests that an initial genetic event leads to maturational arrest in a myeloid progenitor cell, and subsequent genetic events induce proliferation and block apoptosis. Together, these genetic abnormalities lead to clonal expansion and frank leukemia. The purpose of this chapter is to review the biology of receptor tyrosine kinases (RTKs) in AML, exploring how RTKs are being used as novel prognostic factors and potential therapeutic targets.

Acute myeloid leukemia presenting with panhypopituitarism or diabetes insipidus: a case series with molecular genetic analysis and review of the literature.

PubMed

Cull, Elizabeth H; Watts, Justin M; Tallman, Martin S; Kopp, Peter; Frattini, Mark; Rapaport, Franck; Rampal, Raajit; Levine, Ross; Altman, Jessica K

2014-09-01

Central diabetes insipidus (DI) is a rare finding in patients with acute myeloid leukemia (AML), usually occurring in patients with chromosome 3 or 7 abnormalities. We describe four patients with AML and concurrent DI and a fifth patient with AML and panhypopituitarism. Four of five patients had monosomy 7. Three patients had chromosome 3q21q26/EVI-1 gene rearrangements. The molecular genotype of patients with AML and DI is not known. Therefore, we performed gene sequencing of 30 genes commonly mutated in AML in three patients with available leukemia cell DNA. One patient had no identifiable mutations, and two had RUNX1 F158S mutations.

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

PubMed

Shlush, Liran I; Zandi, Sasan; Mitchell, Amanda; Chen, Weihsu Claire; Brandwein, Joseph M; Gupta, Vikas; Kennedy, James A; Schimmer, Aaron D; Schuh, Andre C; Yee, Karen W; McLeod, Jessica L; Doedens, Monica; Medeiros, Jessie J F; Marke, Rene; Kim, Hyeoung Joon; Lee, Kwon; McPherson, John D; Hudson, Thomas J; Brown, Andrew M K; Yousif, Fouad; Trinh, Quang M; Stein, Lincoln D; Minden, Mark D; Wang, Jean C Y; Dick, John E

2014-02-20

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

Tunneling nanotube (TNT) formation is downregulated by cytarabine and NF-κB inhibition in acute myeloid leukemia (AML)

PubMed Central

Omsland, Maria; Bruserud, Øystein; Gjertsen, Bjørn T; Andresen, Vibeke

2017-01-01

Acute myeloid leukemia (AML) is a bone marrow derived blood cancer where intercellular communication in the leukemic bone marrow participates in disease development, progression and chemoresistance. Tunneling nanotubes (TNTs) are intercellular communication structures involved in transport of cellular contents and pathogens, also demonstrated to play a role in both cell death modulation and chemoresistance. Here we investigated the presence of TNTs by live fluorescent microscopy and identified TNT formation between primary AML cells and in AML cell lines. We found that NF-κB activity was involved in TNT regulation and formation. Cytarabine downregulated TNTs and inhibited NF-κB alone and in combination with daunorubicin, providing additional support for involvement of the NF-κB pathway in TNT formation. Interestingly, daunorubicin was found to localize to lysosomes in TNTs connecting AML cells indicating a novel function of TNTs as drug transporting devices. We conclude that TNT communication could reflect important biological features of AML that may be explored in future therapy development. PMID:27974700

Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells

PubMed Central

George, Joshy; Uyar, Asli; Young, Kira; Kuffler, Lauren; Waldron-Francis, Kaiden; Marquez, Eladio; Ucar, Duygu; Trowbridge, Jennifer J.

2016-01-01

The precise identity of a tumour's cell of origin can influence disease prognosis and outcome. Methods to reliably define tumour cell of origin from primary, bulk tumour cell samples has been a challenge. Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstrate that transforming haematopoietic stem cells (HSCs) and multipotent progenitors results in more aggressive AML than transforming committed progenitor cells. Transcriptome profiling reveals a gene expression signature broadly distinguishing stem cell-derived versus progenitor cell-derived AML, including genes involved in immune escape, extravasation and small GTPase signal transduction. However, whole-genome profiling of open chromatin reveals precise and robust biomarkers reflecting each cell of origin tested, from bulk AML tumour cell sampling. We find that bulk AML tumour cells exhibit distinct open chromatin loci that reflect the transformed cell of origin and suggest that open chromatin patterns may be leveraged as prognostic signatures in human AML. PMID:27397025

Quantitative Analysis of Global Proteome and Lysine Acetylome Reveal the Differential Impacts of VPA and SAHA on HL60 Cells.

PubMed

Zhu, Xiaoyu; Liu, Xin; Cheng, Zhongyi; Zhu, Jun; Xu, Lei; Wang, Fengsong; Qi, Wulin; Yan, Jiawei; Liu, Ning; Sun, Zimin; Liu, Huilan; Peng, Xiaojun; Hao, Yingchan; Zheng, Nan; Wu, Quan

2016-01-29

Valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) are both HDAC inhibitors (HDACi). Previous studies indicated that both inhibitors show therapeutic effects on acute myeloid leukaemia (AML), while the differential impacts of the two different HDACi on AML treatment still remains elusive. In this study, using 3-plex SILAC based quantitative proteomics technique, anti-acetyllysine antibody based affinity enrichment, high resolution LC-MS/MS and intensive bioinformatic analysis, the quantitative proteome and acetylome in SAHA and VPA treated AML HL60 cells were extensively studied. In total, 5,775 proteins and 1,124 lysine acetylation sites were successfully obtained in response to VAP and SAHA treatment. It is found that VPA and SAHA treatment differently induced proteome and acetylome profiling in AML HL60 cells. This study revealed the differential impacts of VPA and SAHA on proteome/acetylome in AML cells, deepening our understanding of HDAC inhibitor mediated AML therapeutics.

KIT mutations correlate with adverse survival in children with core-binding factor acute myeloid leukemia.

PubMed

Chen, Xi; Dou, Hu; Wang, Xingjuan; Huang, Yi; Lu, Ling; Bin, Junqing; Su, Yongchun; Zou, Lin; Yu, Jie; Bao, Liming

2018-04-01

The prevalence and clinical relevance of KIT mutations in childhood core-binding factor (CBF) acute myeloid leukemia (AML) have not been well characterized. In this study, a total of 212 children with de novo AML were enrolled from a Chinese population and 50 (23.5%) of the patients were deemed CBF-AML. KIT mutations were identified in 30% of the CBF-AML cohort. The KIT mutations were clustered in exon 17 and exon 8, and KIT mutations in exons 8 and 17 were correlated with a shorter overall survival (OS) (5-year OS: 30.0 ± 14.5% vs. 73.0 ± 8.5%, p = .007) and event-free survival (EFS) (5-year EFS: 30.0 ± 14.5% vs. 73.0 ± 8.5%, p = .003). Multivariate analysis revealed KIT mutations as an independent risk factor in CBF-AML. Our results suggest that KIT mutations are a molecular marker for an inferior prognosis in pediatric CBF-AML.

Pyrimethamine as a Potent and Selective Inhibitor of Acute Myeloid Leukemia Identified by High-throughput Drug Screening.

PubMed

Sharma, Amit; Jyotsana, Nidhi; Lai, Courteney K; Chaturvedi, Anuhar; Gabdoulline, Razif; Görlich, Kerstin; Murphy, Cecilia; Blanchard, Jan E; Ganser, Arnold; Brown, Eric; Hassell, John A; Humphries, R Keith; Morgan, Michael; Heuser, Michael

2016-01-01

Hematopoietic stem and progenitor cell differentiation are blocked in acute myeloid leukemia (AML) resulting in cytopenias and a high risk of death. Most patients with AML become resistant to treatment due to lack of effective cytotoxic and differentiation promoting compounds. High MN1 expression confers poor prognosis to AML patients and induces resistance to cytarabine and alltrans-retinoic acid (ATRA) induced differentiation. Using a high-throughput drug screening, we identified the dihydrofolate reductase (DHFR) antagonist pyrimethamine to be a potent inducer of apoptosis and differentiation in several murine and human leukemia cell lines. Oral pyrimethamine treatment was effective in two xenograft mouse models and specifically targeted leukemic cells in human AML cell lines and primary patient cells, while CD34+ cells from healthy donors were unaffected. The antileukemic effects of PMT could be partially rescued by excess folic acid, suggesting an oncogenic function of folate metabolism in AML. Thus, our study identifies pyrimethamine as a candidate drug that should be further evaluated in AML treatment.

Mediterranean Diet and Breast Cancer Risk

PubMed Central

Carioli, Greta; Ferraroni, Monica; Serraino, Diego; Montella, Maurizio; Giacosa, Attilio; Toffolutti, Federica; Negri, Eva; Levi, Fabio

2018-01-01

The Mediterranean diet has been related to a reduced risk of several common cancers but its role on breast cancer has not been quantified yet. We investigated the association between adherence to the Mediterranean diet and breast cancer risk by means of a hospital-based case-control study conducted in Italy and Switzerland. 3034 breast cancer cases and 3392 controls admitted to the same network of hospitals for acute, non-neoplastic and non-gynaecologic diseases were studied. Adherence to the Mediterranean diet was quantitatively measured through a Mediterranean Diet Score (MDS), summarizing the major characteristics of the Mediterranean dietary pattern and ranging from 0 (lowest adherence) to 9 (highest adherence). We estimated the odds ratios (ORs) of breast cancer for the MDS using multiple logistic regression models, adjusting for several covariates. Compared to a MDS of 0–3, the ORs for breast cancer were 0.86 (95% confidence interval, CI, 0.76–0.98) for a MDS of 4–5 and 0.82 (95% CI, 0.71–0.95) for a MDS of 6–9 (p for trend = 0.008). The exclusion of the ethanol component from the MDS did not materially modify the ORs (e.g., OR = 0.81, 95% CI, 0.70–0.95, for MDS ≥ 6). Results were similar in pre- and post-menopausal women. Adherence to the Mediterranean diet was associated with a reduced breast cancer risk. PMID:29518016

Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS

PubMed Central

Zhou, Li; Nguyen, Aaron N.; Sohal, Davendra; Ying Ma, Jing; Pahanish, Perry; Gundabolu, Krishna; Hayman, Josh; Chubak, Adam; Mo, Yongkai; Bhagat, Tushar D.; Das, Bhaskar; Kapoun, Ann M.; Navas, Tony A.; Parmar, Simrit; Kambhampati, Suman; Pellagatti, Andrea; Braunchweig, Ira; Zhang, Ying; Wickrema, Amittha; Medicherla, Satyanarayana; Boultwood, Jacqueline; Platanias, Leonidas C.; Higgins, Linda S.; List, Alan F.; Bitzer, Markus

2008-01-01

MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor–β (TGF-β) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34+ cells, providing direct evidence of overactivation of TGF-β pathway in this disease. Suppression of the TGF-β signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-β–mediated gene activation in BM stromal cells, and reverses TGF-β–mediated cell-cycle arrest in BM CD34+ cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-β1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-β signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS. PMID:18474728

[3D printing in health care facilities: What legislation in France?].

PubMed

Montmartin, M; Meyer, C; Euvrard, E; Pazart, L; Weber, E; Benassarou, M

2015-11-01

Health care facilities more and more use 3D printing, including making their own medical devices (MDs). However, production and marketing of MDs are regulated. The goal of our work was to clarify what is the current French regulation that should be applied concerning the production of custom-made MDs produced by 3D printing in a health care facility. MDs consist of all devices used for diagnosis, prevention, or treatment of diseases in patients. Prototypes and anatomic models are not considered as MDs and no specific laws apply to them. Cutting guides, splints, osteosynthesis plates or prosthesis are MDs. In order to become a MD manufacturer in France, a health care facility has to follow the requirements of the 93/42/CEE directive. In addition, custom-made 3D-printed MDs must follow the annex VIII of the directive. This needs the writing of a declaration of conformity and the respect of the essential requirements (proving that a MD is secure and conform to what is expected), the procedure has to be qualified, a risk analysis and a control of the biocompatibility of the material have to be fulfilled. The documents proving that these rules have been respected have to be available. Becoming a regulatory manufacturer of MD in France is possible for a health care facility but the specifications have to be respected. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population.

PubMed

Wei, Hui; Wang, Ying; Zhou, Chunlin; Lin, Dong; Liu, Bingcheng; Liu, Kaiqi; Qiu, Shaowei; Gong, Benfa; Li, Yan; Zhang, Guangji; Wei, Shuning; Gong, Xiaoyuan; Liu, Yuntao; Zhao, Xingli; Gu, Runxia; Mi, Yingchang; Wang, Jianxiang

2018-02-10

Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.

Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia.

PubMed

Shiba, Norio; Yoshida, Kenichi; Shiraishi, Yuichi; Okuno, Yusuke; Yamato, Genki; Hara, Yusuke; Nagata, Yasunobu; Chiba, Kenichi; Tanaka, Hiroko; Terui, Kiminori; Kato, Motohiro; Park, Myoung-Ja; Ohki, Kentaro; Shimada, Akira; Takita, Junko; Tomizawa, Daisuke; Kudo, Kazuko; Arakawa, Hirokazu; Adachi, Souichi; Taga, Takashi; Tawa, Akio; Ito, Etsuro; Horibe, Keizo; Sanada, Masashi; Miyano, Satoru; Ogawa, Seishi; Hayashi, Yasuhide

2016-11-01

Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence. © 2016 John Wiley & Sons Ltd.

Obatoclax potentiates the cytotoxic effect of cytarabine on acute myeloid leukemia cells by enhancing DNA damage.

PubMed

Xie, Chengzhi; Edwards, Holly; Caldwell, J Timothy; Wang, Guan; Taub, Jeffrey W; Ge, Yubin

2015-02-01

Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl-2, Bcl-xL, and/or Mcl-1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti-apoptotic Bcl-2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan-Bcl-2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double-strand breaks (DSBs) preceded a decrease of Mcl-1 levels, nuclear translocation of Bcl-2, Bcl-xL, and Mcl-1, and apoptosis. These results indicate that obatoclax enhances cytarabine-induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA-damaging agents in AML and possibly a broader range of malignancies. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2.

PubMed

Karathedath, Sreeja; Rajamani, Bharathi M; Musheer Aalam, Syed Mohammed; Abraham, Ajay; Varatharajan, Savitha; Krishnamurthy, Partha; Mathews, Vikram; Velayudhan, Shaji Ramachandran; Balasubramanian, Poonkuzhali

2017-01-01

Cytarabine (Ara-C) and Daunorubicin (Dnr) forms the backbone of acute myeloid leukemia (AML) therapy. Drug resistance and toxic side effects pose a major threat to treatment success and hence alternate less toxic therapies are warranted. NF-E2 related factor-2 (Nrf2), a master regulator of antioxidant response is implicated in chemoresistance in solid tumors. However, little is known about the role of Nrf2 in AML chemoresistance and the effect of pharmacological inhibitor brusatol in modulating this resistance. Primary AML samples with high ex-vivo IC50 to Ara-C, ATO, Dnr had significantly high NRF2 RNA expression. Gene-specific knockdown of NRF2 improved sensitivity to these drugs in resistant AML cell lines by decreasing the expression of downstream antioxidant targets of Nrf2 by compromising the cell's ability to scavenge the ROS. Treatment with brusatol, a pharmacological inhibitor of Nrf2, improved sensitivity to Ara-C, ATO, and Dnr and reduced colony formation capacity. AML cell lines stably overexpressing NRF2 showed increased resistance to ATO, Dnr and Ara-C and increased expression of downstream targets. This study demonstrates that Nrf2 could be an ideal druggable target in AML, more so to the drugs that function through ROS, suggesting the possibility of using Nrf2 inhibitors in combination with chemotherapeutic agents to modulate drug resistance in AML.

Genetic polymorphisms of IL-18 rs1946518 and IL-1β rs16944 are associated with prognosis and survival of acute myeloid leukemia.

PubMed

Wang, Hong; Hua, Mingqiang; Wang, Shukang; Yu, Jie; Chen, Chen; Zhao, Xueyun; Zhang, Chen; Zhong, Chaoqin; Wang, Ruiqing; He, Na; Hou, Ming; Ma, Daoxin

2017-03-01

Though the pathogenesis of AML is still unknown, accumulating evidence revealed that immune response plays a vital part in it. NLRP3 inflammasome as a component of immune system has been found related to several cancers. The single nucleotide polymorphisms (SNPs) of NLRP3 inflammasome genes may be related to pathogenesis and prognosis of AML. We determined polymorphisms of NLRP3 (rs35829419), CARD8 (rs2043211), IL-1β (rs16944), IL-18 (rs1946518) and NF-κB -94 ins/del ATTG in de novo AML patients to find out whether they play roles in the susceptibility and severity of AML. In our study, 383 AML cases and 300 randomly selected healthy individuals were examined for the polymorphisms and expression of NLRP3 genes. IL-1β (rs16944) polymorphism in different risk AML subgroups was found statistically different, with more GA genotype in favorable-risk cytogenetics group. We also demonstrated that the bone marrow blasts of patients carrying IL-18 (rs1946518) GG or GT genotype were higher than patients of TT genotype. IL-18 plasma level of patients with IL-18 (rs1946518) GT or TT genotype was higher than GG genotype. Moreover, the GT genotype of IL-18 (rs1946518) led to statistically poorer AML-specific survival. IL-1β (rs16944) and IL-18 (rs1946518) may be served as potential predictors for AML.

[Expression of BAG3 Gene in Acute Myeloid Leukemia and Its Prognostic Value].

PubMed

Zhu, Hua-Yuan; Fu, Yuan; Wu, Wei; Xu, Jia-Dai; Chen, Ting-Mei; Qiao, Chun; Li, Jian-Yong; Liu, Peng

2015-08-01

To investigate the expression of BAG3 gene in acue myeloid leukemia (AML) and its prognostic value. Real-time quantitative RT-PCR was used to detect the expression of BAG3 mRNA in 88 previously untreated AML patients. The corelation of BAG3 expression level with clinical characteristics and known prognostic markers of AML was analyzed. In 88 patients with AML, the expression of BAG3 mRNA in NPMI mutated AML patients was obviously lower than that in NPMI unmutated patients (P = 0.018). The expression level of BAG3 mRNA did not related to clinical parameters, such as age, sex, FAB subtype, WBC count, extra-modullary presentation, and to prognostic factors including cytogenetics, FLT3-ITD, c-kit and CEBPα mutation status (P > 0.05). The expression level of BAG3 had no obvious effect on complete remission (CR) of patients in first treatment. The expression level of BAG3 in non-M3 patients was higher than that in relapsed patients (P = 0.036). The expression level of BAG3 had no effect on overall survival (OS) of patients. The expression level of BAG3 does not correlated with known-prognostic markers of AML, only the expression level of BAG3 in NPM1 mutated patients is lower than that in NPM1 unmutated patients. The expression level of BAG3 has no effect on OS of AML patients, the BAG3 can not be difined as a prognostic marker in AML.

MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia

PubMed Central

Verboon, Lonneke J.; Obulkasim, Askar; de Rooij, Jasmijn D.E.; Katsman, Jenny E.; Sonneveld, Edwin; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Pieters, Rob; Cloos, Jacqueline; Kaspers, Gertjan J.L.; Klusmann, Jan-Henning; Zwaan, Christian Michel; Fornerod, Maarten; van den Heuvel-Eibrink, Marry M.

2016-01-01

The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements. PMID:27351222

Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network

PubMed Central

Carter, Bing Z.; Mak, Po Yee; Chen, Ye; Mak, Duncan H.; Mu, Hong; Jacamo, Rodrigo; Ruvolo, Vivian; Arold, Stefan T.; Ladbury, John E.; Burks, Jared K.; Kornblau, Steven; Andreeff, Michael

2016-01-01

To better understand how the apoptosis repressor with caspase recruitment domain (ARC) protein confers drug resistance in acute myeloid leukemia (AML), we investigated the role of ARC in regulating leukemia-mesenchymal stromal cell (MSC) interactions. In addition to the previously reported effect on AML apoptosis, we have demonstrated that ARC enhances migration and adhesion of leukemia cells to MSCs both in vitro and in a novel human extramedullary bone/bone marrow mouse model. Mechanistic studies revealed that ARC induces IL1β expression in AML cells and increases CCL2, CCL4, and CXCL12 expression in MSCs, both through ARC-mediated activation of NFκB. Expression of these chemokines in MSCs increased by AML cells in an ARC/IL1β-dependent manner; likewise, IL1β expression was elevated when leukemia cells were co-cultured with MSCs. Further, cells from AML patients expressed the receptors for and migrated toward CCL2, CCL4, and CXCL12. Inhibition of IL1β suppressed AML cell migration and sensitized the cells co-cultured with MSCs to chemotherapy. Our results suggest the existence of a complex ARC-regulated circuit that maintains intimate connection of AML with the tumor microenvironment through NFκB/IL1β-regulated chemokine receptor/ligand axes and reciprocal crosstalk resulting in cytoprotection. The data implicate ARC as a promising drug target to potentially sensitize AML cells to chemotherapy. PMID:26956049

Systematic review of health state utility values for acute myeloid leukemia.

PubMed

Forsythe, Anna; Brandt, Patricia S; Dolph, Mike; Patel, Sachin; Rabe, Adrian Paul J; Tremblay, Gabriel

2018-01-01

Cost-utility analyses for acute myeloid leukemia (AML) require health state utility values (HSUVs) in order to calculate quality-adjusted life-years (QALYs) for each health state. This study reviewed AML-related HSUVs that could be used in economic evaluation studies. EMBASE, MEDLINE, and Cochrane databases were searched from January 2000 to November 2016 for relevant studies that reported quality of life (QoL) and HSUVs in AML. Identified relevant European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 values were mapped to HSUVs. HSUVs for each health state in the AML treatment pathway were then collated. Ten relevant studies were identified. Six were cost-effectiveness analyses utilizing HSUVs for calculation of QALYs, one was an effectiveness analysis (incremental QALY), and two were QoL studies reporting AML-specific utilities. An additional study reported QoL for patients undergoing stem cell transplantation (SCT). Since no study reported HSUVs for relapse, values from a study of secondary AML patients who failed prior treatment for myelodysplastic syndrome were used. Where multiple HSUVs were available, collected values were given priority over assumed values. AML treatment (induction, consolidation, or SCT) was associated with decreased HSUV, while post-treatment complete remission led to increased HSUV. There are some methodologically robust HSUVs that can be directly used in economic evaluations for AML. Careful interpretation is advised considering significant differences in methodologies and patient population (inclusion, size). We need to develop HSUVs with larger-sized studies, making greater use of condition-specific data.

Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

PubMed Central

Kamga, Paul Takam; Bassi, Giulio; Cassaro, Adriana; Midolo, Martina; Di Trapani, Mariano; Gatti, Alessandro; Carusone, Roberta; Resci, Federica; Perbellini, Omar; Gottardi, Michele; Bonifacio, Massimiliano; Kamdje, Armel Hervé Nwabo; Ambrosetti, Achille; Krampera, Mauro

2016-01-01

Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB. These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML. PMID:26967055

Design for Social Presence and Exploring Its Mediating Effect in Mobile Data Communication Services

ERIC Educational Resources Information Center

Ogara, Solomon Omondi

2011-01-01

The mobility, flexibility, convenience, and ubiquity of mobile data services (MDS) have contributed to their enormous growth and popularity with users. MDS allow users to communicate through mobile texting (mTexting), mobile Instant Messaging (mIM), multimedia messaging services (MMS), and email. A unique feature of MDS that enhances its…

Enhanced plasma protein carbonylation in patients with myelodysplastic syndromes.

PubMed

Hlaváčková, Alžběta; Štikarová, Jana; Pimková, Kristýna; Chrastinová, Leona; Májek, Pavel; Kotlín, Roman; Čermák, Jaroslav; Suttnar, Jiří; Dyr, Jan Evangelista

2017-07-01

Myelodysplastic syndromes (MDS) represent a heterogeneous group of pre-leukemic disorders, characterized by ineffective hematopoiesis and the abnormal blood cell development of one or more lineages. Oxidative stress, as an important factor in the carcinogenesis of onco-hematological diseases, is also one of the known factors involved in the pathogenesis of MDS. An increase of reactive oxygen species (ROS) may lead to the oxidation of DNA, lipids, and proteins, thereby causing cell damage. Protein carbonylation caused by ROS is defined as an irreversible post-translational oxidative modification of amino acid side chains, and could play an important role in signaling processes. The detection of protein carbonyl groups is a specific useful marker of oxidative stress. In this study, we examined 32 patients divided into three different subtypes of MDS according to the World Health Organization (WHO) classification criteria as refractory anemia with ringed sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with excess blasts-1,2 (RAEB-1,2). We found significant differences in protein carbonylation between the group of all MDS patients and healthy controls (P=0.0078). Furthermore, carbonylated protein levels were significantly elevated in RARS patients compared to healthy donors (P=0.0013) and to RCMD patients (P=0.0277). We also found a significant difference in the total iron binding capacity (TIBC) between individual subgroups of MDS patients (P=0.0263). Moreover, TIBC was decreased in RARS patients compared to RCMD patients (P=0.0203). TIBC moderately negatively correlated with carbonyl levels (r=-0.5978, P=0.0054) in the MDS patients as a whole. Additionally we observed changes in the carbonylated proteins of RARS patients in comparison with healthy controls and their negative controls. Using tandem mass spectrometry (LC-MS/MS) we identified 27 uniquely carbonylated proteins of RARS patients, which were generated by ROS and could influence the pathophysiology of low-risk MDS. These data indicate that increased protein carbonylation is related with RARS as low-risk MDS subgroup. We suggest that this type of post-translational modification in MDS disease is not "only" a consequence of oxidative stress, but also plays an active role in the pathophysiology and iron metabolism within the RARS subgroup of MDS. Measurement of plasma carbonyl levels and the isolation of carbonylated plasma proteins, followed by their identification, could serve as a potential diagnostic and prognostic tool in MDS. Copyright © 2017 Elsevier Inc. All rights reserved.

Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies.

PubMed

Komrokji, Rami; Swern, Arlene S; Grinblatt, David; Lyons, Roger M; Tobiasson, Magnus; Silverman, Lewis R; Sayar, Hamid; Vij, Ravi; Fliss, Albert; Tu, Nora; Sugrue, Mary M

2018-02-01

After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response. Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by anemia. After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta-analysis of 233 azacitidine-treated red blood cell (RBC) transfusion-dependent patients with LR-MDS (92.3% non-del[5q]) from 7 studies showed 38.9% became RBC transfusion-independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non-del(5q) LR-MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR-MDS patients. © AlphaMed Press 2017.

Nuances of Morphology in Myelodysplastic Diseases in the Age of Molecular Diagnostics.

PubMed

Shaver, Aaron C; Seegmiller, Adam C

2017-10-01

Morphologic dysplasia is an important factor in diagnosis of myelodysplastic syndrome (MDS). However, the role of dysplasia is changing as new molecular genetic and genomic technologies take a more prominent place in diagnosis. This review discusses the role of morphology in the diagnosis of MDS and its interactions with cytogenetic and molecular testing. Recent changes in diagnostic criteria have attempted to standardize approaches to morphologic diagnosis of MDS, recognizing significant inter-observer variability in assessment of dysplasia. Definitive correlates between cytogenetic/molecular and morphologic findings have been described in only a small set of cases. However, these genetic and morphologic tools do play a complementary role in the diagnosis of both MDS and other myeloid neoplasms. Diagnosis of MDS requires a multi-factorial approach, utilizing both traditional morphologic as well as newer molecular genetic techniques. Understanding these tools, and the interplay between them, is crucial in the modern diagnosis of myeloid neoplasms.

Simplified model of mean double step (MDS) in human body movement

NASA Astrophysics Data System (ADS)

Dusza, Jacek J.; Wawrzyniak, Zbigniew M.; Mugarra González, C. Fernando

In this paper we present a simplified and useful model of the human body movement based on the full gait cycle description, called the Mean Double Step (MDS). It enables the parameterization and simplification of the human movement. Furthermore it allows a description of the gait cycle by providing standardized estimators to transform the gait cycle into a periodical movement process. Moreover the method of simplifying the MDS model and its compression are demonstrated. The simplification is achieved by reducing the number of bars of the spectrum and I or by reducing the number of samples describing the MDS both in terms of reducing their computational burden and their resources for the data storage. Our MDS model, which is applicable to the gait cycle method for examining patients, is non-invasive and provides the additional advantage of featuring a functional characterization of the relative or absolute movement of any part of the body.

Graphical representation of clinical outcomes for patients with myelodysplastic syndromes.

PubMed

Steensma, David P

2016-01-01

The causes of death in patients with myelodysplastic syndromes (MDS) are diverse: infections, hemorrhage, complications of chronic anemia and repeated blood transfusions, and complications of progression to acute myeloid leukemia. Since most patients with MDS are diagnosed late in life, some individuals with MDS will succumb to an unrelated condition, such as one of the disorders that are common in geriatric populations. Currently, only a small proportion of patients with MDS - less than 5% - undergo allogeneic stem cell transplantation, a procedure that offers the only possibility of cure. This brief review summarizes outcomes for patients diagnosed with MDS using a pictographical format that illustrates both the challenges patients face and the pressing need for development of novel therapies, as well as highlighting the potential for increased use of allogeneic stem cell transplant. This informational graphic may be useful for teaching or in counseling certain patients.

Hospital-Based Case-Control Study of MDS Subtypes and Benzene Exposure in Shanghai

PubMed Central

Copley, G. Bruce; Schnatter, A. Robert; Armstrong, Thomas W.; Irons, Richard D.; Chen, Min; Wang, Xiao Qin; Kerzic, Patrick

2017-01-01

Objective: Due to the sparse data on benzene exposure and myelodysplastic syndrome (MDS) subtypes, we studied this relationship in patients from 29 hospitals in Shanghai, China. Methods: We recruited 604 cases of MDS and 1193 controls matched on age, sex, and admission date. We interviewed subjects for information on workplace and lifestyle exposures, and developed semi-quantitative exposure estimates. Results: Benzene exposure showed a direct exposure–response pattern with refractory cytopenia with multilineage dysplasia, a less certain association with refractory cytopenia with unilineage dysplasia, and no association with other MDS subtypes. A different pattern was observed with farm residence and smoking, which was primarily related to refractory anemias. Conclusions: This research demonstrates the importance of MDS subtype specification for more robust etiologic insights. Our data suggests that subtypes with non-erythroid dysplasia are associated with benzene exposure. PMID:28146040

Blood disorders typically associated with renal transplantation

PubMed Central

Yang, Yu; Yu, Bo; Chen, Yun

2015-01-01

Renal transplantation has become one of the most common surgical procedures performed to replace a diseased kidney with a healthy kidney from a donor. It can help patients with kidney failure live decades longer. However, renal transplantation also faces a risk of developing various blood disorders. The blood disorders typically associated with renal transplantation can be divided into two main categories: (1) Common disorders including post-transplant anemia (PTA), post-transplant lymphoproliferative disorder (PTLD), post-transplant erythrocytosis (PTE), and post-transplant cytopenias (PTC, leukopenia/neutropenia, thrombocytopenia, and pancytopenia); and (2) Uncommon but serious disorders including hemophagocytic syndrome (HPS), thrombotic microangiopathy (TMA), therapy-related myelodysplasia (t-MDS), and therapy-related acute myeloid leukemia (t-AML). Although many etiological factors involve the development of post-transplant blood disorders, immunosuppressive agents, and viral infections could be the two major contributors to most blood disorders and cause hematological abnormalities and immunodeficiency by suppressing hematopoietic function of bone marrow. Hematological abnormalities and immunodeficiency will result in severe clinical outcomes in renal transplant recipients. Understanding how blood disorders develop will help cure these life-threatening complications. A potential therapeutic strategy against post-transplant blood disorders should focus on tapering immunosuppression or replacing myelotoxic immunosuppressive drugs with lower toxic alternatives, recognizing and treating promptly the etiological virus, bacteria, or protozoan, restoring both hematopoietic function of bone marrow and normal blood counts, and improving kidney graft survival. PMID:25853131

Posaconazole vs fluconazole or itraconazole for prevention of invasive fungal diseases in patients with acute myeloid leukemia or myelodysplastic syndrome: a cost-effectiveness analysis in an Asian teaching hospital.

PubMed

Chan, Thomas S Y; Marcella, Stephen W; Gill, Harinder; Hwang, Yu-Yan; Kwong, Yok-Lam

2016-01-01

Posaconazole is superior to fluconazole/itraconazole in preventing invasive fungal diseases (IFDs) in neutropenic patients. Whether the higher cost of posaconazole is offset by decreases in IFDs in a given institute requires cost-effective analysis encompassing the spectrum of IFDs and socioeconomic factors specific to that geographic area. This study performed a cost-effective analysis of posaconazole prophylaxis for IFDs in an Asian teaching hospital, employing decision modeling and data of IFDs and medication costs specific to the institute, in neutropenic patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In the cost-effectiveness analysis, the higher cost of posaconazole was partially offset by a reduction in the cost of treating IFDs that were prevented, resulting in an incremental cost of 125,954 Hong Kong dollars/16,148 USD per IFD avoided. Over a lifetime horizon, assuming same case fatality rate of IFDs in both groups, use of posaconazole results in 0.07 discounted life years saved. This corresponds to an incremental cost of 116,023 HKD/14,875 USD per life year saved. This incremental cost per life year saved in posaconazole prophylaxis fulfilled the World Health Organization defined threshold for cost-effectiveness. Posaconazole prophylaxis was cost-effective in Hong Kong.

Experience with Saccharomyces boulardii Probiotic in Oncohaematological Patients.

PubMed

Sulik-Tyszka, Beata; Snarski, Emilian; Niedźwiedzka, Magda; Augustyniak, Małgorzata; Myhre, Thorvald Nilsen; Kacprzyk, Anna; Swoboda-Kopeć, Ewa; Roszkowska, Marta; Dwilewicz-Trojaczek, Jadwiga; Jędrzejczak, Wiesław Wiktor; Wróblewska, Marta

2018-06-01

Very few reports have been published to date on the bloodstream infections caused by Saccharomyces spp. in oncohaematological patients, and there are no guidelines on the use of this probiotic microorganism in this population. We describe the use of probiotic preparation containing Saccharomyces boulardii in a large group of oncohaematological patients. We retrospectively analysed the data from 32,000 patient hospitalisations at the haematological centre during 2011-2013 (including 196 haematopoietic stem cell transplant recipients) in a tertiary care university-affiliated hospital. During the study period, 2270 doses of Saccharomyces boulardii probiotic were administered to the oncohaematological patients. In total, 2816 mycological cultures were performed, out of which 772 (27.4%) were positive, with 52 indicating digestive tract colonisation by Saccharomyces spp., mainly in patients with acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) or multiple myeloma (MM). While colonised, they were hospitalised for 1683 days and 416 microbiological cultures of their clinical samples were performed. In the studied group of patients, there were six blood cultures positive for fungi; however, they comprised Candida species: two C. glabrata, one C. albicans, one C. krusei, one C. tropicalis and one C. parapsilosis. There was no blood culture positive for Saccharomyces spp. Our study indicates that despite colonisation of many oncohaematological patients with Saccharomyces spp., there were no cases of fungal sepsis caused by this species.

Long-term safety and outcome of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimen in previously untreated patients with advanced follicular lymphoma: 12 years follow-up of a phase 2 trial.

PubMed

Magnano, Laura; Montoto, Silvia; González-Barca, Eva; Briones, Javier; Sancho, Juan Manuel; Muntañola, Ana; Salar, Antonio; Besalduch, Joan; Escoda, Lourdes; Moreno, Carol; Domingo-Domenech, Eva; Estany, Cristina; Oriol, Albert; Altés, Albert; Pedro, Carmen; Gardella, Santiago; Asensio, Antoni; Vivancos, Pilar; Fernández de Sevilla, Alberto; Ribera, Josep María; Colomer, Dolors; Campo, Elias; López-Guillermo, Armando

2017-04-01

Fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible.

Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML

ClinicalTrials.gov

2018-03-05

Relapsed Acute Lymphoblastic Leukemia (ALL); Refractory Acute Lymphoblastic Leukemia (ALL); Relapsed Acute Myelogenous Leukemia (AML); Refractory Acute Myelogenous Leukemia (AML); Relapsed Mixed Lineage Leukemia; Refractory Mixed Lineage Leukemia; Relapsed Biphenotypic Leukemia; Refractory Biphenotypic Leukemia; Chronic Myelogenous Leukemia (CML) in Blast Crisis

Dawn of Aurora kinase inhibitors as anticancer drugs.

PubMed

Doggrell, Sheila A

2004-09-01

With the current standard chemotherapy regimens only approximately 25% of acute myelogenous leukaemia (AML) patients survive > 5 years. Aurora kinases are overexpressed in many human cancers. VX-680 inhibited Aurora-A, -B, -C and the FMS-like tyrosine kinase-3 with apparent inhibitory constants of 0.6, 18, 4.6 and 30 nM, respectively. In primary leukaemia cells from patients with AML, which were refractory to standard therapies, VX-680 inhibited colony formation. In nude mice, VX-680 markedly reduced human AML tumours. The development of VX-680 for use in AML should continue.

Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia.

PubMed

Alachkar, Houda; Mutonga, Martin B G; Metzeler, Klaus H; Fulton, Noreen; Malnassy, Gregory; Herold, Tobias; Spiekermann, Karsten; Bohlander, Stefan K; Hiddemann, Wolfgang; Matsuo, Yo; Stock, Wendy; Nakamura, Yusuke

2014-12-15

Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.

Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

PubMed Central

Alachkar, Houda; Mutonga, Martin B.G.; Metzeler, Klaus H.; Fulton, Noreen; Malnassy, Gregory; Herold, Tobias; Spiekermann, Karsten; Bohlander, Stefan K.; Hiddemann, Wolfgang; Matsuo, Yo; Stock, Wendy; Nakamura, Yusuke

2014-01-01

Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients. PMID:25365263

[Identification of novel pathogenic gene mutations in pediatric acute myeloid leukemia by whole-exome resequencing].

PubMed

Shiba, Norio

2015-12-01

A new class of gene mutations, identified in the pathogenesis of adult acute myeloid leukemia (AML), includes DNMT3A, IDH1/2, TET2 and EZH2. However, these mutations are rare in pediatric AML cases, indicating that pathogeneses differ between adult and pediatric forms of AML. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across entire genomes or proteincoding sequences. In order to reveal a complete registry of gene mutations, we performed whole exome resequencing of paired tumor-normal specimens from 19 pediatric AML cases using Illumina HiSeq 2000. In total, 80 somatic mutations or 4.2 mutations per sample were identified. Many of the recurrent mutations identified in this study involved previously reported targets in AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1 and EZH2. On the other hand, several genes were newly identified in the current study, including BCORL1 and major cohesin components such as SMC3 and RAD21. Whole exome resequencing revealed a complex array of gene mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that could be discriminated from its adult counterpart, in terms of the spectrum of gene mutations.

Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches

PubMed Central

Pereira, Olga; Sampaio-Marques, Belém; Paiva, Artur; Correia-Neves, Margarida; Castro, Isabel; Ludovico, Paula

2015-01-01

The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes. PMID:25537507

Paracentric inversion-associated t(8;21) variant in de novo acute myelogenous leukemia: characteristic patterns of conventional cytogenetics, FISH, and multicolor banding analysis.

PubMed

Park, Tae Sung; Song, Jaewoo; Lee, Kyung-A; Min, Yoo Hong; Lee, Sang-Guk; Park, Yongjung; Kim, Juwon; Lee, Eun Yup; Choi, Jong Rak

2008-05-01

Acute myelogenous leukemia (AML) with t(8;21)(q22;q22) demonstrates unique clinico-pathologic disease entity in patients with hematologic malignancies. The t(8;21), which results in fusion of the AML1 gene on 21q22 and the ETO gene on 8q22 on a molecular level, is one of the most common nonrandom chromosomal changes, and it is found in about 5-12% of patients with AML. Among these cases, complex variants involving chromosomes 8 and 21, as well as a third or fourth chromosome, account for approximately 6-10% of patients with an AML1/ETO chimeric gene, and about 100 variant cases with AML1/ETO fusion transcript have been reported in the literature. Here, we describe a rare case report of reciprocal paracentric inversion-associated t(8;21) variant in a 28-year old male patient with de novo AML. The abnormal results of conventional cytogenetics and interphase fluorescent in situ hybridization in this patient drove us to perform further studies and a literature review. This report emphasizes the value of "conventional" cytogenetics, as well as "newly developed" molecular cytogenetic methods in the diagnosis of rare complex t(8;21) variant in patients with AML. Copyright 2008 Elsevier Inc.

The role of HOXB2 and HOXB3 in acute myeloid leukemia.

PubMed

Lindblad, Oscar; Chougule, Rohit A; Moharram, Sausan A; Kabir, Nuzhat N; Sun, Jianmin; Kazi, Julhash U; Rönnstrand, Lars

2015-11-27

Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML. Copyright © 2015 Elsevier Inc. All rights reserved.

The role of HOXB2 and HOXB3 in acute myeloid leukemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindblad, Oscar; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund; Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund

2015-11-27

Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2more » and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML.« less

New molecular abnormalities and clonal architecture in AML: from reciprocal translocations to whole-genome sequencing.

PubMed

Graubert, Timothy A; Brunner, Andrew M; Fathi, Amir T

2014-01-01

Acute myeloid leukemia (AML) is characterized by recurrent genetic alterations, including amplifications, deletions, rearrangements, and point mutations. Clinically, these lesions can be used to stratify patients into categories of risk, which directs further clinical management and prognostication. Patient risk categories were first described based on recurrent karyotypic abnormalities; most patients with AML, however, fall into intermediate cytogenetic risk, the majority harboring a normal karyotype. Subsequently, identification of recurrently mutated genes, including FLT3, NPM1, and CEBPA, allowed further stratification of patients with a normal karyotype. More extensive genomic and epigenomic analysis of AML samples has expanded the number of known molecular alterations present in this disease. The further understanding of this mutational landscape has shed light into the pathogenesis of AML. AML arises in a founding clone that often gives rise to subclones. Clonal evolution is a feature of the natural history of the disease but may also be influenced by the selective pressure of chemotherapy. The complex network of genetic and epigenetic alterations in this disease has yielded numerous new targets for intervention. In the future, further understanding of this mutational framework, along with the development of novel therapeutic targets, may lead to improved outcomes for patients with AML.

Multidetector Computed Tomography Features in Differentiating Exophytic Renal Angiomyolipoma from Retroperitoneal Liposarcoma

PubMed Central

Wang, Qiushi; Juan, Yu-Hsiang; Li, Yong; Xie, Jia-Jun; Liu, Hui; Huang, Hongfei; Liu, Zaiyi; Zheng, Junhui; Saboo, Ujwala S.; Saboo, Sachin S.; Liang, Changhong

2015-01-01

Abstract This study aims to evaluate the multidetector computed tomography (CT) imaging features in differentiating exophytic renal angiomyolipoma (AML) from retroperitoneal liposarcoma. We retrospectively enrolled 42 patients with confirmed exophytic renal AML (31 patients) or retroperitoneal liposarcoma (11 patients) during 8 years period to assess: renal parenchymal defect at site of tumor contact, supply from branches of renal artery, tumoral vessel extending through the renal parenchyma, dilated intratumoral vessels, hemorrhage, non–fat-containing intratumoral nodules with postcontrast enhancement, calcification, renal sinus enlargement, anterior displacement of kidneys, and other associated AML. Renal parenchymal defect, renal arterial blood supply, tumoral vessel through the renal parenchyma, dilated intratumoral vessels, intratumoral/perirenal hemorrhage, renal sinus enlargement, and associated AML were seen only or mainly in exophytic renal AML (all P value < 0.05); however, non–fat-attenuating enhancing intratumoral nodules, intratumoral calcification, and anterior displacement of the kidney were more common in liposarcoma (all P value < 0.05). AMLs reveal renal parenchymal defect at the site of tumor contact, supply from renal artery, tumoral vessel extending through the renal parenchyma, dilated intratumoral vessels, intratumoral and/or perirenal hemorrhage, renal sinus enlargement, and associated AML. Non–fat-attenuating enhancing intratumoral nodules, intratumoral calcifications, and anterior displacement of kidney were more commonly seen in liposarcoma. PMID:26376398

Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients.

PubMed

Rapin, Nicolas; Bagger, Frederik Otzen; Jendholm, Johan; Mora-Jensen, Helena; Krogh, Anders; Kohlmann, Alexander; Thiede, Christian; Borregaard, Niels; Bullinger, Lars; Winther, Ole; Theilgaard-Mönch, Kim; Porse, Bo T

2014-02-06

Gene expression profiling has been used extensively to characterize cancer, identify novel subtypes, and improve patient stratification. However, it has largely failed to identify transcriptional programs that differ between cancer and corresponding normal cells and has not been efficient in identifying expression changes fundamental to disease etiology. Here we present a method that facilitates the comparison of any cancer sample to its nearest normal cellular counterpart, using acute myeloid leukemia (AML) as a model. We first generated a gene expression-based landscape of the normal hematopoietic hierarchy, using expression profiles from normal stem/progenitor cells, and next mapped the AML patient samples to this landscape. This allowed us to identify the closest normal counterpart of individual AML samples and determine gene expression changes between cancer and normal. We find the cancer vs normal method (CvN method) to be superior to conventional methods in stratifying AML patients with aberrant karyotype and in identifying common aberrant transcriptional programs with potential importance for AML etiology. Moreover, the CvN method uncovered a novel poor-outcome subtype of normal-karyotype AML, which allowed for the generation of a highly prognostic survival signature. Collectively, our CvN method holds great potential as a tool for the analysis of gene expression profiles of cancer patients.

Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death.

PubMed

Heo, Sook-Kyoung; Noh, Eui-Kyu; Kim, Jeong Yi; Jeong, Yoo Kyung; Jo, Jae-Cheol; Choi, Yunsuk; Koh, SuJin; Baek, Jin Ho; Min, Young Joo; Kim, Hawk

2017-11-10

Dasatinib and radotinib are oral BCR-ABL tyrosine kinase inhibitors that were developed as drugs for the treatment of chronic myeloid leukemia. We report here that the c-KIT (CD117) targeting with dasatinib and radotinib promotes acute myeloid leukemia (AML) cell death, and c-KIT endocytosis is essential for triggering c-KIT-positive AML cell death by dasatinib and radotinib during the early stages. In addition, dasatinib and radotinib reduce heat shock protein 90β (HSP90β) expression and release Apaf-1 in c-KIT-positive AML cells. Finally, this activates a caspase-dependent apoptotic pathway in c-KIT-positive AML cells. Moreover, the inhibition of c-KIT endocytosis by dynamin inhibitor (DY) reversed cell viability and c-KIT expression by dasatinib and radotinib. HSP90β expression was recovered by DY in c-KIT-positive AML cells as well. Furthermore, the effect of radotinib on c-KIT and HSP90β showed the same pattern in a xenograft animal model using HEL92.1.7 cells. Therefore, dasatinib and radotinib promote AML cell death by targeting c-KIT. Taken together, these results indicate that dasatinib and radotinib treatment have a potential role in anti-leukemic therapy on c-KIT-positive AML cells.

Efficacy and safety of long-term treatment with the combination of amlodipine besylate and olmesartan medoxomil in patients with hypertension.

PubMed

Chrysant, Steven G; Oparil, Suzanne; Melino, Michael; Karki, Sulekha; Lee, James; Heyrman, Reinilde

2009-09-01

J Clin Hypertens (Greenwich). 2009;11:475-482. (c) 2009 Wiley Periodicals, Inc.The authors report on the 44-week open-label extension of the 8-week, double-blind Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial in 1684 patients. Initial therapy was amlodipine (AML) plus olmesartan medoxomil (OM) 5+40 mg/d, up-titrated to AML+OM 10+40 mg/d plus hydrochlorothiazide (HCTZ) 12.5 mg then 25 mg if patients did not achieve blood pressure (BP) goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes). Baseline mean BP decreased from 164/102 mm Hg to 131/82 mm Hg at end of study, with an overall 66.7% of patients, including those with diabetes, achieving BP goal. The BP goal achievement was 80% for AML+OM 5+40 mg/d, 70.6% for AML+OM 10+40 mg/d, 66.6% for AML+OM+HCTZ 10+40+12.5 mg/d, and 46.3% for AML+OM+HCTZ 10+40+25 mg/d. Study medication was safe and well tolerated. Combination antihypertensive therapy with AML+OM+/-HTCZ, up-titrated as necessary, allowed a majority of patients to achieve BP goal.

Delineation of yet unknown cryptic subtelomere aberrations in 50% of acute myeloid leukemia with normal GTG-banding karyotype.

PubMed

Gross, Madeleine; Mkrtchyan, Hasmik; Glaser, Melanie; Fricke, Hans Jörg; Höffken, Klaus; Heller, Anita; Weise, Anja; Liehr, Thomas

2009-02-01

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to clinical prognosis and acquired chromosomal aberrations. After routine banding cytogenetic analysis 45% of AML patients show a normal karyotype (NK-AML). For a better understanding of development and progression in AML, it is important to find markers which could be primary genetic aberrations. Therefore, in this study 31 patients with NK-AML were analyzed by new high resolution molecular cytogenetic approaches. A combination of multitude multicolor banding and metaphase microdissection-based comparative genomic hybridization revealed deletions of the subtelomeric regions in 6% of the studied cases. According to these results, locus-specific probes for the subtelomeric regions of chromosomes 5, 9, 11, 12 and 13 were applied on 22 of the studied 31 NK-AML cases. Surprisingly, 50% of them showed deletions or duplications. These aberrations occurred in the in vitro proliferating as well as in the non-proliferating cells. Meta-analysis of the aberrant regions revealed that they often include genes known to be associated with tumors, e.g. RASA3 on chromosome 13. These results implicate that aberrations in the subtelomeric regions of NK-AML occur quite often and may be considered as primary genetic changes, and should not be neglected in future diagnostic approaches.

Reovirus-Mediated Cytotoxicity and Enhancement of Innate Immune Responses Against Acute Myeloid Leukemia

PubMed Central

Hall, Kathryn; Scott, Karen J.; Rose, Ailsa; Desborough, Michael; Harrington, Kevin; Pandha, Hardev; Parrish, Christopher; Vile, Richard; Coffey, Matt; Bowen, David; Errington-Mais, Fiona

2012-01-01

Abstract Reovirus is a naturally occurring oncolytic virus that has shown preclinical efficacy in the treatment of a wide range of tumor types and has now reached phase III testing in clinical trials. The anti-cancer activity of reovirus has been attributed to both its direct oncolytic activity and the enhancement of anti-tumor immune responses. In this study, we have investigated the direct effect of reovirus on acute myeloid leukemia (AML) cells and its potential to enhance innate immune responses against AML, including the testing of primary samples from patients. Reovirus was found to replicate in and kill AML cell lines, and to reduce cell viability in primary AML samples. The pro-inflammatory cytokine interferon alpha (IFNα) and the chemokine (C-C motif) ligand 5 (known as RANTES [regulated upon activation, normal T-cell expressed, and secreted]) were also secreted from AML cells in response to virus treatment. In addition, reovirus-mediated activation of natural killer (NK) cells, within the context of peripheral blood mononuclear cells, stimulated their anti-leukemia response, with increased NK degranulation and IFNγ production and enhanced killing of AML targets. These data suggest that reovirus has the potential as both a direct cytotoxic and an immunotherapeutic agent for the treatment of AML. PMID:23515241

Constitutional sequence variation in the Fanconi anaemia group C (FANCC) gene in childhood acute myeloid leukaemia.

PubMed

Barber, Lisa M; McGrath, Helen E N; Meyer, Stefan; Will, Andrew M; Birch, Jillian M; Eden, Osborn B; Taylor, G Malcolm

2003-04-01

The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

HZE Radiation Leukemogenesis in Mice

NASA Astrophysics Data System (ADS)

Peng, Yuanlin

Radiation exposure is a risk factor for acute myeloid leukemia (AML). The Leukemogenesis NSCOR was developed to compare this risk for low LET vs HZE radiations as a means to better assess the leukemia risk to astronauts posed by space radiation. Individual projects within the NSCOR explore HZE radiation leukemogenesis in murine model systems and extend the findings to AML in humans. AML sensitive CBA/CaJ mice have been irradiated with 1 GeV 56 Fe particles at NSRL and with 137 Cs gamma-rays at Colorado State University and followed to 800 days of age for the development of AML. Molecular and cytogenetic analyses of HZE- and gamma-induced AML, including assays for chromosomal aberrations, PU.1 deletion, gene expression, array CGH and microsatellite instability are ongoing. Preliminary data indicate that 56 Fe particles are no more effective in inducing AML or shortening lifespan than gamma-rays. Studies designed to address the individual molecular steps in leukemogenesis and determine the effects of radiation and genetic background on each step have been initiated using knockout mice. Deletion of the PU.1 gene on mouse chromosome 2 is a critical step in this murine model of radiation leukemogenesis. Two of the three HZE-induced AMLs that could be assayed and thirteen of fourteen γ-induced AMLs had PU.1 loss as determined by Fluorescence in Situ Hybridization (FISH). We have found that AML sensitive CBA/CaJ mice have a higher incidence of Chr. 2 deletion in bone marrow cells following 56 Fe irradiation than AML resistant C57BL/6 mice. This study is being extended to proton irradiated mice. Our preliminary results indicate that microsatellite instability may be common in HZE irradiated progenitor cells. To determine if these cytogenetic changes can be induced in human myeloid progenitor cells by gamma, proton or HZE irradiation we are generating NOD/SCID mice that have been "humanized" by being transplanted with human hematopoietic stem cells. We are currently irradiating the humanized NOD/SCID mice with gamma-rays and then harvesting human cells from their bone marrow. These cells will be assayed for specific cytogenetic and molecular changes consistent with AML. In addition to screening the cells for chromosomal aberrations and specific deletions and translocations, we will also screen them for microsatellite instability by small pool PCR.(Funded by NASA Grant NAG9 1569)

[Current understanding of iron overload hazard in patients with myelodysplastic syndrome].

PubMed

Song, Lu-Xi; Su, Ji-Ying; Zhang, Zhen; Chang, Chun-Kang

2013-04-01

Patients with myelodysplastic syndromes (MDS) become dependent on blood transfusions and develop into transfusional iron overload, which is exacerbated by increased absorption of dietary iron in response to ineffective erythropoiesis. However, it is uncertain whether there is an association among iron accumulation, clinical complications, and decreased likelihood of survival in MDS patients. Thereby our current understanding of the effects of transfusion dependency and iron overload in MDS are discussed. Particular emphasis should be placed on further characterizing the role of redox-active forms of labile iron and oxidative stress in iron overload, decreased life expectancy and increased risk of leukemic transformation in MDS patients with iron overload.

Iron overload in myelodysplastic syndromes (MDS).

PubMed

Gattermann, Norbert

2018-01-01

Iron overload (IOL) starts to develop in MDS patients before they become transfusion-dependent because ineffective erythropoiesis suppresses hepcidin production in the liver and thus leads to unrestrained intestinal iron uptake. However, the most important cause of iron overload in MDS is chronic transfusion therapy. While transfusion dependency by itself is a negative prognostic factor reflecting poor bone marrow function, the ensuing transfusional iron overload has an additional dose-dependent negative impact on the survival of patients with lower risk MDS. Cardiac dysfunction appears to be important in this context, as a consequence of chronic anemia, age-related cardiac comorbidity, and iron overload. Another potential problem is iron-related endothelial dysfunction. There is some evidence that with increasing age, high circulating iron levels worsen the atherosclerotic phenotype. Transfusional IOL also appears to aggravate bone marrow failure in MDS, through unfavorable effects on mesenchymal stromal cells as well a hematopoietic cells, particularly erythroid precursors. Patient series and clinical trials have shown that the iron chelators deferoxamine and deferasirox can improve hematopoiesis in a minority of transfusion-dependent patients. Analyses of registry data suggest that iron chelation provides a survival benefit for patients with MDS, but data from a prospective randomized clinical trial are still lacking.

[TOPICS-MDS: a versatile resource for generating scientific and social knowledge for elderly care].

PubMed

van den Brink, Danielle; Lutomski, Jennifer E; Qin, Li; den Elzen, Wendy P J; Kempen, Gertrudis I J M; Krabbe, Paul F M; Steyerberg, Ewout W; Muntinga, Maaike; Moll van Charante, Eric P; Bleijenberg, Nienke; Olde Rikkert, Marcel G M; Melis, René J F

2015-04-01

Developed as part of the National Care for the Elderly Programme (NPO), TOPICS-MDS is a uniform, national database on the health and wellbeing of the older persons and caregivers who participated in NPO-funded projects. TOPICS-MDS Consortium has gained extensive experience in constructing a standardized questionnaire to collect relevant health care data on quality of life, health services utilization, and informal care use. A proactive approach has been undertaken not only to ensure the standardization and validation of instruments but also the infrastructure for external data requests. Efforts have been made to promote scientifically and socially responsible use of TOPICS-MDS; data has been available for secondary use since early 2014. Through this data sharing initiative, researchers can explore health issues in a broader framework which may have not been possible within individual NPO projects; this broader framework is highly relevant for influencing health policy. In this article, we provide an overview of the development and on-going progress of TOPICS-MDS. We further describe how information derived from TOPICS-MDS can be applied to facilitate future scientific innovations and public health initiatives to improve care for frail older persons and their caregivers.

Classification of Multiple Chinese Liquors by Means of a QCM-based E-Nose and MDS-SVM Classifier.

PubMed

Li, Qiang; Gu, Yu; Jia, Jing

2017-01-30

Chinese liquors are internationally well-known fermentative alcoholic beverages. They have unique flavors attributable to the use of various bacteria and fungi, raw materials, and production processes. Developing a novel, rapid, and reliable method to identify multiple Chinese liquors is of positive significance. This paper presents a pattern recognition system for classifying ten brands of Chinese liquors based on multidimensional scaling (MDS) and support vector machine (SVM) algorithms in a quartz crystal microbalance (QCM)-based electronic nose (e-nose) we designed. We evaluated the comprehensive performance of the MDS-SVM classifier that predicted all ten brands of Chinese liquors individually. The prediction accuracy (98.3%) showed superior performance of the MDS-SVM classifier over the back-propagation artificial neural network (BP-ANN) classifier (93.3%) and moving average-linear discriminant analysis (MA-LDA) classifier (87.6%). The MDS-SVM classifier has reasonable reliability, good fitting and prediction (generalization) performance in classification of the Chinese liquors. Taking both application of the e-nose and validation of the MDS-SVM classifier into account, we have thus created a useful method for the classification of multiple Chinese liquors.

Phenotypic characterization of aberrant stem and progenitor cell populations in myelodysplastic syndromes.

PubMed

Ostendorf, Benjamin N; Flenner, Eva; Flörcken, Anne; Westermann, Jörg

2018-01-01

Recent reports have revealed myelodysplastic syndromes (MDS) to arise from cancer stem cells phenotypically similar to physiological hematopoietic stem cells. Myelodysplastic hematopoiesis maintains a hierarchical organization, but the proportion of several hematopoietic compartments is skewed and multiple surface markers are aberrantly expressed. These aberrant antigen expression patterns hold diagnostic and therapeutic promise. However, eradication of MDS requires targeting of early myelodysplasia propagating stem cells. This warrants an exact assessment of the differentiation stage at which aberrant expression occurs in transformed hematopoiesis. Here, we report results on the prospective and extensive dissection of the hematopoietic hierarchy in 20 patients with either low-risk MDS or MDS with excess blasts and compare it to hematopoiesis in patients with non-malignancy-associated cytopenia or B cell lymphoma without bone marrow infiltration. We found patients with MDS with excess blasts to exhibit characteristic expansions of specific immature progenitor compartments. We also identified the aberrant expression of several markers including ALDH, CLL-1, CD44, and CD47 to be specific features of hematopoiesis in MDS with excess blasts. We show that amongst these, aberrant CLL-1 expression manifested at the early uncommitted hematopoietic stem cell level, suggesting a potential role as a therapeutic target.

Current state of prognostication and risk stratification in myelodysplastic syndromes.

PubMed

Zeidan, Amer M; Gore, Steven D; Padron, Eric; Komrokji, Rami S

2015-03-01

Myelodysplastic syndromes (MDS) are characterized by significant biologic and clinical heterogeneity. Because of the wide outcome variability, accurate prognostication is vital to high-quality risk-adaptive care of MDS patients. In this review, we discuss the current state of prognostic schemes for MDS and overview efforts aimed at utilizing molecular aberrations for prognostication in clinical practice. Several prognostic instruments have been developed and validated with increasing accuracy and complexity. Oncologists should be aware of the inherent limitations of these prognostic tools as they counsel patients and make clinical decisions. As more therapies are becoming available for MDS, the focus of model development is shifting from prognostic to treatment-specific predictive instruments. In addition to providing additional prognostic data beyond traditional clinical and pathologic parameters, the improved understanding of the genetic landscape and pathophysiologic consequences in MDS may allow the construction of treatment-specific predictive instruments. How to best use the results of molecular mutation testing to inform clinical decision making in MDS is still a work in progress. Important steps in this direction include standardization in performance and interpretation of assays and better understanding of the independent prognostic importance of the recurrent mutations, especially the less frequent ones.

HEALTH TECHNOLOGY ASSESSMENT OF MEDICAL DEVICES IN EUROPE: PROCESSES, PRACTICES, AND METHODS.

PubMed

Fuchs, Sabine; Olberg, Britta; Panteli, Dimitra; Busse, Reinhard

2016-01-01

To review and compare current Health Technology Assessment (HTA) activities for medical devices (MDs) across European HTA institutions. A comprehensive approach was adopted to identify institutions involved in HTA in European countries. We systematically searched institutional Web sites and other online sources by using a structured tool to extract information on the role and link to decision making, structure, scope, process, methodological approach, and available HTA reports for each included institution. Information was obtained from eighty-four institutions, forty-seven of which were analyzed. Fifty-four methodological documents from twenty-three agencies in eighteen countries were identified. Only five agencies had separate documents for the assessment of MDs. A few agencies made separate provisions for the assessment of MDs in their general methods. The amount of publicly available HTA reports on MDs varied by device category and agency remit. Despite growing consensus on their importance and international initiatives, such as the EUnetHTA Core Model®, specific tools for the assessment of MDs are rarely developed and implemented at the national level. Separate additional signposts incorporated in existing general methods guides may be sufficient for the evaluation of MDs.

Validating diagnostic information on the Minimum Data Set in Ontario Hospital-based long-term care.

PubMed

Wodchis, Walter P; Naglie, Gary; Teare, Gary F

2008-08-01

Over 20 countries currently use the Minimum Data Set Resident Assessment Instrument (MDS) in long-term care settings for care planning, policy, and research purposes. A full assessment of the quality of the diagnostic information recorded on the MDS is lacking. The primary goal of this study was to examine the quality of diagnostic coding on the MDS. Subjects for this study were admitted to Ontario Complex Continuing Care Hospitals (CCC) directly from acute hospitals between April 1, 1997 and March 31, 2005 (n = 80,664). Encrypted unique identifiers, common across acute and CCC administrative databases, were used to link administrative records for patients in the sample. After linkage, each resident had 2 sources of diagnostic information: the acute discharge abstract database and the MDS. Using the discharge abstract database as the reference standard, we calculated the sensitivity for each of 43 MDS diagnoses. Compared with primary diagnoses coded in acute care abstracts, 12 of 43 MDS diagnoses attained a sensitivity of at least 0.80, including 7 of the 10 diagnoses with the highest prevalence as an acute care primary diagnosis before CCC admission. Although the sensitivity was high for many of the most prevalent conditions, important diagnostic information is missed increasing the potential for suboptimal clinical care. Emphasis needs to be put on improving information flow across care settings during patient transitions. Researchers should exercise caution when using MDS diagnoses to identify patient populations, particularly those shown to have low sensitivity in this study.

Purification of Bone Marrow Clonal Cells from Patients with Myelodysplastic Syndrome via IGF-IR

PubMed Central

He, Qi; Chang, Chun-Kang; Xu, Feng; Zhang, Qing-Xia; Shi, Wen-Hui; Li, Xiao

2015-01-01

Malignant clonal cells purification can greatly benefit basic and clinical studies in myelodysplastic syndrome (MDS). In this study, we investigated the potential of using type 1 insulin-like growth factor receptor (IGF-IR) as a marker for purification of malignant bone marrow clonal cells from patients with MDS. The average percentage of IGF-IR expression in CD34+ bone marrow cells among 15 normal controls was 4.5%, 70% of which also express the erythroid lineage marker CD235a. This indicates that IGF-IR mainly express in erythropoiesis. The expression of IGF-IR in CD34+ cells of 55 MDS patients was significantly higher than that of cells from the normal controls (54.0 vs. 4.5%). Based on the pattern of IGF-IR expression in MDS patients and normal controls, sorting of IGF-IR-positive and removal of CD235a-positive erythroid lineage cells with combination of FISH detection were performed on MDS samples with chromosomal abnormalities. The percentage of malignant clonal cells significantly increased after sorting. The enrichment effect was more significant in clonal cells with a previous percentage lower than 50%. This enrichment effect was present in samples from patients with +8, 5q-/-5, 20q-/-20 or 7q-/-7 chromosomal abnormalities. These data suggest that IGF-IR can be used as a marker for MDS bone marrow clonal cells and using flow cytometry for positive IGF-IR sorting may effectively purify MDS clonal cells. PMID:26469401

New polymorphisms of Xeroderma Pigmentosum DNA repair genes in myelodysplastic syndrome.

PubMed

Santiago, Sabrina Pinheiro; Junior, Howard Lopes Ribeiro; de Sousa, Juliana Cordeiro; de Paula Borges, Daniela; de Oliveira, Roberta Taiane Germano; Farias, Izabelle Rocha; Costa, Marília Braga; Maia, Allan Rodrigo Soares; da Nóbrega Ito, Mayumi; Magalhães, Silvia Maria Meira; Pinheiro, Ronald Feitosa

2017-07-01

The association between Xeroderma Pigmentosum DNA repair genes (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) polymorphisms and myelodysplastic syndrome (MDS) have not been reported. To assess the functional role between these polymorphisms and MDS, we evaluated 189 samples stratified in two groups: 95 bone marrow samples from MDS patients and 94 from healthy elderly volunteers used as controls. Genotypes for all polymorphisms were identified in DNA samples in an allelic discrimination experiment by real-time polymerase chain reaction (qPCR). We also studied the mRNA expression of XPA and XPC genes to evaluate if its polymorphisms were functional in 53 RNAm MDS patients by qPCR methodologies. To the rs2228000 polymorphism, the CT and TT polymorphic genotype were associated with increased odds ratio (OR) of more profound cytopenia (hemoglobin and neutrophils count). To the rs1799793 polymorphism, we found that the GG homozygous wild-type genotype was associated with a decreased chance of developing MDS. We observed low expression of XPA in younger patients, in hypoplastic MDS and patients with abnormal karyotype when presented AG or AA polymorphic genotypes. We also found that there was a statistically significant interaction between the presence of micromegakaryocyte on down regulation of XPC regarding the CT heterozygous genotype of the rs1800975 polymorphism. Our results suggest that new functional polymorphisms of Xeroderma Pigmentosum DNA repair genes in MDS are related to its pathogenesis and prognosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

MDS1, a dosage suppressor of an mck1 mutant, encodes a putative yeast homolog of glycogen synthase kinase 3.

PubMed Central

Puziss, J W; Hardy, T A; Johnson, R B; Roach, P J; Hieter, P

1994-01-01

The yeast gene MCK1 encodes a serine/threonine protein kinase that is thought to function in regulating kinetochore activity and entry into meiosis. Disruption of MCK1 confers a cold-sensitive phenotype, a temperature-sensitive phenotype, and sensitivity to the microtubule-destabilizing drug benomyl and leads to loss of chromosomes during growth on benomyl. A dosage suppression selection was used to identify genes that, when present at high copy number, could suppress the cold-sensitive phenotype of mck1::HIS3 mutant cells. Several unique classes of clones were identified, and one of these, designated MDS1, has been characterized in some detail. Nucleotide sequence data reveal that MDS1 encodes a serine/threonine protein kinase that is highly homologous to the shaggy/zw3 kinase in Drosophila melanogaster and its functional homolog, glycogen synthase kinase 3, in rats. The presence of MDS1 in high copy number rescues both the cold-sensitive and the temperature-sensitive phenotypes, but not the benomyl-sensitive phenotype, associated with the disruption of MCK1. Analysis of strains harboring an mds1 null mutation demonstrates that MDS1 is not essential during normal vegetative growth but appears to be required for meiosis. Finally, in vitro experiments indicate that the proteins encoded by both MCK1 and MDS1 possess protein kinase activity with substrate specificity similar to that of mammalian glycogen synthase kinase 3. Images PMID:8264650

Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells.

PubMed

Reikvam, Håkon; Nepstad, Ina; Bruserud, Øystein; Hatfield, Kimberley Joanne

2013-06-01

Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects.

Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells

PubMed Central

Reikvam, Håkon; Nepstad, Ina; Bruserud, Øystein; Hatfield, Kimberley Joanne

2013-01-01

Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects. PMID:23919981

SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.

PubMed

Schneider, Constanze; Oellerich, Thomas; Baldauf, Hanna-Mari; Schwarz, Sarah-Marie; Thomas, Dominique; Flick, Robert; Bohnenberger, Hanibal; Kaderali, Lars; Stegmann, Lena; Cremer, Anjali; Martin, Margarethe; Lohmeyer, Julian; Michaelis, Martin; Hornung, Veit; Schliemann, Christoph; Berdel, Wolfgang E; Hartmann, Wolfgang; Wardelmann, Eva; Comoglio, Federico; Hansmann, Martin-Leo; Yakunin, Alexander F; Geisslinger, Gerd; Ströbel, Philipp; Ferreirós, Nerea; Serve, Hubert; Keppler, Oliver T; Cinatl, Jindrich

2017-02-01

The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.

Pubertal development and fertility in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study.

PubMed

Molgaard-Hansen, Lene; Skou, Anne-Sofie; Juul, Anders; Glosli, Heidi; Jahnukainen, Kirsi; Jarfelt, Marianne; Jónmundsson, Guðmundur K; Malmros, Johan; Nysom, Karsten; Hasle, Henrik

2013-12-01

More than 60% of children with acute myeloid leukemia (AML) become long-term survivors. Most are cured using chemotherapy without hematopoietic stem cell transplantation (HSCT). We report on pubertal development and compare self-reported parenthood among AML survivors and their siblings. We included 137 children treated for AML according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML-84, -88, and -93 trials, who were alive by June 2007. Patients with relapse or treated with HSCT were excluded. AML survivors participated in a physical and biochemical examination (n = 102) and completed a questionnaire (n = 101). One of their siblings completed an identical questionnaire (n = 84). At a median follow-up of 11 years (range 5-25) after diagnosis of AML the survivors (median age 16 years, range 5-36) were either prepubertal or had entered puberty normally. Serum levels of FSH, LH, testosterone, estradiol, sex hormone binding globulin (SHBG), inhibin A and B, and testicular volumes were within normal ranges. Anti-Müllerian hormone (AMH) levels were decreased in 5 of 40 postpubertal females. Mean reported age at menarche was 13.1 (range 11-17) years. Among survivors 15 years of age or older 31% of females reported pregnancies and 9% of males reported pregnancies in their partners, rates comparable with the frequency reported by their siblings. Most AML survivors treated with chemotherapy had normal pubertal development and fertility, however, AMH levels were decreased in 13% of postpubertal females. Longer follow-up is necessary to evaluate possible risk of premature ovarian failure. © 2013 Wiley Periodicals, Inc.

Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.

PubMed

Novak, Rachel L; Harper, David P; Caudell, David; Slape, Christopher; Beachy, Sarah H; Aplan, Peter D

2012-12-01

NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) are oncogenic fusion proteins produced by recurrent chromosomal translocations in patients with acute myeloid leukemia (AML). Transgenic mice that express these fusions develop AML with a long latency and incomplete penetrance, suggesting that collaborating genetic events are required for leukemic transformation. We employed genetic techniques to identify both preleukemic abnormalities in healthy transgenic mice as well as collaborating events leading to leukemic transformation. Candidate gene resequencing revealed that 6 of 27 (22%) CA10 AMLs spontaneously acquired a Ras pathway mutation and 8 of 27 (30%) acquired an Flt3 mutation. Two CA10 AMLs acquired an Flt3 internal-tandem duplication, demonstrating that these mutations can be acquired in murine as well as human AML. Gene expression profiles revealed a marked upregulation of Hox genes, particularly Hoxa5, Hoxa9, and Hoxa10 in both NHD13 and CA10 mice. Furthermore, mir196b, which is embedded within the Hoxa locus, was overexpressed in both CA10 and NHD13 samples. In contrast, the Hox cofactors Meis1 and Pbx3 were differentially expressed; Meis1 was increased in CA10 AMLs but not NHD13 AMLs, whereas Pbx3 was consistently increased in NHD13 but not CA10 AMLs. Silencing of Pbx3 in NHD13 cells led to decreased proliferation, increased apoptosis, and decreased colony formation in vitro, suggesting a previously unexpected role for Pbx3 in leukemic transformation. Published by Elsevier Inc.

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

PubMed Central

Novotny-Diermayr, V; Hart, S; Goh, K C; Cheong, A; Ong, L-C; Hentze, H; Pasha, M K; Jayaraman, R; Ethirajulu, K; Wood, J M

2012-01-01

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations. PMID:22829971

CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia.

PubMed

Wang, Jinghua; Chen, Siyu; Xiao, Wei; Li, Wende; Wang, Liang; Yang, Shuo; Wang, Weida; Xu, Liping; Liao, Shuangye; Liu, Wenjian; Wang, Yang; Liu, Nawei; Zhang, Jianeng; Xia, Xiaojun; Kang, Tiebang; Chen, Gong; Cai, Xiuyu; Yang, Han; Zhang, Xing; Lu, Yue; Zhou, Penghui

2018-01-10

Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. The CLL-1 CAR-T cells specifically lysed CLL-1 + cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1 + myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.

Circulating endothelial cells and their progenitors in acute myeloid leukemia

PubMed Central

Zahran, Asmaa Mohammed; Aly, Sanaa Shaker; Altayeb, Hanan Ahmed; Ali, Arwa Mohammed

2016-01-01

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the accumulation of immature myeloid progenitor cells in the bone marrow. Studies are required to investigate the prognostic and predictive value of surrogate biomarkers. Given the importance of angiogenesis in oncology in terms of pathogenesis as well as being a target for treatment, circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) are promising candidates to serve as such markers. The aim of the present study was to quantify CECs and EPCs in patients with AML at initial diagnosis and following induction chemotherapy, and to correlate these findings with the response to treatment in AML patients. The present study included 40 patients with de novo AML and 20 age- and gender-matched healthy controls. CECs and EPCs were evaluated by flow cytometry at initial diagnosis and after induction chemotherapy (3+7 protocol for AML other than M3 and all-trans-retinoic acid plus anthracycline for M3 disease). CECs and EPCs were significantly higher in AML patients at diagnosis and after induction chemotherapy than in controls. After induction chemotherapy, CECs and EPCs were significantly decreased compared with the levels at initial diagnosis. Patients who achieved complete response (n=28) had lower initial CEC and EPC levels compared with patients who did not respond to treatment. These results suggest that CEC levels are higher in AML patients and may correlate with disease status and treatment response. Further investigations are required to better determine the predictive value and implication of these cells in AML management. PMID:27602121

The incidence and distribution characteristics of MLL rearrangements in Chinese acute myeloid leukemia patients by multiplex nested RT-PCR.

PubMed

Yang, Hua; Cao, Tingting; Gao, Li; Wang, Lili; Zhu, Chengying; Xu, Yuanyuan; Jing, Yu; Zhu, Haiyan; Lv, Na; Yu, Li

2017-07-20

Occurrence of MLL (Mixed Lineage Leukemia) gene rearrangements indicates poor prognosis in acute myeloid leukemia (AML) patients. This is the first study to report the positive rate and distribution characteristics of MLL rearrangements in AML patients in north China. We used multiplex nested real time PCR (RT-PCR) to screen for incidence of 11 MLL rearrangements in 433 AML patients. Eleven MLL rearrangements included (MLL-PTD, MLL-AF9, MLL-ELL, MLL-AF10, MLL-AF17, MLL-AF6, MLL-ENL, MLL-AF1Q, MLL-CBP, MLL-AF1P, MLL-AFX1). There were 68 AML patients with MLL rearrangements, and the positive rate was 15.7%. MLL-PTD (4.84%) was detected in 21 patients, MLL-AF9 in 15, (3.46%), MLL-ELL in 10 (2.31%), MLL-AF10 in 8 (1.85%), MLL-AF1Q in 2 (0.46%), 3 cases each of MLL-AF17, MLL-AF6, MLL-ENL (0.69% each), a and single case each of MLL-CBP, MLL-AF1P, and MLL-AFX1 (0.23% each). The highest rate of MLL rearrangements was found in 24 patients with M5 subtype AML, occurring in 24 cases (35.3%). MLL rearrangements occurred in 21 patients with M2 subtype AML (30.9%), and in 10 patients with M4 subtype AML (14.7%). Screening fusion genes by multiplex nested RT-PCR is a convenient, fast, economical, and accurate method for diagnosis and predicting prognosis of AML.

A novel antibody-drug conjugate targeting SAIL for the treatment of hematologic malignancies.

PubMed

Kim, S Y; Theunissen, J-W; Balibalos, J; Liao-Chan, S; Babcock, M C; Wong, T; Cairns, B; Gonzalez, D; van der Horst, E H; Perez, M; Levashova, Z; Chinn, L; D'Alessio, J A; Flory, M; Bermudez, A; Jackson, D Y; Ha, E; Monteon, J; Bruhns, M F; Chen, G; Migone, T-S

2015-05-29

Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin's lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody-drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs.