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Sample records for acute leukemia cell

  1. [Acute plasma cell leukemia].

    PubMed

    Monsalbe, V; Domíngues, C; Roa, I; Busel, D; González, S

    1989-01-01

    Plasma Cell Leukemia is a very rare form of plasmocytic dyscrasia, whose clinical and pathological characteristics warrant its recognition as a distinct subentity. We report the case of a 60 years old man who presented a rapidly fatal acute plasma cell leukemia, with multiple osteolytic lesions, hipercalcemia, renal and cardiac failure.

  2. Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

    ClinicalTrials.gov

    2017-03-27

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  3. [Presence of B cell clones in acute myelomonocytic leukemia].

    PubMed

    Novoa, Viviana; Nuñez, Neri; Cervellini, Mirta; Starosta, Aida; Carballo, Orlando G

    2010-01-01

    The coexistence of acute myeloid leukemia and chronic lymphocytic leukemia in the same patient is rare. The majority of the cases correspond to patients that developed acute leukemia during the evolutionary course of a chronic lymphatic leukemia following treatment with chemotherapy drugs. We report a case of acute myelomonocytic leukemia concurrent with untreated B-cell chronic lymphocytic leukemia in which the use of flow cytometry analysis with a large panel of monoclonal antibodies, allowed the demonstration of different pathological populations and determine immunophenotyping patterns. Published cases of simultaneous chronic lymphocytic leukemia and acute leukemia are reviewed. The use of multiparametric flow cytometry to differentiate the populations demonstrates the utility of this technology in the diagnosis of these hematological malignancies.

  4. What Is Acute Lymphocytic Leukemia (ALL)?

    MedlinePlus

    ... Adults About Acute Lymphocytic Leukemia (ALL) What Is Acute Lymphocytic Leukemia? Cancer starts when cells in the body begin ... Acute Lymphocytic Leukemia Research and Treatment? More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

  5. A Case of T-cell Acute Lymphoblastic Leukemia Relapsed As Myeloid Acute Leukemia.

    PubMed

    Paganin, Maddalena; Buldini, Barbara; Germano, Giuseppe; Seganfreddo, Elena; Meglio, Annamaria di; Magrin, Elisa; Grillo, Francesca; Pigazzi, Martina; Rizzari, Carmelo; Cazzaniga, Giovanni; Khiabanian, Hossein; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo A; Basso, Giuseppe

    2016-09-01

    A 4-year-old male with the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) relapsed after 19 months with an acute myeloid leukemia (AML). Immunoglobulin and T-cell receptor gene rearrangements analyses reveal that both leukemias were rearranged with a clonal relationship between them. Comparative genomic hybridization (Array-CGH) and whole-exome sequencing analyses of both samples suggest that this leukemia may have originated from a common T/myeloid progenitor. The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T-ALL.

  6. Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

    ClinicalTrials.gov

    2017-03-13

    Adult Acute Myeloid Leukemia in Remission; Donor; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm

  7. What Is Acute Myeloid Leukemia?

    MedlinePlus

    ... Acute Myeloid Leukemia (AML) What Is Acute Myeloid Leukemia? Cancer starts when cells in a part of ... the body from doing their jobs. Types of leukemia Not all leukemias are the same. There are ...

  8. Acute Lymphocytic Leukemia

    MedlinePlus

    ... hard for blood to do its work. In acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia, there are too ... of white blood cells called lymphocytes or lymphoblasts. ALL is the most common type of cancer in ...

  9. Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-09

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  10. Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells

    SciTech Connect

    Eshel, Rinat; Ben-Zaken, Olga; Vainas, Oded; Nadir, Yona; Minucci, Saverio; Polliack, Aaron; Naparstek, Ella; Vlodavsky, Israel; Katz, Ben-Zion; E-mail: bkatz@tasmc.healt.gov.il

    2005-10-07

    Heparanase is a heparan sulfate-degrading endoglycosidase expressed by mature monocytes and myeloid cells, but not by immature hematopoietic progenitors. Heparanase gene expression is upregulated during differentiation of immature myeloid cells. PML-RAR{alpha} and PLZF-RAR{alpha} fusion gene products associated with acute promyelocytic leukemia abrogate myeloid differentiation and heparanase expression. AML-Eto, a translocation product associated with AML FAB M2, also downregulates heparanase gene expression. The common mechanism that underlines the activity of these three fusion gene products involves the recruitment of histone deacetylase complexes to specific locations within the DNA. We found that retinoic acid that dissociates PML-RAR{alpha} from the DNA, and which is used to treat acute promyelocytic leukemia patients, restores heparanase expression to normal levels in an acute promyelocytic leukemia cell line. The retinoic acid effects were also observed in primary acute promyelocytic leukemia cells and in a retinoic acid-treated acute promyelocytic leukemia patient. Histone deacetylase inhibitor reverses the downregulation of heparanase expression induced by the AML-Eto fusion gene product in M2 type AML. In summary, we have characterized a link between leukomogenic factors and the downregulation of heparanase in myeloid leukemic cells.

  11. Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

    PubMed Central

    Poglio, Sandrine; Lewandowski, Daniel; Calvo, Julien; Caye, Aurélie; Gros, Audrey; Laharanne, Elodie; Leblanc, Thierry; Landman-Parker, Judith; Baruchel, André; Soulier, Jean; Ballerini, Paola; Clappier, Emmanuelle; Pflumio, Françoise

    2016-01-01

    T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7+/CD34+ leukemic cell transplantations. Here we investigated the genetic characteristics of CD7+/CD34+ and CD7+/CD34− cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7+/CD34+ or CD7+/CD34− T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7+/CD34+ or CD7+/CD34− cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments. PMID:27191650

  12. Acute megakaryoblastic leukemia. Blast cell aggregates simulating metastatic tumor.

    PubMed

    Pui, C H; Rivera, G; Mirro, J; Stass, S; Peiper, S; Murphy, S B

    1985-11-01

    Acute megakaryoblastic leukemia is a rare leukemia that can present diagnostic problems. We describe two children who have this disease and had clumps of blast cells in their bone marrow, a finding usually attributed to metastatic tumor. The megakaryocytic origin of the cells was supported by their cytochemical staining pattern (positive alpha-naphthyl acetate esterase resistant to sodium fluoride inhibition and negative alpha-naphthyl butyrate esterase) and by the presence of factor VIII-related antigen. Ultrastructural studies of blast cells from one patient demonstrated platelet peroxidase. The mechanism of blast cell clump formation in these cases is unknown; nevertheless, awareness that this feature can occur in acute megakaryoblastic leukemia may avoid a misdiagnosis of metastatic solid tumor.

  13. Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells.

    PubMed

    Petrov, Ivan; Suntsova, Maria; Mutorova, Olga; Sorokin, Maxim; Garazha, Andrew; Ilnitskaya, Elena; Spirin, Pavel; Larin, Sergey; Kovalchuk, Olga; Prassolov, Vladimir; Zhavoronkov, Alex; Roumiantsev, Alexander; Buzdin, Anton

    2016-11-19

    Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.

  14. Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

    PubMed Central

    Petrov, Ivan; Suntsova, Maria; Mutorova, Olga; Sorokin, Maxim; Garazha, Andrew; Ilnitskaya, Elena; Spirin, Pavel; Larin, Sergey; Zhavoronkov, Alex; Kovalchuk, Olga; Prassolov, Vladimir; Roumiantsev, Alexander; Buzdin, Anton

    2016-01-01

    Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies. PMID:27870639

  15. GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

    PubMed Central

    Cao, Yanan; Xuan, Binbin; Fan, Yingchao; Sheng, Huiming; Zhuang, Wenfang

    2017-01-01

    Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients’ AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients. PMID:28114350

  16. Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-09-09

    Adult Acute Lymphoblastic Leukemia in Remission; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Adult L1 Acute Lymphoblastic Leukemia; Adult L2 Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  17. Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2017-04-05

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; 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); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  18. Beating the Clock in T-cell Acute Lymphoblastic Leukemia.

    PubMed

    Carroll, William L; Aifantis, Iannis; Raetz, Elizabeth

    2017-02-15

    CDK4/6 inhibition was synergistic with dexamethasone and everolimus but antagonistic with conventional chemotherapy in T-cell acute lymphoblastic leukemia (T-ALL) preclinical models. Cyclin-dependent kinase inhibition in combination with glucocorticoids and mTOR inhibition offers a unique therapeutic opportunity in T-ALL. Clin Cancer Res; 23(4); 873-5. ©2016 AACRSee related article by Pikman et al., p. 1012.

  19. Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2017-03-14

    Acute Biphenotypic Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Mixed Phenotype Acute Leukemia; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Pancytopenia; Refractory Anemia; Secondary Acute Myeloid Leukemia

  20. T-cell acute lymphoid leukemia resembling Burkitt leukemia cell morphology: A case report

    PubMed Central

    YUE, QINGFANG; LIU, XINYUE; CHEN, LEI; LIU, ZHONGPING; CHEN, WANXIN

    2015-01-01

    Biphenotypic acute leukemia (BAL) is an uncommon type of cancer, which accounts for <5% of all adult ALs. Based upon a previously described scoring system, the European Group for the Immunological Classification of Leukemias (EGIL) proposed a set of diagnostic criteria for BAL. This scoring system is based upon the number and degree of specificity of several markers for myeloid or T/B-lymphoid blasts. The present study describes a case of T-cell acute lymphoblastic leukemia (T-ALL) with Burkitt-like cytology, which according to the French-American-British classification, corresponded to a diagnosis of Burkitt type L3 ALL. Flow cytometry analysis demonstrated that the blasts were positive for T-lymphoid markers, cytoplasmic cluster of differentiation (CD)3, CD7 and CD56, and myeloid markers, CD13, CD33 and CD15. At first, a diagnosis of BAL was suggested by the EGIL score, however, according to the 2008 World Health Organization criteria, a case of T-ALL with aberrant myeloid markers was established. The study also reviewed the literature and discussed the limitations of the EGIL scoring system in clinical decision making, to aid in the selection of an appropriate therapeutic regimen. PMID:25663889

  1. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-01-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  2. Reprint of: Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-02-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  3. Acute myeloid leukemia cells polarize macrophages towards a leukemia supporting state in a Growth factor independence 1 dependent manner

    PubMed Central

    Al-Matary, Yahya S.; Botezatu, Lacramioara; Opalka, Bertram; Hönes, Judith M.; Lams, Robert F.; Thivakaran, Aniththa; Schütte, Judith; Köster, Renata; Lennartz, Klaus; Schroeder, Thomas; Haas, Rainer; Dührsen, Ulrich; Khandanpour, Cyrus

    2016-01-01

    The growth of malignant cells is not only driven by cell-intrinsic factors, but also by the surrounding stroma. Monocytes/Macrophages play an important role in the onset and progression of solid cancers. However, little is known about their role in the development of acute myeloid leukemia, a malignant disease characterized by an aberrant development of the myeloid compartment of the hematopoietic system. It is also unclear which factors are responsible for changing the status of macrophage polarization, thus supporting the growth of malignant cells instead of inhibiting it. We report herein that acute myeloid leukemia leads to the invasion of acute myeloid leukemia-associated macrophages into the bone marrow and spleen of leukemic patients and mice. In different leukemic mouse models, these macrophages support the in vitro expansion of acute myeloid leukemia cell lines better than macrophages from non-leukemic mice. The grade of macrophage infiltration correlates in vivo with the survival of the mice. We found that the transcriptional repressor Growth factor independence 1 is crucial in the process of macrophage polarization, since its absence impedes macrophage polarization towards a leukemia supporting state and favors an anti-tumor state both in vitro and in vivo. These results not only suggest that acute myeloid leukemia-associated macrophages play an important role in the progression of acute myeloid leukemia, but also implicate Growth factor independence 1 as a pivotal factor in macrophage polarization. These data may provide new insights and opportunities for novel therapies for acute myeloid leukemia. PMID:27390361

  4. Therapeutic Effects of Myeloid Cell Leukemia-1 siRNA on Human Acute Myeloid Leukemia Cells

    PubMed Central

    Karami, Hadi; Baradaran, Behzad; Esfahani, Ali; Sakhinia, Masoud; Sakhinia, Ebrahim

    2014-01-01

    Purpose: Up-regulation of Mcl-1, a known anti-apoptotic protein, is associated with the survival and progression of various malignancies including leukemia. The aim of this study was to explore the effect of Mcl-1 small interference RNA (siRNA) on the proliferation and apoptosis of HL-60 acute myeloid leukemia (AML) cells. Methods: siRNA transfection was performed using Lipofectamine™2000 reagent. Relative mRNA and protein expressions were quantified by quantitative real-time PCR and Western blotting, respectively. Trypan blue assay was performed to assess tumor cell proliferation after siRNA transfection. The cytotoxic effect of Mcl-1 siRNA on leukemic cells was measured using MTT assay. Apoptosis was detected using ELISA cell death assay. Results: Mcl-1 siRNA clearly lowered both Mcl-1 mRNA and protein levels in a time-dependent manner, leading to marked inhibition of cell survival and proliferation. Furthermore, Mcl-1 down-regulation significantly enhanced the extent of HL-60 apoptotic cells. Conclusion: Our results suggest that the down-regulation of Mcl-1 by siRNA can effectively trigger apoptosis and inhibit the proliferation of leukemic cells. Therefore, Mcl-1 siRNA may be a potent adjuvant in AML therapy. PMID:24754007

  5. PHF6 mutations in T-cell acute lymphoblastic leukemia.

    PubMed

    Van Vlierberghe, Pieter; Palomero, Teresa; Khiabanian, Hossein; Van der Meulen, Joni; Castillo, Mireia; Van Roy, Nadine; De Moerloose, Barbara; Philippé, Jan; González-García, Sara; Toribio, María L; Taghon, Tom; Zuurbier, Linda; Cauwelier, Barbara; Harrison, Christine J; Schwab, Claire; Pisecker, Markus; Strehl, Sabine; Langerak, Anton W; Gecz, Jozef; Sonneveld, Edwin; Pieters, Rob; Paietta, Elisabeth; Rowe, Jacob M; Wiernik, Peter H; Benoit, Yves; Soulier, Jean; Poppe, Bruce; Yao, Xiaopan; Cordon-Cardo, Carlos; Meijerink, Jules; Rabadan, Raul; Speleman, Frank; Ferrando, Adolfo

    2010-04-01

    Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.

  6. Donor Stem Cell Transplant in Treating Patients With High Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-29

    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 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(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); Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  7. [Effect of Ikaros in B Cell Acute Lymphoblastic Leukemia].

    PubMed

    Zhang, Hai-Ying; Bai, Hai

    2015-08-01

    The Ikaros - a DNA-binding zinc finger protein, acting as a regulator of chromatin remodeling and gene transcription, is crucial for regulating the development and function of the immune system and acting as a master regulator of hematopoietic differentiation. Function-loss mutations of IKZF1, gene encoding Ikaros are frequent in B cell acute lymphoblastic leukemia (B-ALL) and are associated with a poor prognosis. This review briefly summarizes the available data regarding the structure and function of Ikaros, the role of Ikaros as a tumor suppressor in B-ALL, and its regulation mechanism.

  8. Lenalidomide in Treating Older Patients With Acute Myeloid Leukemia Who Have Undergone Stem Cell Transplant

    ClinicalTrials.gov

    2015-03-02

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia

  9. [Development of acute myeloid leukemia from donor cells after allogeneic peripheral blood stem cell transplantation in a female patient with acute monoblastic leukemia].

    PubMed

    2011-01-01

    Development of leukemia from donor cells is a rare complication of allogeneic blood stem cells (BSC). The paper describes a case of evolving acute myeloid leukemia of a graft in a patient with resistant acute monoblastic leukemia after related allogeneic peripheral BSC transplantation. The rarity of this complication, difficulties in providing evidence for the donor origin of a leukemic clone demonstrate a need for all-round careful dynamic assessment of the hematopoietic system after allogeneic transplantation, by applying the current cytogenetic (fluorescence in situ hybridization) and molecular (hypervariable genomic region amplification test using the polymerase chain reaction, hypervariable number of tandem repeats (VNTR), and short number of tandem repeats (STR)) techniques, which permits errors to be avoided in the assessment of a clinical situation and in the diagnosis of leukemia from donor cells. There is no developed policy for treatment of acute graft-versus-leukemia.

  10. Alemtuzumab and Combination Chemotherapy in Treating Patients With Untreated Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2014-03-20

    Acute Undifferentiated Leukemia; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; L1 Adult Acute Lymphoblastic Leukemia; L1 Childhood Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  11. Targeting prohibitins induces apoptosis in acute myeloid leukemia cells

    PubMed Central

    Pomares, Helena; Palmeri, Claudia M; Iglesias-Serret, Daniel; Moncunill-Massaguer, Cristina; Saura-Esteller, José; Núñez-Vázquez, Sonia; Gamundi, Enric; Arnan, Montserrat; Preciado, Sara; Albericio, Fernando; Lavilla, Rodolfo; Pons, Gabriel; González-Barca, Eva M

    2016-01-01

    Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins (PHBs). In this study, the pro-apoptotic effect of fluorizoline was assessed in two cell lines and 21 primary samples from patients with debut of acute myeloid leukemia (AML). Fluorizoline induced apoptosis in AML cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespectively of patients' clinical or genetic features. In addition, fluorizoline inhibited the clonogenic capacity and induced differentiation of AML cells. Fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. These results suggest that targeting PHBs could be a new therapeutic strategy for AML. PMID:27542247

  12. Stem Cell Hierarchy and Clonal Evolution in Acute Lymphoblastic Leukemia

    PubMed Central

    Lang, Fabian; Wojcik, Bartosch; Rieger, Michael A.

    2015-01-01

    Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission. In the clonal evolution model, a consecutive accumulation of mutations starting in a single cell results in competitive growth of subclones with divergent fitness in either a linear or a branching succession. Acute lymphoblastic leukemia (ALL) is a highly malignant cancer of the lymphoid system in the bone marrow with a dismal prognosis after relapse. However, stabile phenotypes and functional data of CSCs in ALL, the so-called leukemia-initiating cells (LICs), are highly controversial and the question remains whether there is evidence for their existence. This review discusses the concepts of CSCs and clonal evolution in respect to LICs mainly in B-ALL and sheds light onto the technical controversies in LIC isolation and evaluation. These aspects are important for the development of strategies to eradicate cells with LIC capacity. Common properties of LICs within different subclones need to be defined for future ALL diagnostics, treatment, and disease monitoring to improve the patients' outcome in ALL. PMID:26236346

  13. Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2013-01-22

    Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  14. Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia

    PubMed Central

    Qin, Lei; Dominguez, Donye; Chen, Siqi; Fan, Jie; Long, Alan; Zhang, Minghui; Fang, Deyu; Zhang, Yi; Kuzel, Timothy M.; Zhang, Bin

    2016-01-01

    Emerging studies suggest that dominant peripheral tolerance is a major mechanism of immune escape in disseminated leukemia. Using an established murine acute myeloid leukemia (AML) model, we here show that systemic administration of recombinant IL-33 dramatically inhibits the leukemia growth and prolongs the survival of leukemia-bearing mice in a CD8+ T cell dependent manner. Exogenous IL-33 treatment enhanced anti-leukemia activity by increasing the expansion and IFN-γ production of leukemia-reactive CD8+ T cells. Moreover, IL-33 promoted dendritic cell (DC) maturation and activation in favor of its cross presentation ability to evoke a vigorous anti-leukemia immune response. Finally, we found that the combination of PD-1 blockade with IL-33 further prolonged the survival, with half of the mice achieving complete regression. Our data establish a role of exogenous IL-33 in reversing T cell tolerance, and suggest its potential clinical implication into leukemia immunotherapy. PMID:27517629

  15. Donor cell-derived acute myeloblastic leukemia after allogeneic peripheral blood hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia.

    PubMed

    Cetin, Zafer; Tezcan, Gulsun; Karauzum, Sibel Berker; Kupesiz, Alphan; Manguoglu, Ayse Esra; Yesilipek, Akif; Luleci, Guven; Hazar, Volkan

    2006-11-01

    Despite its rarity, donor cell leukemia (DCL) is a most intriguing entity. We report here the case of a 5 year-old girl with juvenile myelomonocytic leukemia and normal female karyotype who developed acute myeloblastic leukemia with a karyotype of 46, X, t(X; 7) (p21; p11.2), der(7) t(3; 7) (q13.3; q22) 5 months after peripheral blood hematopoietic stem cell transplantation from her HLA-matched sister. We performed the analysis of short tandem repeat sequence markers to DNA obtained from donor peripheral blood, patient's peripheral blood including leukemic blasts and patient's hair root. This analysis showed that the leukemic blood DNA matched the donor blood DNA and not the patient's DNA, thus confirming DCL. To our knowledge, this is the first case of DCL after peripheral blood SCT for juvenile myelomonocytic leukemia.

  16. Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-12-08

    CD19-Positive Neoplastic Cells Present; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma

  17. Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy.

    PubMed

    Thomas, Xavier

    2012-06-26

    Leukemia stem cells (LSCs), which constitute a minority of the tumor bulk, are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal. The presence of LSCs has been demonstrated in acute lymphoblastic leukemia (ALL), of which ALL with Philadelphia chromosome-positive (Ph(+)). The use of imatinib, a tyrosine kinase inhibitor (TKI), as part of front-line treatment and in combination with cytotoxic agents, has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph(+) ALL. New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations. An important recent addition to the arsenal against Ph(+) leukemias in general was the development of novel TKIs, such as nilotinib and dasatinib. However, in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells. None of the TKIs in clinical use target the LSC. Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs. Allogeneic stem cell transplantation (SCT) remains the only curative treatment available for these patients. Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations. Hence, TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy. Better understanding the biology of Ph(+) ALL will open new avenues for effective management. In this review, we highlight recent findings relating to the question of LSCs in Ph(+) ALL.

  18. Epigenetics in T-cell acute lymphoblastic leukemia.

    PubMed

    Peirs, Sofie; Van der Meulen, Joni; Van de Walle, Inge; Taghon, Tom; Speleman, Frank; Poppe, Bruce; Van Vlierberghe, Pieter

    2015-01-01

    Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T-ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL.

  19. Leukemia - B-Cell Prolymphocytic Leukemia and Hairy Cell Leukemia

    MedlinePlus

    ... and Hairy Cell Leukemia: Introduction Request Permissions Leukemia - B-cell Prolymphocytic Leukemia and Hairy Cell Leukemia: Introduction ... t k e P Types of Cancer Leukemia - B-cell Prolymphocytic Leukemia and Hairy Cell Leukemia Guide ...

  20. Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation

    ClinicalTrials.gov

    2017-02-13

    Acute Leukemias of Ambiguous Lineage; Bacterial Infection; Diarrhea; Fungal Infection; Musculoskeletal Complications; Neutropenia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  1. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia.

    PubMed

    Stringaris, Kate; Sekine, Takuya; Khoder, Ahmad; Alsuliman, Abdullah; Razzaghi, Bonnie; Sargeant, Ruhena; Pavlu, Jiri; Brisley, Gill; de Lavallade, Hugues; Sarvaria, Anushruthi; Marin, David; Mielke, Stephan; Apperley, Jane F; Shpall, Elizabeth J; Barrett, A John; Rezvani, Katayoun

    2014-05-01

    The majority of patients with acute myeloid leukemia will relapse, and older patients often fail to achieve remission with induction chemotherapy. We explored the possibility that leukemic suppression of innate immunity might contribute to treatment failure. Natural killer cell phenotype and function was measured in 32 consecutive acute myeloid leukemia patients at presentation, including 12 achieving complete remission. Compared to 15 healthy age-matched controls, natural killer cells from acute myeloid leukemia patients were abnormal at presentation, with downregulation of the activating receptor NKp46 (P=0.007) and upregulation of the inhibitory receptor NKG2A (P=0.04). Natural killer cells from acute myeloid leukemia patients had impaired effector function against autologous blasts and K562 targets, with significantly reduced CD107a degranulation, TNF-α and IFN-γ production. Failure to achieve remission was associated with NKG2A overexpression and reduced TNF-α production. These phenotypic and functional abnormalities were partially restored in the 12 patients achieving remission. In vitro co-incubation of acute myeloid leukemia blasts with natural killer cells from healthy donors induced significant impairment in natural killer cell TNF-α and IFN-γ production (P=0.02 and P=0.01, respectively) against K562 targets and a trend to reduced CD107a degranulation (P=0.07). Under transwell conditions, the inhibitory effect of AML blasts on NK cytotoxicity and effector function was still present, and this inhibitory effect was primarily mediated by IL-10. These results suggest that acute myeloid leukemia blasts induce long-lasting changes in natural killer cells, impairing their effector function and reducing the competence of the innate immune system, favoring leukemia survival.

  2. Flow cytometric analysis of cell-surface and intracellular antigens in the diagnosis of acute leukemia.

    PubMed

    Paredes-Aguilera, R; Romero-Guzman, L; Lopez-Santiago, N; Burbano-Ceron, L; Camacho-Del Monte, O; Nieto-Martinez, S

    2001-10-01

    To evaluate the usefulness of flow cytometric detection of intracellular antigens (Ags) in establishing proper lineage affiliation and its contribution to the diagnosis of acute leukemia, we studied 100 consecutive patients in whom acute leukemia was diagnosed between January 1997 and July 1998. Immunological classification was assessed using a three-line panel of monoclonal antibodies for phenotypic characterization of leukemic blast cells as proposed at the First Latin American Consensus Conference for Flow Cytometric Immunophenotyping of Leukemia. We found 74 cases of B-cell lineage acute lymphoblastic leukemia (ALL), seven cases of T-cell ALL, and 19 cases of acute myeloid leukemia (AML). In this study cytoplasmic (cy) CD79a, cyCD22, cyCD3, and cyMPO were highly sensitive, specific B, T, and myeloid markers that were expressed in virtually all cases of B and T cell ALL and in all subtypes of AML. Applied in combination with immunophenotyping this knowledge led to improvement in diagnostic precision and refinement of immunological classification, ensuring the selection of the most appropriate therapy for the patients studied. In conclusion, intracellular Ags detection was of utmost importance in establishing correct lineage affiliation in cases lacking expression of B, T, or myeloid surface Ags or disclosing equivocal or ambiguous immunophenotypic features and in identifying biphenotypic acute leukemia. In combination with FAB morphology and immunophenotyping, we were able to reliably classify all patients with acute leukemia in this study.

  3. B Cell Acute Lymphocytic Leukemia Presenting as a Bile Duct Stricture Diagnosed With Cholangioscopy

    PubMed Central

    Bartel, Michael J.; Jiang, Liuyan; Lukens, Frank

    2016-01-01

    Indeterminate biliary strictures represent a diagnostic challenge requiring further work-up, which encompasses a variety of diagnostic modalities. We report a very rare case of B-cell acute lymphocytic leukemia presenting as a biliary stricture following remission of acute myeloid leukemia, which was initially treated with allogenic stem cell transplant. After multiple diagnostic modalities were implemented with no success, the use of cholangioscopy-guided biopsies was the key for the final diagnosis. PMID:27807569

  4. Targeting Leukemia Stem Cells in vivo with AntagomiR-126 Nanoparticles in Acute Myeloid Leukemia

    PubMed Central

    Dorrance, Adrienne M.; Neviani, Paolo; Ferenchak, Greg J.; Huang, Xiaomeng; Nicolet, Deedra; Maharry, Kati S.; Ozer, Hatice G; Hoellarbauer, Pia; Khalife, Jihane; Hill, Emily B.; Yadav, Marshleen; Bolon, Brad N.; Lee, Robert J.; Lee, L.James; Croce, Carlo M.; Garzon, Ramiro; Caligiuri, Michael A.; Bloomfield, Clara D.; Marcucci., Guido

    2015-01-01

    Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to “stemness” and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (≥60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles (NP) containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, i.e., miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients. PMID:26055302

  5. Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma

    ClinicalTrials.gov

    2017-04-04

    Adult T Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Stage II Adult T-Cell Leukemia/Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-Cell Leukemia/Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-Cell Leukemia/Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  6. The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia.

    PubMed

    Durinck, Kaat; Wallaert, Annelynn; Van de Walle, Inge; Van Loocke, Wouter; Volders, Pieter-Jan; Vanhauwaert, Suzanne; Geerdens, Ellen; Benoit, Yves; Van Roy, Nadine; Poppe, Bruce; Soulier, Jean; Cools, Jan; Mestdagh, Pieter; Vandesompele, Jo; Rondou, Pieter; Van Vlierberghe, Pieter; Taghon, Tom; Speleman, Frank

    2014-12-01

    Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34(+) thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34(+) and Notch inactive CD4(+)CD8(+) thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia.

  7. Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

    ClinicalTrials.gov

    2016-11-30

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  8. Targeted Therapy for Acute Lymphocytic Leukemia

    MedlinePlus

    ... Adults Treating Acute Lymphocytic Leukemia Targeted Therapy for Acute Lymphocytic Leukemia In recent years, new drugs that target specific ... Typical Treatment of Acute Lymphocytic Leukemia More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

  9. Treatment of Acute Promyelocytic (M3) Leukemia

    MedlinePlus

    ... Acute Myeloid Leukemia Treatment of Acute Promyelocytic (M3) Leukemia Early diagnosis and treatment of acute promyelocytic leukemia ( ... Comes Back After Treatment? More In Acute Myeloid Leukemia About Acute Myeloid Leukemia Causes, Risk Factors, and ...

  10. Acute Myeloid Leukemia

    MedlinePlus

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  11. Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-09

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

  12. Donor Peripheral Blood Stem Cell Transplant and Pretargeted Radioimmunotherapy in Treating Patients With High-Risk Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2017-02-27

    Chronic Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts; Secondary Acute Myeloid Leukemia

  13. Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia

    PubMed Central

    Abu-Arja, Rolla F.; Chernin, Leah R.; Abusin, Ghada; Auletta, Jeffery; Cabral, Linda; Egler, Rachel; Ochs, Hans D.; Torgerson, Troy R.; Lopez-Guisa, Jesus; Hostoffer, Robert W.; Tcheurekdjian, Haig; Cooke, Kenneth R.

    2016-01-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient’s leukemia. PMID:25900577

  14. Identification of Merkel Cell Polyomavirus from a Patient with Acute Myeloid Leukemia

    PubMed Central

    Song, Y.

    2017-01-01

    ABSTRACT Merkel cell polyomavirus (MCPyV) is an oncogenic virus associated with Merkel cell carcinoma, an aggressive form of skin cancer with a high (>30%) mortality rate. The virus has a high incidence in patients with immunosuppressed conditions, such as AIDS or leukemia, or following organ transplantation. Here, we report the complete genomic sequence of MCPyV identified from a blood sample from a patient with acute myeloid leukemia. PMID:28104648

  15. Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia

    ClinicalTrials.gov

    2017-03-22

    Adult Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia in Remission; Myelodysplastic Syndrome; Secondary Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Therapy-Related Myelodysplastic Syndrome

  16. Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8 Followed by Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2017-03-27

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Secondary Acute Myeloid Leukemia

  17. huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2017-03-31

    Adult B Acute Lymphoblastic Leukemia; CD19 Positive; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Adult Acute Lymphoblastic Leukemia; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

  18. Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells.

    PubMed

    Torelli, Giovanni F; Peragine, Nadia; Raponi, Sara; Pagliara, Daria; De Propris, Maria S; Vitale, Antonella; Bertaina, Alice; Barberi, Walter; Moretta, Lorenzo; Basso, Giuseppe; Santoni, Angela; Guarini, Anna; Locatelli, Franco; Foà, Robin

    2014-07-01

    In this study, we aimed to investigate the pathways of recognition of acute lymphoblastic leukemia blasts by natural killer cells and to verify whether differences in natural killer cell activating receptor ligand expression among groups defined by age of patients, or presence of cytogenetic/molecular aberrations correlate with the susceptibility to recognition and killing. We analyzed 103 newly diagnosed acute lymphoblastic leukemia patients: 46 adults and 57 children. Pediatric blasts showed a significantly higher expression of Nec-2 (P=0.03), ULBP-1 (P=0.01) and ULBP-3 (P=0.04) compared to adult cells. The differential expression of these ligands between adults and children was confined to B-lineage acute lymphoblastic leukemia with no known molecular alterations. Within molecularly defined subgroups of patients, a high surface expression of NKG2D and DNAM1 ligands was found on BCR-ABL(+) blasts, regardless of patient age. Accordingly, BCR-ABL(+) blasts proved to be significantly more susceptible to natural killer-dependent lysis than B-lineage blasts without molecular aberrations (P=0.03). Cytotoxic tests performed in the presence of neutralizing antibodies indicated a pathway of acute lymphoblastic leukemia cell recognition in the setting of the Nec-2/DNAM-1 interaction. These data provide a biological explanation of the different roles played by alloreactive natural killer cells in pediatric versus adult acute lymphoblastic leukemia and suggest that new natural killer-based strategies targeting specific subgroups of patients, particularly those BCR-ABL(+), are worth pursuing further.

  19. S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

    ClinicalTrials.gov

    2017-02-23

    Acute Leukemias of Ambiguous Lineage; B-cell Adult Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma

  20. Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Acute Leukemia

    ClinicalTrials.gov

    2013-10-07

    Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  1. Decitabine, Donor Natural Killer Cells, and Aldesleukin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-12-02

    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); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  2. Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-10-29

    B-cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  3. Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia.

    PubMed

    Jost, Tanja Rezzonico; Borga, Chiara; Radaelli, Enrico; Romagnani, Andrea; Perruzza, Lisa; Omodho, Lorna; Cazzaniga, Giovanni; Biondi, Andrea; Indraccolo, Stefano; Thelen, Marcus; Te Kronnie, Geertruy; Grassi, Fabio

    2016-06-01

    Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic

  4. Bioelectrical Impedance Measurement for Predicting Treatment Outcome in Patients With Newly Diagnosed Acute Leukemia

    ClinicalTrials.gov

    2017-01-17

    Acute Undifferentiated Leukemia; 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); Mast Cell Leukemia; Myeloid/NK-cell Acute Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  5. Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells*

    PubMed Central

    Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P.; Balys, Marlene; Ashton, John M.; Neering, Sarah J.; Lagadinou, Eleni D.; Corbett, Cheryl; Ye, Haobin; Liesveld, Jane L.; O'Dwyer, Kristen M.; Li, Zheng; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril; Hagen, Fred K.; Munger, Joshua; Crooks, Peter A.; Becker, Michael W.; Jordan, Craig T.

    2013-01-01

    The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34+) leukemic versus normal specimens. Our data indicate that CD34+ AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34+ AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34+ cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34+ AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34+ cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. PMID:24089526

  6. The establishment of a cell line from an acute megakaryoblastic leukemia with evidence of emperipolesis

    SciTech Connect

    Zheng, C.Y.; Pabello, P.; Skinnider, L.F.

    1994-09-01

    Acute megakaryoblstic leukemia is uncommon and comprises about 5% of acute non-lymphoid leukemia in the Franco-American-British (FAB) classification. Cell lines from such leukemias are relatively rare with only 6 reported in the literature. We have established a cell line from a case of acute megakaryoblastic leukemia arising in a 2-year-old child. Surface marker studies of the cells confirm their megakaryoblastic nature with 54.1% of the cells being CD61-positive. The cells have a doubling time of 72 hours. Morphologically they appear blast-like with Wright Giemsa stain and electron microscopy and some have small cytoplasmic blebs. Emperipolesis of one blast into another large one is occasionally seen and review of the original bone marrow specimen also showed emperipolesis of neutrophils into the megakaryoblasts (emperipolesis is a phenomenon in which a cell, usually a lymphocyte or neutrophil, enters another cell, moves about and leaves without undergoing phagocytosis). Karyotyping of the cells showed 45,XX + marker chromosome. The marker chromosome is apparently chromosome 16 with a small segment of a chromosome translocated to the terminal portion of chromosome 16. The origin of the translocated material will be elucidated using fluorescence in situ hybridization (FISH). This cell line may be useful in studying factors that contribute to the phenomenon of emperipolesis.

  7. Unusual configurations of endoplasmic reticulum in cells of acute promyelocytic leukemia.

    PubMed

    Parkin, J L; Brunning, R D

    1978-08-01

    An ultrastructural study of leukemia cells from 8 patients with acute promyelocytic leukemia revealed several features that have not previously been emphasized: prominent dilated rough endoplasmic reticulum and two unusual configurations of endoplasmic reticulum (ER). The two membrane structures, multilaminar ER and complex stellate arrangements of ER, appeared to be morphogenetically related. The multilaminar ER was observed in every mitotic cell and less frequently in interphase cells. The stellate ER complex was observed only in interphase cells. Ultrastructural evidence is presented to support the possible evolution of the stellate ER complex from the multilaminar ER.

  8. Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

    ClinicalTrials.gov

    2016-10-24

    Childhood B Acute Lymphoblastic Leukemia; Childhood Burkitt Leukemia; Childhood Diffuse Large Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma

  9. Acute myelogenous leukemia cells with the MLL-ELL translocation convert morphologically and functionally into adherent myofibroblasts

    SciTech Connect

    Tashiro, Haruko; Mizutani-Noguchi, Mitsuho; Shirasaki, Ryosuke

    2010-01-01

    Bone marrow-myofibroblasts, a major component of bone marrow-stroma, are reported to originate from hematopoietic stem cells. We show in this paper that non-adherent leukemia blasts can change into myofibroblasts. When myeloblasts from two cases of acute myelogenous leukemia with a fusion product comprising mixed lineage leukemia and RNA polymerase II elongation factor, were cultured long term, their morphology changed to that of myofibroblasts with similar molecular characteristics to the parental myeloblasts. The original leukemia blasts, when cultured on the leukemia blast-derived myofibroblasts, grew extensively. Leukemia blasts can create their own microenvironment for proliferation.

  10. Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

    ClinicalTrials.gov

    2016-07-18

    Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia

  11. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement.

    PubMed

    Bardini, M; Woll, P S; Corral, L; Luc, S; Wittmann, L; Ma, Z; Lo Nigro, L; Basso, G; Biondi, A; Cazzaniga, G; Jacobsen, S E W

    2015-01-01

    Distinct from other forms of acute lymphoblastic leukemia (ALL), infant ALL with mixed lineage leukemia (MLL) gene rearrangement, the most common leukemia occurring within the first year of life, might arise without the need for cooperating genetic lesions. Through Ig/TCR rearrangement analysis of MLL-AF4+ infant ALL at diagnosis and xenograft leukemias from mice transplanted with the same diagnostic samples, we established that MLL-AF4+ infant ALL is composed of a branching subclonal architecture already at diagnosis, frequently driven by an Ig/TCR-rearranged founder clone. Some MLL-AF4+ clones appear to be largely quiescent at diagnosis but can reactivate and dominate when serially transplanted into immunodeficient mice, whereas other dominant clones at diagnosis can become more quiescent, suggesting a dynamic competition between actively proliferating and quiescent subclones. Investigation of paired diagnostic and relapse samples suggested that relapses often occur from subclones already present but more quiescent at diagnosis. Copy-number alterations identified at relapse might contribute to the activation and expansion of previously quiescent subclones. Finally, each of the identified subclones is able to contribute to the diverse phenotypic pool of MLL-AF4+ leukemia-propagating cells. Unraveling of the subclonal architecture and dynamics in MLL+ infant ALL may provide possible explanations for the therapy resistance and frequent relapses observed in this group of poor prognosis ALL.

  12. Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

    PubMed Central

    Chen, Yu-Jen; Fang, Li-Wen; Su, Wen-Chi; Hsu, Wen-Yi; Yang, Kai-Chien; Huang, Huey-Lan

    2016-01-01

    Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her) superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA) partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of macrophagic differentiation in AML U937 cells by lapatinib. We also noted the synergistic effects of the use of lapatinib and cytotoxic drugs in U937 leukemia cells. These results indicate that lapatinib may have potential for development as a novel antileukemia agent. PMID:27499639

  13. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  14. Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2014-04-03

    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); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic Syndrome With Isolated Del(5q); Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  15. Extensive nuclear lobulation in the cells of a patient with acute myelomonocytic leukemia. The role of electron microscopy for establishment of a correct diagnosis.

    PubMed

    Djaldetti, M; Cohen, A; Gardyn, J; Bendayan, D

    1990-07-01

    Extensive nuclear convolution and lobulation was found in the peripheral blood cells of a patient with acute leukemia. While the morphology of the cells, such as observed with the light microscope, was compatible with the diagnosis of acute myeloid leukemia, the finding of Sezary-like cells with the electron microscope helped to establish the diagnosis of acute myelomonocytic leukemia. This report emphasizes the importance of the electron microscope for the correct diagnosis of leukemias.

  16. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents.

    PubMed

    Yu, Yan; Xie, Yangchun; Cao, Lizhi; Yang, Liangchun; Yang, Minghua; Lotze, Michael T; Zeh, Herbert J; Kang, Rui; Tang, Daolin

    2015-01-01

    Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Development of resistance to chemotherapeutic agents is a major hurdle in the effective treatment of patients with AML. The quinazolinone derivative erastin was originally identified in a screen for small molecules that exhibit synthetic lethality with expression of the RAS oncogene. This lethality was subsequently shown to occur by induction of a novel form of cell death termed ferroptosis. In this study we demonstrate that erastin enhances the sensitivity of AML cells to chemotherapeutic agents in an RAS-independent manner. Erastin dose-dependently induced mixed types of cell death associated with ferroptosis, apoptosis, necroptosis, and autophagy in HL-60 cells (AML, NRAS_Q61L), but not Jurkat (acute T-cell leukemia, RAS wild type), THP-1 (AML, NRAS_G12D), K562 (chronic myelogenous leukemia, RAS wild type), or NB-4 (acute promyelocytic leukemia M3, KRAS_A18D) cells. Treatment with ferrostatin-1 (a potent ferroptosis inhibitor) or necrostatin-1 (a potent necroptosis inhibitor), but not with Z-VAD-FMK (a general caspase inhibitor) or chloroquine (a potent autophagy inhibitor), prevented erastin-induced growth inhibition in HL-60 cells. Moreover, inhibition of c-JUN N-terminal kinase and p38, but not of extracellular signal-regulated kinase activation, induced resistance to erastin in HL-60 cells. Importantly, low-dose erastin significantly enhanced the anticancer activity of 2 first-line chemotherapeutic drugs (cytarabine/ara-C and doxorubicin/adriamycin) in HL-60 cells. Collectively, the induction of ferroptosis and necroptosis contributed to erastin-induced growth inhibition and overcame drug resistance in AML cells.

  17. Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia

    PubMed Central

    Yuan, Na; Song, Lin; Zhang, Suping; Lin, Weiwei; Cao, Yan; Xu, Fei; Fang, Yixuan; Wang, Zhen; Zhang, Han; Li, Xin; Wang, Zhijian; Cai, Jinyang; Wang, Jian; Zhang, Yi; Mao, Xinliang; Zhao, Wenli; Hu, Shaoyan; Chen, Suning; Wang, Jianrong

    2015-01-01

    B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H+-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia. PMID:25512644

  18. Combination Chemotherapy With or Without PSC 833, Peripheral Stem Cell Transplantation, and/or Interleukin-2 in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-06-03

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); 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 Del(5q); 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); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  19. Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang

    PubMed Central

    Zhou, Hong-Sheng; Carter, Bing Z.; Andreeff, Michael

    2016-01-01

    Acute myeloid leukemia (AML) is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow (BM) niche is critical to the maintenance and retention of hematopoietic stem cells (HSC), including leukemia stem cells (LSC), and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy-induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDF1/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors. PMID:27458532

  20. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults

    PubMed Central

    Lee, Kum Ja; Chow, Vivian; Weissman, Ashley; Tulpule, Sunil; Aldoss, Ibrahim; Akhtari, Mojtaba

    2016-01-01

    Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated. Blinatumomab is a novel bispecific T-cell engager that simultaneously binds CD3-positive cytotoxic T-cells and CD19-positive B-cells, resulting in selective lysis of tumor cells. It has shown promising results in patients with relapsed or refractory acute lymphoblastic leukemia or those achieving hematologic response with persistent minimum residual disease. Future clinical trials will answer questions regarding its optimal place in the treatment paradigm. Dose-limiting toxicities include immunological toxicities and cytokine release syndrome. However, most patients tolerate the therapy relatively well. This review will focus on the pharmacology, clinical efficacy, and safety of blinatumomab in the treatment of adult B-cell acute lymphoblastic leukemia while highlighting its unique drug warnings and toxicity management. PMID:27601914

  1. Can Acute Myeloid Leukemia Be Prevented?

    MedlinePlus

    ... Causes, Risk Factors, and Prevention Can Acute Myeloid Leukemia Be Prevented? It’s not clear what causes most ... Myeloid Leukemia Be Prevented? More In Acute Myeloid Leukemia About Acute Myeloid Leukemia Causes, Risk Factors, and ...

  2. Clonal analysis of childhood acute lymphoblastic leukemia with "cytogenetically independent" cell populations.

    PubMed Central

    Pui, C H; Raskind, W H; Kitchingman, G R; Raimondi, S C; Behm, F G; Murphy, S B; Crist, W M; Fialkow, P J; Williams, D L

    1989-01-01

    Acute lymphoblastic leukemia (ALL) is generally regarded as a clonal disease in which a single abnormal progenitor cell gives rise to neoplastic progeny. Five of 463 cases of childhood ALL with adequately banded leukemic cells were found to have two cytogenetically independent cell populations. In addition, two of the four cases tested had more than two rearranged immunoglobulin genes and (or) T cell receptor genes. To investigate the clonality of these unusual leukemias, we examined the neoplastic cells for X-linked markers extrinsic to the disease. Leukemic cells from each of the three patients heterozygous for an X-linked, restriction fragment length polymorphism showed a single active parental allele, suggesting that both apparently independent cell populations developed from a common progenitor. These cases provide evidence that leukemogenesis involves a multistep process of mutation and suggest that karyotypic abnormalities may be a late event of malignant transformation. Images PMID:2566623

  3. [Analysis of Flt-3 expression and Flt-3/ITD mutation in acute myeloid leukemia cells].

    PubMed

    Wang, Ya-Lun; Wang, Tong; Xu, Feng; Gang, Yan; Wang, Jie

    2006-06-01

    This study was aimed to explore the relationship between Flt-3 expression, Flt-3/ITD mutation in acute leukemia (AL) cell line and pathogenesis of AL, especially AML. The Flt-3 expression and Flt-3/ITD mutation were detected by RT-PCR and sequencing method in 82 leukemia cell lines including 20 AML, 57 ALL and 5 CML cell lines. The results indicated that positive results of Flt-3 expression were obtained in 48 out of 77 AL cell line, the positive rate was 62%; 12 cell lines were positive in 20 AML cell lines, the positive rate was 60%; 33 cell lines was positive in 57 ALL cell lines, the positive rate was 58%; 3 cell lines were positive in 5 CML cell lines, the positive rate was 60%. There was abnormal gene product in 1 AMOL cell line out of 12 AML cell lines with Flt-3 positive expression (positive rate 8.3%). DNA sequencing of abnormal gene product showed two coding duplication sequence with 29 bp long. The positive rate of Flt-3 expression in undifferentiated cell line was prominently higher than that in mature B cell ALL (P < 0.05). It is concluded that the Flt-3 expression is different in various leukemia cells. Flt-3/ITD duplication was found in one AML cell line. The detection of Flt-3 gene and Flt-3/ITD mutation may contribute to the diagnosis of ALL, especially to AML.

  4. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells

    PubMed Central

    Guzman, Monica L.; Rossi, Randall M.; Neelakantan, Sundar; Li, Xiaojie; Corbett, Cheryl A.; Hassane, Duane C.; Becker, Michael W.; Bennett, John M.; Sullivan, Edmund; Lachowicz, Joshua L.; Vaughan, Andrew; Sweeney, Christopher J.; Matthews, William; Carroll, Martin; Liesveld, Jane L.; Crooks, Peter A.

    2007-01-01

    Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylamino-parthenolide (DMAPT), which induces rapid death of primary human LSCs from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-κB, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo. PMID:17804695

  5. Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes.

    PubMed

    Tremblay, Mathieu; Tremblay, Cédric S; Herblot, Sabine; Aplan, Peter D; Hébert, Josée; Perreault, Claude; Hoang, Trang

    2010-06-01

    Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that the SCL and LMO1 oncogenes collaborate to expand primitive thymocyte progenitors and inhibit later stages of differentiation. Together with pre-T-cell antigen receptor (pre-TCR) signaling, these oncogenes provide a favorable context for the acquisition of activating Notch1 mutations and the emergence of self-renewing leukemia-initiating cells in T-ALL. All tumor cells harness identical and specific Notch1 mutations and Tcrbeta clonal signature, indicative of clonal dominance and concurring with the observation that Notch1 gain of function confers a selective advantage to SCL-LMO1 transgenic thymocytes. Accordingly, a hyperactive Notch1 allele accelerates leukemia onset induced by SCL-LMO1 and bypasses the requirement for pre-TCR signaling. Finally, the time to leukemia induced by the three transgenes corresponds to the time required for clonal expansion from a single leukemic stem cell, suggesting that SCL, LMO1, and Notch1 gain of function, together with an active pre-TCR, might represent the minimum set of complementing events for the transformation of susceptible thymocytes.

  6. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations.

    PubMed

    Emadi, Ashkan; Jun, Sung Ah; Tsukamoto, Takashi; Fathi, Amir T; Minden, Mark D; Dang, Chi V

    2014-04-01

    The incidence of mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in de novo acute myeloid leukemia (AML) is approximately 20%. These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for α-ketoglutarate, which is consumed by leukemia cells to produce a cancer-derived metabolite, 2-hydroxyglutarate. We sought to exploit this glutamine addiction therapeutically in mutant IDH primary AML cells from patients by measuring cell growth after exposure to a small molecule glutaminase inhibitor, BPTES. We found that BPTES only suppressed the growth of AML cells expressing mutant IDH compared with those expressing wild type IDH. This study lays the groundwork for strategies to target a specific subtype of AML metabolically with IDH mutations with a unique reprogramming of intermediary metabolism that culminates in glutamine dependency of cancer cells for survival.

  7. Articulatin-D induces apoptosis via activation of caspase-8 in acute T-cell leukemia cell line.

    PubMed

    Mishra, Ruchi; Das, Mrinal K; Singh, Savita; Sharma, Radhey Shyam; Sharma, Sadhna; Mishra, Vandana

    2017-02-01

    Leukemia is among the most aggressive and prevalent human malignant carcinoma. Chemotherapy is the preferred therapeutic strategy; however, recurrence of cancer and non-selective cytotoxicity are the major concerns. Unlike synthetic chemotherapeutic agents, mistletoe ribosome-inactivating protein (RIP) displays anti-tumor function in various types of cancers. However, its effect on leukemia cells is little explored. In this study, we assessed the impact of Viscum articulatum RIP (Articulatin-D) on the survival of acute T-cell leukemia cells and the involved molecular and cellular mechanisms. Cell proliferation assay showed that Articulatin-D suppressed the viability of leukemia cells selectively. We further confirmed that the elevation of mitochondrial membrane potential and exposure of phosphatidylserine are the early events of apoptosis induction in Articulatin-D-treated Jurkat cells. Subsequently, we found that Articulatin-D treatment induces apoptosis in Jurkat cells in a time- and concentration-dependent manner. In conclusion, we provided evidence that Articulatin-D efficiently activates caspase-8 involved in extrinsic pathway of apoptosis induction, which ultimately results in caspase-3-dependent DNA fragmentation of Jurkat cells. Further evaluation of Articulatin-D in cell culture and animal models may provide novel information on selective cytotoxicity to acute T-cell leukemia and its involvement in targeting tumor cell survival pathways.

  8. Metastatic Calcinosis Cutis: A Case in a Child with Acute Pre-B Cell Lymphoblastic Leukemia

    PubMed Central

    Castanedo-Cázares, Juan Pablo; Reyes-Herrera, Amalia; Hernández-Blanco, Diana; Oros-Ovalle, Cuauhtémoc; Torres-Álvarez, Bertha

    2015-01-01

    Hypercalcemia in children with malignancy is an uncommon condition. It has been described in leukemia patients with impaired renal excretion of calcium or osteolytic lesions. Metastatic calcinosis cutis (MCC) may develop if hypercalcemia persists. We report the case of a 5-year-old girl with an atypical dermatosis and unspecific gastrointestinal symptoms. Considered clinical diagnoses were xanthomas, histiocytosis, molluscum contagiosum, and nongenital warts. Cutaneous histological analysis showed amorphous basophilic deposits in the dermis suggestive of calcium deposits. Laboratory tests confirmed serum hypercalcemia. Extensive investigations such as bone marrow biopsy established the diagnosis of an acute pre-B cell lymphoblastic leukemia. Hypercalcemia in hematopoietic malignancies is unusual, especially as initial manifestation of the disease. Careful review of the literature fails to reveal previous reports of these peculiar cutaneous lesions of MCC in children with leukemia. PMID:26346120

  9. SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

    PubMed Central

    Alachkar, Houda; Santhanam, Ramasamy; Maharry, Kati; Metzeler, Klaus H.; Huang, Xiaomeng; Kohlschmidt, Jessica; Mendler, Jason H.; Benito, Juliana M.; Hickey, Christopher; Neviani, Paolo; Dorrance, Adrienne M.; Anghelina, Mirela; Khalife, Jihane; Tarighat, Somayeh S.; Volinia, Stefano; Whitman, Susan P.; Paschka, Peter; Hoellerbauer, Pia; Wu, Yue-Zhong; Han, Lina; Bolon, Brad N.; Blum, William; Mrózek, Krzysztof; Carroll, Andrew J.; Perrotti, Danilo; Andreeff, Michael; Caligiuri, Michael A.; Konopleva, Marina; Garzon, Ramiro; Bloomfield, Clara D.; Marcucci, Guido

    2014-01-01

    Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML. PMID:24590286

  10. AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair.

    PubMed

    Ford, James B; Baturin, Dmitry; Burleson, Tamara M; Van Linden, Annemie A; Kim, Yong-Mi; Porter, Christopher C

    2015-09-29

    While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine and that mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia.

  11. Segmentation and Classification of Bone Marrow Cells Images Using Contextual Information for Medical Diagnosis of Acute Leukemias

    PubMed Central

    Reta, Carolina; Altamirano, Leopoldo; Gonzalez, Jesus A.; Diaz-Hernandez, Raquel; Peregrina, Hayde; Olmos, Ivan; Alonso, Jose E.; Lobato, Ruben

    2015-01-01

    Morphological identification of acute leukemia is a powerful tool used by hematologists to determine the family of such a disease. In some cases, experienced physicians are even able to determine the leukemia subtype of the sample. However, the identification process may have error rates up to 40% (when classifying acute leukemia subtypes) depending on the physician’s experience and the sample quality. This problem raises the need to create automatic tools that provide hematologists with a second opinion during the classification process. Our research presents a contextual analysis methodology for the detection of acute leukemia subtypes from bone marrow cells images. We propose a cells separation algorithm to break up overlapped regions. In this phase, we achieved an average accuracy of 95% in the evaluation of the segmentation process. In a second phase, we extract descriptive features to the nucleus and cytoplasm obtained in the segmentation phase in order to classify leukemia families and subtypes. We finally created a decision algorithm that provides an automatic diagnosis for a patient. In our experiments, we achieved an overall accuracy of 92% in the supervised classification of acute leukemia families, 84% for the lymphoblastic subtypes, and 92% for the myeloblastic subtypes. Finally, we achieved accuracies of 95% in the diagnosis of leukemia families and 90% in the diagnosis of leukemia subtypes. PMID:26107374

  12. Segmentation and Classification of Bone Marrow Cells Images Using Contextual Information for Medical Diagnosis of Acute Leukemias.

    PubMed

    Reta, Carolina; Altamirano, Leopoldo; Gonzalez, Jesus A; Diaz-Hernandez, Raquel; Peregrina, Hayde; Olmos, Ivan; Alonso, Jose E; Lobato, Ruben

    2015-01-01

    Morphological identification of acute leukemia is a powerful tool used by hematologists to determine the family of such a disease. In some cases, experienced physicians are even able to determine the leukemia subtype of the sample. However, the identification process may have error rates up to 40% (when classifying acute leukemia subtypes) depending on the physician's experience and the sample quality. This problem raises the need to create automatic tools that provide hematologists with a second opinion during the classification process. Our research presents a contextual analysis methodology for the detection of acute leukemia subtypes from bone marrow cells images. We propose a cells separation algorithm to break up overlapped regions. In this phase, we achieved an average accuracy of 95% in the evaluation of the segmentation process. In a second phase, we extract descriptive features to the nucleus and cytoplasm obtained in the segmentation phase in order to classify leukemia families and subtypes. We finally created a decision algorithm that provides an automatic diagnosis for a patient. In our experiments, we achieved an overall accuracy of 92% in the supervised classification of acute leukemia families, 84% for the lymphoblastic subtypes, and 92% for the myeloblastic subtypes. Finally, we achieved accuracies of 95% in the diagnosis of leukemia families and 90% in the diagnosis of leukemia subtypes.

  13. Transcription factor AP-2α regulates acute myeloid leukemia cell proliferation by influencing Hoxa gene expression.

    PubMed

    Ding, Xiaofeng; Yang, Zijian; Zhou, Fangliang; Wang, Fangmei; Li, Xinxin; Chen, Cheng; Li, Xiaofeng; Hu, Xiang; Xiang, Shuanglin; Zhang, Jian

    2013-08-01

    Transcription factor AP-2α mediates transcription of a number of genes implicated in mammalian development, cell proliferation and carcinogenesis. In the current study, we identified Hoxa7, Hoxa9 and Hox cofactor Meis1 as AP-2α target genes, which are involved in myeloid leukemogenesis. Luciferase reporter assays revealed that overexpression of AP-2α activated transcription activities of Hoxa7, Hoxa9 and Meis1, whereas siRNA of AP-2α inhibited their transcription activities. We found that AP-2 binding sites in regulatory regions of three genes activated their transcription by mutant analysis and AP-2α could interact with AP-2 binding sites in vivo by chromatin immunoprecipitation (ChIP). Further results showed that the AP-2α shRNA efficiently inhibited mRNA and protein levels of Hoxa7, Hoxa9 and Meis1 in AML cell lines U937 and HL60. Moreover, decreased expression of AP-2α resulted in a significant reduction in the growth and proliferation of AML cells in vitro. Remarkably, AP-2α knockdown leukemia cells exhibit decreased tumorigenicity in vivo compared with controls. Finally, AP-2α and target genes in clinical acute myeloid leukemia samples of M5b subtype revealed variable expression levels and broadly paralleled expression. These data support a role of AP-2α in mediating the expression of Hoxa genes in acute myeloid leukemia to influence the proliferation and cell survival.

  14. MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia.

    PubMed

    Mets, Evelien; Van Peer, Gert; Van der Meulen, Joni; Boice, Michael; Taghon, Tom; Goossens, Steven; Mestdagh, Pieter; Benoit, Yves; De Moerloose, Barbara; Van Roy, Nadine; Poppe, Bruce; Vandesompele, Jo; Wendel, Hans-Guido; Van Vlierberghe, Pieter; Speleman, Frank; Rondou, Pieter

    2014-08-01

    T-cell acute lymphoblastic leukemia arises from the leukemic transformation of developing thymocytes and results from cooperative genetic lesions. Inactivation of the PHF6 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting an important tumor suppressive role for PHF6 in the pathobiology of this leukemia. Although the precise function of PHF6 is still unknown, this gene is most likely involved in chromatin regulation, a strongly emerging theme in T-cell acute lymphoblastic leukemia. In this context, our previous description of a cooperative microRNA regulatory network controlling several well-known T-cell acute lymphoblastic leukemia tumor suppressor genes, including PHF6, is of great importance. Given the high frequency of PHF6 lesions in T-cell acute lymphoblastic leukemia and the integration of PHF6 in this microRNA regulatory network, we aimed to identify novel oncogenic microRNAs in T-cell acute lymphoblastic leukemia which suppress PHF6. To this end, we performed an unbiased PHF6 3'UTR-microRNA library screen and combined the results with microRNA profiling data of samples from patients with T-cell acute lymphoblastic leukemia and normal thymocyte subsets. We selected miR-128-3p as a candidate PHF6-targeting, oncogenic microRNA and demonstrated regulation of PHF6 expression upon modulation of this microRNA in T-cell acute lymphoblastic leukemia cell lines. In vivo evidence of an oncogenic role of this microRNA in T-cell acute lymphoblastic leukemia was obtained through accelerated leukemia onset in a NOTCH1-induced T-cell acute lymphoblastic leukemia mouse model upon miR-128-3p over-expression. We conclude that miR-128-3p is a strong novel candidate oncogenic microRNA in T-cell acute lymphoblastic leukemia which targets the PHF6 tumor suppressor gene.

  15. Phagocytosis by macrophages and endothelial cells inhibits procoagulant and fibrinolytic activity of acute promyelocytic leukemia cells.

    PubMed

    Xie, Rui; Gao, Chunyan; Li, Wen; Zhu, Jiuxin; Novakovic, Valerie; Wang, Jing; Ma, Ruishuang; Zhou, Jin; Gilbert, Gary E; Shi, Jialan

    2012-03-08

    The coagulopathy of acute promyelocytic leukemia (APL) is mainly related to procoagulant substances and fibrinolytic activators of APL blasts, but the fate of these leukemic cells is unknown. The aim of this study was to investigate the removal of APL blasts by macrophages and endothelial cells in vitro and consequent procoagulant and fibrinolytic activity of APL cells. We found that human umbilical vein endothelial cells as well as THP-1 and monocyte-derived macrophages bound, engulfed, and subsequently degraded immortalized APL cell line NB4 and primary APL cells. Lactadherin promoted phagocytosis of APL cells in a time-dependent fashion. Furthermore, factor Xa and prothrombinase activity of phosphatidylserine-exposed target APL cells was time-dependently decreased after incubation with phagocytes (THP-1-derived macrophages or HUVECs). Thrombin production on target APL cells was reduced by 40%-45% after 2 hours of coincubation with phagocytes and 80% by a combination of lactadherin and phagocytes. Moreover, plasmin generation of target APL cells was inhibited 30% by 2 hours of phagocytosis and ∼ 50% by lactadherin-mediated engulfment. These results suggest that engulfment by macrophages and endothelial cells reduce procoagulant and fibrinolytic activity of APL blasts. Lactadherin and phagocytosis could cooperatively ameliorate the clotting disorders in APL.

  16. Sensitization of acute lymphoblastic leukemia cells for LCL161-induced cell death by targeting redox homeostasis.

    PubMed

    Haß, Christina; Belz, Katharina; Schoeneberger, Hannah; Fulda, Simone

    2016-04-01

    Disturbed redox homeostasis with both elevated reactive oxygen species (ROS) levels and antioxidant defense mechanisms has been reported in acute lymphoblastic leukemia (ALL). We therefore hypothesized that inhibition of pathways responsible for ROS detoxification renders ALL cells more susceptible for cell death. Here, we report that pharmacological inhibitors of key pathways for the elimination of ROS, i.e. Erastin, buthionine sulfoximine (BSO) and Auranofin, sensitize ALL cells for cell death upon treatment with the Smac mimetic LCL161 that antagonizes Inhibitor of Apoptosis (IAP) proteins. Erastin, BSO or Auranofin significantly increase LCL161-induced cell death and also act in concert with LCL161 to profoundly suppress long-term clonogenic survival in several ALL cell lines. Erastin or BSO cooperates with LCL161 to stimulate ROS production and lipid peroxidation prior to cell death. ROS production and lipid peroxidation are required for this cotreatment-induced cell death, since ROS scavengers or pharmacological inhibition of lipid peroxidation provides significant protection against cell death. These results emphasize that inhibition of antioxidant defense mechanisms can serve as a potent approach to prime ALL cells for LCL161-induced cell death.

  17. Acute Myeloid Leukemia (AML) (For Parents)

    MedlinePlus

    ... Your 1- to 2-Year-Old Acute Myeloid Leukemia (AML) KidsHealth > For Parents > Acute Myeloid Leukemia (AML) ... Treatment Coping en español Leucemia mieloide aguda About Leukemia Leukemia is a type of cancer that affects ...

  18. 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.

  19. Gene Signature of High White Blood Cell Count in B-Precursor Acute Lymphoblastic Leukemia.

    PubMed

    Edwards, Holly; Rubenstein, Mara; Dombkowski, Alan A; Caldwell, J Timothy; Chu, Roland; Xavier, Ana C; Thummel, Ryan; Neely, Melody; Matherly, Larry H; Ge, Yubin; Taub, Jeffrey W

    2016-01-01

    In this study we sought to identify genetic factors associated with the presenting white blood cell (WBC) count in B-precursor acute lymphoblastic leukemia (BP-ALL). Using ETV6-RUNX1-positive BP-ALL patient samples, a homogeneous subtype, we identified 16 differentially expressed genes based on the presenting WBC count (< 50,000/cumm vs > 50,000). We further confirmed that IL1R1, BCAR3, KCNH2, PIR, and ZDHHC23 were differentially expressed in a larger cohort of ETV6-RUNX1-negative BP-ALL patient samples. Statistical analysis demonstrated that expression levels of these genes could accurately categorize high and low WBC count subjects using two independent patient sets, representing positive and negative ETV6-RUNX1 cases. Further studies in leukemia cell line models will better delineate the role of these genes in regulating the white blood cell count and potentially identify new therapeutic targets.

  20. Laboratory-Treated T Cells in Treating Patients With High-Risk Relapsed Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia Previously Treated With Donor Stem Cell Transplant

    ClinicalTrials.gov

    2017-01-05

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Myelodysplastic Syndrome; Childhood Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia

  1. Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2017-02-06

    Chimerism; Hematopoietic Cell Transplantation Recipient; Myelodysplastic Syndrome With Excess Blasts-1; Myelodysplastic Syndrome With Excess Blasts-2; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  2. Fucoidan Suppresses the Growth of Human Acute Promyelocytic Leukemia Cells In Vitro and In Vivo.

    PubMed

    Atashrazm, Farzaneh; Lowenthal, Ray M; Woods, Gregory M; Holloway, Adele F; Karpiniec, Samuel S; Dickinson, Joanne L

    2016-03-01

    Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia.

  3. Secondary Philadelphia chromosome and erythrophagocytosis in a relapsed acute myeloid leukemia after hematopoietic cell transplantation

    PubMed Central

    Kelemen, Katalin; Galani, Komal; Conley, Christopher R.; Greipp, Patricia T.

    2015-01-01

    The acquisition of Philadelphia chromosome (Ph) as a secondary change during the course of hematopoietic malignancies is rare and is associated with poor prognosis. Few cases of secondary Ph have been reported after hematopoietic cell transplantation (HCT). A secondary Ph at relapse is of clinical importance because it provides a therapeutic target for tyrosine kinase inhibitors along with or in replacement of chemotherapy. We describe a case of relapsed acute myeloid leukemia after HCT that developed a BCR/ABL-1 translocation along with erythrophagocytosis by blasts as a secondary change at the time of relapse. The progression of this patient's myeloid neoplasm from myelodysplastic syndrome to acute myeloid leukemia and relapsed AML after HCT was accompanied by a stepwise cytogenetic evolution: a deletion 20q abnormality subsequently acquired deletion 7q and, finally, at relapse after HCT, a secondary Ph was gained. The relationship between the secondary Ph and the erythrophagocytosis by blasts is not clear. We review the possible pathogenesis and cytogenetic associations of erythrophagocytosis by blasts, a rare feature in acute leukemias. PMID:25074248

  4. ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival

    PubMed Central

    Zhong, Wenbin; Yi, Qing; Xu, Bing; Li, Shiqian; Wang, Tong; Liu, Fupei; Zhu, Biying; Hoffmann, Peter R.; Ji, Guangju; Lei, Pingsheng; Li, Guoping; Li, Jiwei; Li, Jian; Olkkonen, Vesa M.; Yan, Daoguang

    2016-01-01

    Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gαq/11 and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP3 production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP3-induced endoplasmic reticulum Ca2+ release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment. PMID:27581363

  5. Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia

    PubMed Central

    Ohayon, Delphine; De Chiara, Alessia; Chapuis, Nicolas; Candalh, Céline; Mocek, Julie; Ribeil, Jean-Antoine; Haddaoui, Lamya; Ifrah, Norbert; Hermine, Olivier; Bouillaud, Frédéric; Frachet, Philippe; Bouscary, Didier; Witko-Sarsat, Véronique

    2016-01-01

    Cytosolic proliferating cell nuclear antigen (PCNA), a scaffolding protein involved in DNA replication, has been described as a key element in survival of mature neutrophil granulocytes, which are non-proliferating cells. Herein, we demonstrated an active export of PCNA involved in cell survival and chemotherapy resistance. Notably, daunorubicin-resistant HL-60 cells (HL-60R) have a prominent cytosolic PCNA localization due to increased nuclear export compared to daunorubicin-sensitive HL-60 cells (HL-60S). By interacting with nicotinamide phosphoribosyltransferase (NAMPT), a protein involved in NAD biosynthesis, PCNA coordinates glycolysis and survival, especially in HL-60R cells. These cells showed a dramatic increase in intracellular NAD+ concentration as well as glycolysis including increased expression and activity of hexokinase 1 and increased lactate production. Furthermore, this functional activity of cytoplasmic PCNA was also demonstrated in patients with acute myeloid leukemia (AML). Our data uncover a novel pathway of nuclear export of PCNA that drives cell survival by increasing metabolism flux. PMID:27759041

  6. Kinetics of indium-111-labeled leukemic cells in patients with acute non-lymphocytic leukemia

    SciTech Connect

    Suzuki, Y.; Yamauchi, K.

    1984-01-01

    The kinetics of autologous leukemic cells labeled with In-111 oxine were studied in 5 patients with acute myeloblastic leukemia (AML) and one patient with acute premyelocytic leukemia (APL), and kinetics of OKM1 monoclonal antibody-treated leukemic cells were studied in one patient with acute monoblastic leukemia (AMoL). Recoveries of 33.7 +- 23.3%(range, 22.0 to 48.1%) were achieved at 10min after injection of In-111 oxine labeled leukemic cells in AML and APL patients. However, in a patient with AMoL recovery of 12.3% was only achieved at 10min after injection of OKM1-treated leukemic cells. Clearance of the activity from blood was rapid up to one in all patients. The clearance curve of the activity in 5 AML patients showed a hump or a plateau from one to 5hr after injection of labeled leukemic cells. In APL patient and AMoL patient, however, this hump or plateau was not noted. In AML and APL patients the activity over the spleen was higher than that of over the liver at from 30min to 3hr after and showed a plateau or gradual rising thereafter. In a patient with AMoL, the hepatic activity was higher than the splenic activity at 30min after, but thereafter the latter became higher than the former. Liver activity curves showed transient fall at 3hr after and then gradual uprising in all patients. In a patient with APL, high activity was noted over the kidneys. This rose to a maximum after 3hr and then decreased rapidly. Since In-111 oxine stays firmly attached to the cells in spite of the possibility of radiation damage in a long-term survey, it seems an ideal label for studying leukemic cell kinetics.

  7. IMMUNOTHERAPY IN ACUTE LEUKEMIA

    PubMed Central

    Leung, Wing

    2010-01-01

    Recent advances in immunotherapy of cancer may represent a successful example in translational research, in which progress in knowledge and technology in immunology has lead to new strategies of immunotherapy, and even past failure in many clinical trials have led to a better understanding of basic cancer immunobiology. This article reviews the latest concepts in antitumor immunology and its application in the treatment of cancer, with particular focus on acute leukemia. PMID:19100371

  8. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.

    PubMed

    Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E; Zhu, Jiang; Lohr, Jens G; Cotton, Matthew J; Gillespie, Shawn M; Fernandez, Daniel; Ku, Manching; Wang, Hongfang; Piccioni, Federica; Silver, Serena J; Jain, Mohit; Pearson, Daniel; Kluk, Michael J; Ott, Christopher J; Shultz, Leonard D; Brehm, Michael A; Greiner, Dale L; Gutierrez, Alejandro; Stegmaier, Kimberly; Kung, Andrew L; Root, David E; Bradner, James E; Aster, Jon C; Kelliher, Michelle A; Bernstein, Bradley E

    2014-04-01

    The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSIs) that prevent NOTCH1 activation. However, responses to these inhibitors have been transient, suggesting that resistance limits their clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant 'persister' cells that expand in the absence of NOTCH1 signaling. Rare persisters are already present in naive T-ALL populations, and the reversibility of their phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persister cells activate distinct signaling and transcriptional programs and exhibit chromatin compaction. A knockdown screen identified chromatin regulators essential for persister viability, including BRD4. BRD4 binds enhancers near critical T-ALL genes, including MYC and BCL2. The BRD4 inhibitor JQ1 downregulates expression of these targets and induces growth arrest and apoptosis in persister cells, at doses well tolerated by GSI-sensitive cells. Consistently, the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia resistance that may be addressed by incorporating epigenetic modulators in combination therapy.

  9. Long term impact of hyperleukocytosis in newly diagnosed acute myeloid leukemia patients undergoing allogeneic stem cell transplantation: an analysis from the acute leukemia working party of the EBMT.

    PubMed

    Canaani, Jonathan; Labopin, Myriam; Socié, Gerard; Nihtinen, Anne; Huynh, Anne; Cornelissen, Jan; Deconinck, Eric; Gedde-Dahl, Tobias; Forcade, Edouard; Chevallier, Patrice; Bourhis, Jean Henri; Blaise, Didier; Mohty, Mohamad; Nagler, Arnon

    2017-03-28

    Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3-ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the EBMT. A cohort of 357 patients with hyperleukocytosis (159 patients with WBC 50K-100K, 198 patients with WBC≥100K) was compared to 918 patients without hyperleukocytosis. Patients with hyperleukocytosis were younger, had an increased rate of favorable risk cytogenetics, and more likely to be FLT3 and NPM1 mutated. In multivariate analysis, hyperleukocytosis was independently associated with increased relapse incidence (hazard ratio [HR] of 1.55, 95% confidence interval [CI], 1.14 - 2.12; p=0.004), decreased leukemia-free survival (HR of 1.38, 95% CI, 1.07 - 1.78; p=0.013), and inferior overall survival (HR of 1.4, 95% CI, 1.07 - 1.84; p=0.013). Hyperleukocytosis retains a significant prognostic role for AML patients undergoing HSCT. This article is protected by copyright. All rights reserved.

  10. Successful cell-mediated cytokine-activated immunotherapy for relapsed acute myeloid leukemia after hematopoietic stem cell transplantation.

    PubMed

    Gesundheit, Benjamin; Shapira, Michael Y; Resnick, Igor B; Amar, Avraham; Kristt, Don; Dray, Lilianne; Budowski, Einat; Or, Reuven

    2009-03-01

    Acute myeloid leukemia (AML) is an extremely aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). We report the successful outcome of cell-mediated cytokine-activated immunotherapy in a high-risk pediatric AML patient who relapsed shortly after allogeneic HSCT. Donor lymphocyte infusion along with interferon induced a graft-versus-leukemia effect, presenting as a reversible episode of graft-versus-host disease, which led to stable complete donor chimerism and total eradication of AML for over 24 months, at the time of this report. The curative potential of immunotherapy in hematological malignancies is discussed.

  11. Soluble mediators released by acute myeloid leukemia cells increase capillary-like networks.

    PubMed

    Hatfield, Kimberley J; Evensen, Lasse; Reikvam, Håkon; Lorens, James B; Bruserud, Øystein

    2012-12-01

    Increased bone marrow angiogenesis is seen in several hematological malignancies, including acute myeloid leukemia (AML). We used a co-culture assay of endothelial and vascular smooth muscle cells (vSMC) to investigate the effects of AML-conditioned medium on capillary networks. We investigated primary AML cells derived from 44 unselected patients and observed that for a large subset of patients, the constitutive cytokine release by the leukemic cells stimulated endothelial cell organization into capillary-like networks, while there were only minor or no effects for other patients. We analyzed the constitutive AML cell release of 31 cytokines for all the patients and performed a hierarchical cluster analysis of the cytokine profile which identified two major patient subsets that differed in their ability to enhance capillary-like networks; increased capillary-like networks was then associated with high constitutive release of several cytokines and especially high levels of several pro-angiogenic chemokines. Significantly increased network formation was not seen for any of the 11 acute lymphoblastic leukemia patients investigated. The cytokine response by activated normal T cells inhibited endothelial network formation in our in vitro model of angiogenesis and activated normal monocytes had only a minor influence on tube formation. Our study shows that AML-derived cytokines can induce the organization of endothelial cells into vessel-like structures.

  12. How Is Acute Lymphocytic Leukemia Classified?

    MedlinePlus

    ... Adults Early Detection, Diagnosis, and Types How Is Acute Lymphocytic Leukemia Classified? Most types of cancers are assigned numbered ... ALL are now named as follows: B-cell ALL Early pre-B ALL (also called pro-B ...

  13. Acute myeloid leukemia presenting as galactorrhea

    PubMed Central

    Nambiar, K. Rakul; Devi, R. Nandini

    2016-01-01

    Acute myeloid leukemia (AML) presents with symptoms related to pancytopenia (weakness, infections, bleeding diathesis) and organ infiltration with leukemic cells. Galactorrhea is an uncommon manifestation of AML. We report a case of AML presenting with galactorrhea. PMID:27695173

  14. Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.

    PubMed

    Muñoz-López, Alvaro; Romero-Moya, Damià; Prieto, Cristina; Ramos-Mejía, Verónica; Agraz-Doblas, Antonio; Varela, Ignacio; Buschbeck, Marcus; Palau, Anna; Carvajal-Vergara, Xonia; Giorgetti, Alessandra; Ford, Anthony; Lako, Majlinda; Granada, Isabel; Ruiz-Xivillé, Neus; Rodríguez-Perales, Sandra; Torres-Ruíz, Raul; Stam, Ronald W; Fuster, Jose Luis; Fraga, Mario F; Nakanishi, Mahito; Cazzaniga, Gianni; Bardini, Michela; Cobo, Isabel; Bayon, Gustavo F; Fernandez, Agustin F; Bueno, Clara; Menendez, Pablo

    2016-10-11

    Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.

  15. B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3

    PubMed Central

    Fei, Fei; Joo, Eun Ji; Tarighat, Somayeh S.; Schiffer, Isabelle; Paz, Helicia; Fabbri, Muller; Abdel-Azim, Hisham; Groffen, John; Heisterkamp, Nora

    2015-01-01

    The molecular interactions between B-cell precursor acute lymphoblastic leukemia (pre-B ALL) cells and stromal cells in the bone marrow that provide microenvironmentally-mediated protection against therapeutic drugs are not well-defined. Galectin-3 (Lgals3) is a multifunctional galactose-binding lectin with reported location in the nucleus, cytoplasm and extracellular space in different cell types. We previously reported that ALL cells co-cultured with stroma contain high levels of Galectin-3. We here establish that, in contrast to more mature B-lineage cancers, Galectin-3 detected in and on the ALL cells originates from stromal cells, which express it on their surface, secrete it as soluble protein and also in exosomes. Soluble and stromal-bound Galectin-3 is internalized by ALL cells, transported to the nucleus and stimulates transcription of endogenous LGALS3 mRNA. When human and mouse ALL cells develop tolerance to different drugs while in contact with protective stromal cells, Galectin-3 protein levels are consistently increased. This correlates with induction of Galectin-3 transcription in the ALL cells. Thus Galectin-3 sourced from stroma becomes supplemented by endogenous Galectin-3 production in the pre-B ALL cells that are under continuous stress from drug treatment. Our data suggest that stromal Galectin-3 may protect ALL cells through auto-induction of Galectin-3 mRNA and tonic NFκB pathway activation. Since endogenously synthesized Galectin-3 protects pre-B ALL cells against drug treatment, we identify Galectin-3 as one possible target to counteract the protective effects of stroma. PMID:25869099

  16. Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Acute Promyelocytic Leukemia

    ClinicalTrials.gov

    2017-02-20

    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); Adult Acute Promyelocytic Leukemia (M3); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

  17. What Are the Key Statistics about Acute Lymphocytic Leukemia?

    MedlinePlus

    ... Leukemia (ALL) What Are the Key Statistics About Acute Lymphocytic Leukemia? The American Cancer Society’s estimates for acute lymphocytic ... Acute Lymphocytic Leukemia Research and Treatment? More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

  18. Plumbagin exerts an immunosuppressive effect on human T-cell acute lymphoblastic leukemia MOLT-4 cells.

    PubMed

    Bae, Kyoung Jun; Lee, Yura; Kim, Soon Ae; Kim, Jiyeon

    2016-04-22

    Of the hematological disorders typified by poor prognoses and survival rates, T-cell acute lymphoblastic leukemia (T-ALL) is one of the most commonly diagnosed. Despite the development of new therapeutic agents, the treatment options for this cancer remain limited. In this manuscript, we investigated the anti-proliferative effects of plumbagin, mediated by the activation of mitogen-activated protein kinase (MAPK) pathways, and inhibition of NF-κB signaling; the human T-ALL MOLT-4 cell line was used as our experimental system. Plumbagin is a natural, plant derived compound, which exerts an anti-proliferative activity against many types of human cancer. Our experiments confirm that plumbagin induces a caspase-dependent apoptosis of MOLT-4 cells, with no significant cytotoxicity seen for normal peripheral blood mononuclear cells (PBMCs). Plumbagin also inhibited LPS-induced phosphorylation of p65, and the transcription of NF-κB target genes. Our results now show that plumbagin is a potent inhibitor of the NF-κB signaling pathway, and suppressor of T-ALL cell proliferation.

  19. Leukemia cutis with lymphoglandular bodies: a clue to acute lymphoblastic leukemia cutis.

    PubMed

    Obiozor, Cynthia; Ganguly, Siddhartha; Fraga, Garth R

    2015-08-15

    Leukemia cutis describes cutaneous lesions produced by infiltrates of leukemic cells. It usually manifests contemporaneously with the initial diagnosis of systemic leukemia, but may also precede or follow systemic leukemia. Most cases are associated with acute myeloid leukemia. Adult B-cell lymphoblastic leukemia cutis is very rare. We report a 59-year-old woman with a history of B-cell acute lymphoblastic leukemia who relapsed with aleukemic lymphoblastic leukemia cutis. Lymphoglandular bodies were conspicuous on biopsy and may serve as a morphologic clue to lymphocytic differentiation while molecular and immunophenotypic studies are pending. The patient was successfully treated with local radiation therapy and oral ponatinib.

  20. Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia.

    PubMed

    Liu, Yuan-Fang; Wang, Bai-Yan; Zhang, Wei-Na; Huang, Jin-Yan; Li, Ben-Shang; Zhang, Ming; Jiang, Lu; Li, Jian-Feng; Wang, Ming-Jie; Dai, Yu-Jun; Zhang, Zi-Guan; Wang, Qiang; Kong, Jie; Chen, Bing; Zhu, Yong-Mei; Weng, Xiang-Qin; Shen, Zhi-Xiang; Li, Jun-Min; Wang, Jin; Yan, Xiao-Jing; Li, Yan; Liang, Ying-Min; Liu, Li; Chen, Xie-Qun; Zhang, Wang-Gang; Yan, Jin-Song; Hu, Jian-Da; Shen, Shu-Hong; Chen, Jing; Gu, Long-Jun; Pei, Deqing; Li, Yongjin; Wu, Gang; Zhou, Xin; Ren, Rui-Bao; Cheng, Cheng; Yang, Jun J; Wang, Kan-Kan; Wang, Sheng-Yue; Zhang, Jinghui; Mi, Jian-Qing; Pui, Ching-Hon; Tang, Jing-Yan; Chen, Zhu; Chen, Sai-Juan

    2016-06-01

    Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.

  1. Underground Adaptation to a Hostile Environment: Acute Myeloid Leukemia vs. Natural Killer Cells

    PubMed Central

    Dulphy, Nicolas; Chrétien, Anne-Sophie; Khaznadar, Zena; Fauriat, Cyril; Nanbakhsh, Arash; Caignard, Anne; Chouaib, Salem; Olive, Daniel; Toubert, Antoine

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which incidence increases with age. The disease affects the differentiation of hematopoietic stem or precursor cells in the bone marrow and can be related to abnormal cytogenetic and/or specific mutational patterns. AML blasts can be sensitive to natural killer (NK) cell antitumor response. However, NK cells are frequently defective in AML patients leading to tumor escape. NK cell defects affect not only the expression of the activating NK receptors, including the natural cytotoxicity receptors, the NK group 2, member D, and the DNAX accessory molecule-1, but also cytotoxicity and IFN-γ release. Such perturbations in NK cell physiology could be related to the adaptation of the AML to the immune pressure and more generally to patient’s clinical features. Various mechanisms are potentially involved in the inhibition of NK-cell functions in AML, including defects in the normal lymphopoiesis, reduced expression of activating receptors through cell-to-cell contacts, and production of immunosuppressive soluble agents by leukemic blasts. Therefore, the continuous cross-talk between AML and NK cells participates to the leukemia immune escape and eventually to patient’s relapse. Methods to restore or stimulate NK cells seem to be attractive strategies to treat patients once the complete remission is achieved. Moreover, our capacity in stimulating the NK cell functions could lead to the development of preemptive strategies to eliminate leukemia-initiating cells before the emergence of the disease in elderly individuals presenting preleukemic mutations in hematopoietic stem cells. PMID:27014273

  2. Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia.

    PubMed

    Aversa, Franco; Reisner, Yair; Martelli, Massimo F

    2004-01-01

    Since 75% of patients with high-risk acute leukemia do not have a human leukocyte antigen (HLA)-identical sibling, alternative sources for hematopoietic stem cell transplantation (HSCT) are matched unrelated donors (MUD), unrelated umbilical cord blood (UD-UCB) and one HLA haplotype mismatched family members (haploidentical). The chance of finding a suitable donor in the international voluntary donor registries is limited by frequency of the HLA phenotype and the time required to identify the right donor from a potential panel, to establish eligibility and to harvest the cells. In adult MUD recipients, event-free survival ranges up to 50% and refers only to patients who undergo transplant, without taking into account those who do not find a donor. Umbilical cord blood offers the advantages of easy procurement, the absence of risks to donors, the reduced risk of transmitting infections, immediate availability of cryopreserved samples and acceptance of mismatches at two of the six antigens. Although UD-UCB transplantation is a viable option for children, it is seldom considered for adults. The great divergency between body weight and the number of hematopoietic cells in a standard cord blood unit, particularly if associated with a two-antigen mismatch, increases the risk of graft failure and delays hematopoietic reconstitution. Work on full-haplotype mismatched transplants has been proceeding for over 20 years. Originally, outcome in leukemia patients was disappointing because of high incidence of severe graft-vs.-host disease in T-replete transplants and high rejection rates in T-cell-depleted transplants. The breakthrough came with the use of a megadose of T-cell-depleted progenitor cells after a high-intensity conditioning regimen. Treating end-stage patients inevitably confounded clinical outcome in the early pilot studies. Today, high-risk acute leukemia patients are treated at less advanced stages of disease, receive a reasonably well tolerated conditioning

  3. T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

    PubMed Central

    Chiu, Chang-Fang; Weng, Jing-Ru; Jadhav, Appaso; Wu, Chia-Yung; Sargeant, Aaron M.; Bai, Li-Yuan

    2016-01-01

    T315, an integrin-linked kinase (ILK) inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt) and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP) cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy. PMID:27537872

  4. NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells

    PubMed Central

    dos Santos, Nuno R.; Ghezzo, Marinella N.; da Silva, Ricardo C.; Fernandes, Mónica T.

    2010-01-01

    Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL. PMID:24281204

  5. Epidemiology of acute lymphoblastic leukemia

    SciTech Connect

    Pendergrass, T.W.

    1985-06-01

    Although the etiology of acute leukemia is largely unknown, some facets of the puzzle are becoming clarified. Recognition of important patterns in age-specific mortality rates has suggested that events early in life, perhaps even prenatally, may have an influence on developing leukemia in childhood. The racial differences evident in mortality, incidence, and immunologic subtype of ALL suggest either differences in exposures to certain factors or differences in responses to those factors by white children. Hereditary factors appear to play a role. Familial and hereditary conditions exist that have high incidences of acute leukemia. Chromosomal anomalies are common in these conditions. Viral infections may play a role by contributing to alteration in genetic material through incorporation of the viral genome. How that virus is dealt with after primary infection seems important. The presence of immunodeficiency may allow wider dissemination or enhanced replication of such viruses, thereby increasing the likelihood of cellular transformation to an abnormal cell. Proliferation of that malignant cell to a clone may depend on other cofactors. Perhaps prolonged exposure to substances like benzene or alkylating agents may enhance these interactions between virus and genetic material. Does this change DNA repair mechanisms. Are viral infections handled differently. Is viral genomic information more easily integrated into host cells. Ionizing radiation has multiple effects. Alteration in genetic material occurs both at the molecular and chromosomal levels. DNA may be altered, lost, or added in the cell's attempt to recover from the injury.

  6. Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-04

    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 t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

  7. Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia

    ClinicalTrials.gov

    2017-03-13

    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); Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia

  8. The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.

    PubMed

    de Thé, Hugues; Le Bras, Morgane; Lallemand-Breitenbach, Valérie

    2012-07-09

    Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.

  9. BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell?

    PubMed

    Pullarkat, Vinod A; Newman, Edward M

    2016-10-01

    Venetoclax is an oral drug with an excellent side-effect profile that has the potential to revolutionize acute myeloid leukemia (AML) therapy in two areas. Venetoclax-based combination therapies could be a bridge to hematopoietic cell transplant with curative intent for patients with refractory/relapsed AML, and venetoclax-based therapy could provide meaningful survival prolongation for older patients with AML who are not candidates for more aggressive therapies. Cancer Discov; 6(10); 1082-3. ©2016 AACR.See related article by Konopleva and colleagues, p. 1106.

  10. Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway.

    PubMed

    Lin, Xiaojing; Fang, Qin; Chen, Shuya; Zhe, Nana; Chai, Qixiang; Yu, Meisheng; Zhang, Yaming; Wang, Ziming; Wang, Jishi

    2015-05-01

    There are few studies on the correlation between heme oxygenase-1 (HO-1) and acute myeloid leukemia (AML). We found that HO-1 was aberrantly overexpressed in the majority of AML patients, especially in patients with acute monocytic leukemia (M5) and leukocytosis, and inhibited the apoptosis of HL-60 and U937 cells. Moreover, silencing HO-1 prolonged the survival of xenograft mouse models. Further studies demonstrated that HO-1 suppressed the apoptosis of AML cells through activating the JNK/c-JUN signaling pathway. These data indicate a molecular role of HO-1 in inhibiting cell apoptosis, allowing it to be a potential target for treating AML.

  11. Reduced Intensity Donor Peripheral Blood Stem Cell Transplant in Treating Patients With De Novo or Secondary Acute Myeloid Leukemia in Remission

    ClinicalTrials.gov

    2017-01-25

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 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(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); Secondary Acute Myeloid Leukemia

  12. Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells.

    PubMed

    Majeti, R

    2011-03-03

    Accumulating evidence indicates that many human cancers are organized as a cellular hierarchy initiated and maintained by self-renewing cancer stem cells. This cancer stem cell model has been most conclusively established for human acute myeloid leukemia (AML), although controversies still exist regarding the identity of human AML stem cells (leukemia stem cell (LSC)). A major implication of this model is that, in order to eradicate the cancer and cure the patient, the cancer stem cells must be eliminated. Monoclonal antibodies have emerged as effective targeted therapies for the treatment of a number of human malignancies and, given their target antigen specificity and generally minimal toxicity, are well positioned as cancer stem cell-targeting therapies. One strategy for the development of monoclonal antibodies targeting human AML stem cells involves first identifying cell surface antigens preferentially expressed on AML LSC compared with normal hematopoietic stem cells. In recent years, a number of such antigens have been identified, including CD123, CD44, CLL-1, CD96, CD47, CD32, and CD25. Moreover, monoclonal antibodies targeting CD44, CD123, and CD47 have demonstrated efficacy against AML LSC in xenotransplantation models. Hopefully, these antibodies will ultimately prove to be effective in the treatment of human AML.

  13. Investigation of deregulated genes of Notch signaling pathway in human T cell acute lymphoblastic leukemia cell lines and clinical samples.

    PubMed

    Paryan, Mahdi; Mohammadi-Yeganeh, Samira; Samiee, Siamak Mirab; Soleimani, Masoud; Arefian, Ehsan; Azadmanesh, Keyhan; Poopak, Behzad; Mostafavi, Ehsan; Karimipoor, Morteza; Mahdian, Reza

    2013-10-01

    In diagnostic research challenges, quantitative real-time PCR (QPCR) has been widely utilized in gene expression analysis because of its sensitivity, accuracy, reproducibility, and most importantly, quantitativeness. Real-time PCR base kits are wildly applicable in cancer signaling pathways, especially in cancer investigations. T-cell acute lymphoblastic leukemia (T-ALL) is a type of leukemia that is more common in older children and teenagers. Deregulation of the Notch signaling pathway promotes proliferation and inhibits apoptosis of the lymphoblastic T cells. The aim of this study was to investigate the effect of Notch signaling activation on the expression of target genes using real-time QPCR and further use this method in clinical examination after validation. Two T-ALL cell lines, Jurkat and Molt-4, were used as models for activation of the Notch signaling via over-expression of the Notch1 intracellular domain. Expression analysis was performed for six downstream target genes (NCSTN, APH1, PSEN1, ADAM17, NOTCH1 and C-MYC) which play critical roles in the Notch signaling pathway. The results showed significant difference in the expression of target genes in the deregulated Notch signaling pathway. These results were also verified in 12 clinical samples bearing over-expression of the Notch signaling pathway. Identification of such downstream Notch target genes, which have not been studied inclusively, provides insights into the mechanisms of the Notch function in T cell leukemia, and may help identify novel diagnoses and therapeutic targets in acute lymphoblastic leukemia.

  14. Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo.

    PubMed

    Miraki-Moud, Farideh; Ghazaly, Essam; Ariza-McNaughton, Linda; Hodby, Katharine A; Clear, Andrew; Anjos-Afonso, Fernando; Liapis, Konstantinos; Grantham, Marianne; Sohrabi, Fareeda; Cavenagh, Jamie; Bomalaski, John S; Gribben, John G; Szlosarek, Peter W; Bonnet, Dominique; Taussig, David C

    2015-06-25

    The strategy of enzymatic degradation of amino acids to deprive malignant cells of important nutrients is an established component of induction therapy of acute lymphoblastic leukemia. Here we show that acute myeloid leukemia (AML) cells from most patients with AML are deficient in a critical enzyme required for arginine synthesis, argininosuccinate synthetase-1 (ASS1). Thus, these ASS1-deficient AML cells are dependent on importing extracellular arginine. We therefore investigated the effect of plasma arginine deprivation using pegylated arginine deiminase (ADI-PEG 20) against primary AMLs in a xenograft model and in vitro. ADI-PEG 20 alone induced responses in 19 of 38 AMLs in vitro and 3 of 6 AMLs in vivo, leading to caspase activation in sensitive AMLs. ADI-PEG 20-resistant AMLs showed higher relative expression of ASS1 than sensitive AMLs. This suggests that the resistant AMLs survive by producing arginine through this metabolic pathway and ASS1 expression could be used as a biomarker for response. Sensitive AMLs showed more avid uptake of arginine from the extracellular environment consistent with their auxotrophy for arginine. The combination of ADI-PEG 20 and cytarabine chemotherapy was more effective than either treatment alone resulting in responses in 6 of 6 AMLs tested in vivo. Our data show that arginine deprivation is a reasonable strategy in AML that paves the way for clinical trials.

  15. Binding of iodinated recombinant human GM-CSF to the blast cells of acute myeloblastic leukemia

    SciTech Connect

    Kelleher, C.A.; Wong, G.G.; Clark, S.C.; Schendel, P.F.; Minden, M.D.; McCulloch, E.A.

    1988-04-01

    Granulocyte/macrophage-colony-stimulating factor (GM-CSF) is an effective growth factor for the blasts of acute myeloblastic leukemia (AML). Radioiodinated Chinese hamster ovary (CHO)-cell derived GM-CSF was prepared using Bolton-Hunter reagent to label free amino groups on the protein. Normal human neutrophils and the blast cells from AML patients were examined for binding. We found that there were fewer receptors of higher affinity on blast cells compared with neutrophils. After brief culture in suspension, receptor number increased and affinity decreased. Experiments provided evidence that GM-CSF from Escherichia coli had a higher affinity for neutrophils (kd = 20 pM) than the CHO-cell derived protein (kd = 500 pM-1 nM). This difference was reflected in the increased effectiveness of the E. coli protein over the CHO protein to stimulate colony formation in both normal bone marrow cells and AML blasts.

  16. Acute Appendicitis in Patients with Acute Leukemia

    PubMed Central

    Kim, Ki Up; Kim, Jin Kyeung; Won, Jong Ho; Hong, Dae Sik; Park, Hee Sook; Park, Kyeung Kyu

    1993-01-01

    The decision to operate for abdominal pain in patients with leukopenia can be exceedingly difficult. Surgical exploration may be the only effective way to differentiate acute appendicitis from other causes, but it involves considerable risk of infectious complications due to immunesuppression. Leukemic patients, who presented significant RLQ pain, had been indicated for operation, despite having advanced disease or having had received chemotherapy or steroids. Four adult leukemia patients, complicated by acute appendictis, were reviewed. Two patients were in induction chemotherapy, one receiving salvage chemotheapy due to relapse and the other was in conservative treatment. Two patients were acute myelocytic leukemia (AML), one had acute lymphocytic leukemia (ALL), and the other had aleukemic leukemia. All patients underwent appendectomy and recovered without complication. Our experience supports the theory that the surgical management of appendicitis in acute leukemia is the most effective way, in spite of leukopenia. PMID:8268146

  17. Association of Human Development Index with rates and outcomes of hematopoietic stem cell transplantation for patients with acute leukemia.

    PubMed

    Giebel, Sebastian; Labopin, Myriam; Ehninger, Gerhard; Beelen, Dietrich; Blaise, Didier; Ganser, Arnold; Bacigalupo, Andrea; Czerw, Tomasz; Holowiecki, Jerzy; Fagundes, Evandro M; Nowara, Elzbieta; Frassoni, Francesco; Rocha, Vanderson

    2010-07-08

    Human Development Index (HDI) is used by the United Nations Organization to measure socioeconomic achievements of countries. We evaluated the association of HDI with rates and outcomes of hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia. For the analysis of HSCT rates, all adults with acute leukemia (n = 16 403) treated in 30 European countries, between 2001 and 2005, were included. Association of HDI with the outcome was analyzed for 2015 patients with acute myeloid leukemia treated with myeloablative allotransplantation. Countries were classified according to HDI quintiles. Highly significant correlation was found for HDI and the total number of HSCT per population (R = 0.78; P < .001), as well as separately for sibling HSCT (R = 0.84; P < .001), unrelated HSCT (R = 0.66; P < .001), and autologous HSCT (R = 0.43; P = .02). The probabilities of leukemia-free survival for 5 consecutive groups of countries with increasing HDI were: 56%, 59%, 63%, 58%, and 68% (P = .01). In a multivariate analysis, transplantations performed in countries belonging to the upper HDI category were associated with higher leukemia-free survival compared with the remaining ones (HR = 1.36, P = .008), which resulted mainly from reduced risk of relapse (HR = 0.72, P = .04). We conclude that, in Europe, the HDI is associated with both rates and results of HSCT for acute leukemia.

  18. Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia.

    PubMed

    Takam Kamga, Paul; Bassi, Giulio; Cassaro, Adriana; Midolo, Martina; Di Trapani, Mariano; Gatti, Alessandro; Carusone, Roberta; Resci, Federica; Perbellini, Omar; Gottardi, Michele; Bonifacio, Massimiliano; Nwabo Kamdje, Armel Hervé; Ambrosetti, Achille; Krampera, Mauro

    2016-04-19

    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.

  19. Hispidulin induces mitochondrial apoptosis in acute myeloid leukemia cells by targeting extracellular matrix metalloproteinase inducer

    PubMed Central

    Gao, Hui; Liu, Yongji; Li, Kan; Wu, Tianhui; Peng, Jianjun; Jing, Fanbo

    2016-01-01

    Acute myeloid leukemia (AML) represents a heterogeneous group of hematological neoplasms with marked heterogeneity in response to both standard therapy and survival. Hispidulin, a flavonoid compound that is anactive ingredient in the traditional Chinese medicinal herb Salvia plebeia R. Br, has recently been reported to have anantitumor effect against solid tumors in vitro and in vivo. The aim of the present study was to investigate the effects of hispidulin on the human leukemia cell line in vitro and the underlying mechanisms of its actions on these cells. Our results showed that hispidulin inhibits AML cell proliferation in a dose- and time-dependent manner, and induces cell apoptosis throughan intrinsic mitochondrial pathway. Our results also revealed that hispidulin treatment significantly inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) expression in both tested AML cell lines in a dose-dependent manner, and that the overexpression of EMMPRIN protein markedly attenuates hispidulin-induced cell apoptosis. Furthermore, our results strongly indicated that the modulating effect of hispidulin on EMMPRIN is correlated with its inhibitory effect on both the Akt and STAT3 signaling pathways. PMID:27158398

  20. Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells

    PubMed Central

    Bontempo, Paola; Mita, Luigi; Doto, Antonella; Miceli, Marco; Nebbioso, Angela; Lepore, Ilaria; Franci, GianLuigi; Menafra, Roberta; Carafa, Vincenzo; Conte, Mariarosaria; De Bellis, Floriana; Manzo, Fabio; Di Cerbo, Vincenzo; Benedetti, Rosaria; D'Amato, Loredana; Marino, Maria; Bolli, Alessandro; Del Pozzo, Giovanna; Diano, Nadia; Portaccio, Marianna; Mita, Gustavo D; Vietri, Maria Teresa; Cioffi, Michele; Nola, Ernesto; Dell'Aversana, Carmela; Sica, Vincenzo; Molinari, Anna Maria; Altucci, Lucia

    2009-01-01

    Background: BPA (bisphenol A or 2,2-bis(4-hydroxy-phenol)propane) is present in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA. Thus, it is necessary to investigate the cytotoxicity and apoptosis-inducing activity of this compound. Methods: Cell cycle, apoptosis and differentiation analyses; western blots. Results: BPA is able to induce cell cycle arrest and apoptosis in three different acute myeloid leukemias. Although some granulocytic differentiation concomitantly occurred in NB4 cells upon BPA treatment, the major action was the induction of apoptosis. BPA mediated apoptosis was caspase dependent and occurred by activation of extrinsic and intrinsic cell death pathways modulating both FAS and TRAIL and by inducing BAD phosphorylation in NB4 cells. Finally, also non genomic actions such as the early decrease of both ERK and AKT phosphorylation were induced by BPA thus indicating that a complex intersection of regulations occur for the apoptotic action of BPA. Conclusion: BPA is able to induce apoptosis in leukemia cells via caspase activation and involvement of both intrinsic and extrinsic pathways of apoptosis. PMID:19538739

  1. The quality and quantity of leukemia-derived dendritic cells from patients with acute myeloid leukemia and myelodysplastic syndrome are a predictive factor for the lytic potential of dendritic cells-primed leukemia-specific T cells.

    PubMed

    Grabrucker, Christine; Liepert, Anja; Dreyig, Julia; Kremser, Andreas; Kroell, Tanja; Freudenreich, Markus; Schmid, Christoph; Schweiger, Cornelia; Tischer, Johanna; Kolb, Hans-Jochen; Schmetzer, Helga

    2010-06-01

    Adoptive immunotherapy is an important therapy option to reduce relapse rates after stem-cell transplantation in patients suffering from acute myeloid leukemia and myelodysplastic syndromes. Myeloid leukemic cells can regularly be induced to differentiate into leukemia-derived dendritic cells (DC(leu)), regaining the stimulatory capacity of professional dendritic cells (DCs) while presenting the known/unknown leukemic antigen repertoire. So far, induced antileukemic T-cell responses are variable or even mediate opposite effects. To further elicit DC/DC(leu)-induced T-cell-response patterns, we generated DC from 17 Acute myeloid leukemia (AML) and 2 myelodysplastic syndrome cases and carried out flowcytometry and (functional) nonradioactive fluorolysis assays before/after mixed lymphocyte cultures of matched (allogeneic) donor T cells (n=6), T cells prepared at relapse after stem-cell transplantation (n=4) or (autologous) patients' T cells (n=7) with blast containing mononuclear cells ("MNC") or DC(leu) ("DC"). Compared with "MNC", "DC" were better mediators of antileukemic-activity, although not in every case effective. We could define DC subtypes and cut-off proportions of DC subtypes/qualities (mature DC/DC(leu)) after "DC" priming, which were predictive for an antileukemic activity of primed T cells and the clinical course of the disease after immunotherapy (allogeneic stem-cell transplantation/donor lymphocytes infusion/therapy). In summary, our data show that the composition and quality of DC after a mixed lymphocyte culture-priming phase is predictive for a successful ex vivo antileukemic response, especially with respect to proportions of mature and leukemia-derived DC. These data contribute not only to predict DC-mediated functions or the clinical course of the diseases but also to develop and refine DC-vaccination strategies that may pave the way to develop and modify adoptive immunotherapy, especially for patients at relapse after allogeneic stem-cell

  2. Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell grafts

    PubMed Central

    Bleakley, Marie; Heimfeld, Shelly; Loeb, Keith R.; Jones, Lori A.; Chaney, Colette; Seropian, Stuart; Gooley, Ted A.; Sommermeyer, Franziska; Riddell, Stanley R.; Shlomchik, Warren D.

    2015-01-01

    BACKGROUND. Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively. METHODS. In a single-arm clinical trial, we transplanted 35 patients with high-risk leukemia with TN-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of TM purged of CD45RA+ TN. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution. RESULTS. All recipients of TN-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell–replete grafts. TM in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years. CONCLUSION. Depletion of TN from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory. TRIAL REGISTRATION. ClinicalTrials.gov (NCT 00914940). FUNDING. NIH, Burroughs Wellcome Fund, Leukemia and Lymphoma Society, Damon Runyon Cancer Research Foundation, and Richard Lumsden Foundation. PMID:26053664

  3. Molecular Targeting of the Oncoprotein PLK1 in Pediatric Acute Myeloid Leukemia: RO3280, a Novel PLK1 Inhibitor, Induces Apoptosis in Leukemia Cells

    PubMed Central

    Wang, Na-Na; Li, Zhi-Heng; Zhao, He; Tao, Yan-Fang; Xu, Li-Xiao; Lu, Jun; Cao, Lan; Du, Xiao-Juan; Sun, Li-Chao; Zhao, Wen-Li; Xiao, Pei-Fang; Fang, Fang; Su, Guang-Hao; Li, Yan-Hong; Li, Gang; Li, Yi-Ping; Xu, Yun-Yun; Zhou, Hui-Ting; Wu, Yi; Jin, Mei-Fang; Liu, Lin; Ni, Jian; Wang, Jian; Hu, Shao-Yan; Zhu, Xue-Ming; Feng, Xing; Pan, Jian

    2015-01-01

    Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined. PMID:25574601

  4. Next-Generation Sequencing in Adult B Cell Acute Lymphoblastic Leukemia Patients.

    PubMed

    Sala Torra, Olga; Othus, Megan; Williamson, David W; Wood, Brent; Kirsch, Ilan; Robins, Harlan; Beppu, Lan; O'Donnell, Margaret R; Forman, Stephen J; Appelbaum, Frederick R; Radich, Jerald P

    2017-04-01

    We used next-generation sequencing (NGS) of the immunoglobulin genes to evaluate residual disease in 153 specimens from 32 patients with adult B cell acute lymphoblastic leukemia enrolled in a single multicenter study. The sequencing results were compared with multiparameter flow cytometry (MFC) data in 66 specimens (25 patients) analyzed by both methods. There was a strong concordance (82%) between the methods in the qualitative determination of the presence of disease. However, in 17% of cases, leukemia was detected by sequencing but not by MFC. In 54 bone marrow (BM) and peripheral blood (PB) paired specimens, the burden of leukemia detected by NGS was lower in PB than in BM, although it was still detectable in 68% of the 28 paired specimens with positive BM. Lastly, patients without disease detected by NGS or MFC had a 5-year relapse free survival of > 80%. The results suggest that residual disease detection by immunoglobulin gene sequencing is an extremely sensitive technique and may identify patients that might benefit from transplantation. Moreover, the increased sensitivity of the method may allow frequent peripheral blood testing to supplement marrow sampling to measure disease response.

  5. The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells.

    PubMed

    Singh, Raminder; Fröbel, Julia; Cadeddu, Ron-Patrick; Bruns, Ingmar; Schroeder, Thomas; Brünnert, Daniela; Wilk, Christian Matthias; Zerbini, Luiz Fernando; Haas, Rainer; Czibere, Akos

    2012-02-01

    Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Treatment of patients suffering from high-risk AML as defined by clinical parameters, cytogenetics, and/or molecular analyses is often unsuccessful. OSI-461 is a pro-apoptotic compound that has been proposed as a novel therapeutic option for patients suffering from solid tumors like prostate or colorectal carcinoma. But little is known about its anti-proliferative potential in AML. Hence, we treated bone marrow derived CD34(+) selected blast cells from 20 AML patients and the five AML cell lines KG-1a, THP-1, HL-60, U-937, and MV4-11 with the physiologically achievable concentration of 1 μM OSI-461 or equal amounts of DMSO as a control. Following incubation with OSI-461, we found a consistent induction of apoptosis and an accumulation of cells in the G2/M phase of the cell cycle. In addition, we demonstrate that the OSI-461 mediated anti-proliferative effects observed in AML are associated with the induction of the pro-apoptotic cytokine mda-7/IL-24 and activation of the growth arrest and DNA-damage inducible genes (GADD) 45α and 45γ. Furthermore, OSI-461 treated leukemia cells did not regain their proliferative potential for up to 8 days after cessation of treatment following the initial 48 h treatment period with 1 μM OSI-461. This indicates sufficient targeting of the leukemia-initiating cells in our in vitro experiments through OSI-461. The AML samples tested in this study included samples from patients who were resistant to conventional chemotherapy and/or had FLT3-ITD mutations demonstrating the high potential of OSI-461 in human AML.

  6. Computer aided detection and classification of acute lymphoblastic leukemia cell subtypes based on microscopic image analysis.

    PubMed

    MoradiAmin, Morteza; Memari, Ahmad; Samadzadehaghdam, Nasser; Kermani, Saeed; Talebi, Ardeshir

    2016-10-01

    Acute lymphoblastic leukemia (ALL) is a cancer that starts from the early version of white blood cells called lymphocytes in the bone marrow. It can spread to different parts of the body rapidly and if not treated, would probably be deadly within a couple of months. Leukemia cells are categorized into three types of L1, L2, and L3. The cancer is detected through screening of blood and bone marrow smears by pathologists. But manual examination of blood samples is a time-consuming and boring procedure as well as limited by human error risks. So to overcome these limitations a computer-aided detection system, capable of discriminating cancer from noncancer cases and identifying the cancerous cell subtypes, seems to be necessary. In this article an automatic detection method is proposed; first cell nucleus is segmented by fuzzy c-means clustering algorithm. Then a rich set of features including geometric, first- and second-order statistical features are obtained from the nucleus. A principal component analysis is used to reduce feature matrix dimensionality. Finally, an ensemble of SVM classifiers with different kernels and parameters is applied to classify cells into four groups, that is noncancerous, L1, L2, and L3. Results show that the proposed method can be used as an assistive diagnostic tool in laboratories.

  7. Cell death induction by the acute promyelocytic leukemia-specific PML/RARα fusion protein

    PubMed Central

    Ferrucci, Pier Francesco; Grignani, Francesco; Pearson, Mark; Fagioli, Marta; Nicoletti, Ildo; Pelicci, Pier Giuseppe

    1997-01-01

    PML/RARα is the abnormal protein product generated by the acute promyelocytic leukemia-specific t(15;17). Expression of PML/RARα in hematopoietic precursor cell lines induces block of differentiation and promotes survival. We report here that PML/RARα has a potent growth inhibitory effect on all nonhematopoietic cell lines and on the majority of the hematopoietic cell lines tested. Inducible expression of PML/RARα in fibroblasts demonstrated that the basis for the growth suppression is induction of cell death. Deletion of relevant promyelocytic leukemia (PML) and retinoic acid receptor (RARα) domains within the fusion protein revealed that its growth inhibitory effect depends on the integrity of the PML aminoterminal region (RING, B1, B2, and coiled coil regions) and the RARα DNA binding region. Analysis of the nuclear localization of the same PML/RARα deletion mutants by immunofluorescence and cell fractionation revealed that the biological activity of the fusion protein correlates with its microspeckled localization and its association to the nuclear matrix. The PML aminoterminal region, but not the RARα zinc fingers, is required for the proper nuclear localization of PML/RARα. We propose that the matrix-associated microspeckles are the active sites of PML/RARα and that targeting of RARα sequences to this specific nuclear subdomain through PML sequences is crucial to the activity of the fusion protein on survival regulation. PMID:9380732

  8. [Effect of metformin on acute promyelocytic leukemia cell line NB4 and its mechanism].

    PubMed

    Huai, Lei; Wang, Cui-Cui; Zhang, Cui-Ping; Li, Qi-Hui; Chen, Yi-Rui; Jia, Yu-Jiao; Wang, Min; Wang, Jian-Xiang

    2012-12-01

    The purpose of this study was to investigate the effect and molecular mechanism of metformin (Met) on biological characteristics of acute promyelocytic leukemia (APL) cell line NB4. NB4 cells were treated with various concentrations of Met for different time, MTT method was used to detect cell proliferation, the alteration of cell apoptosis was analyzed by flow cytometry, and the change of cell adhesion ability was examined by cell adhesion assay. NB4 cells were pretreated with U0126, a specific inhibitor for extracellular signal-regulated kinase (ERK) phosphorylation, ERK phosphorylation was assessed by Western blot analysis, apoptosis and cell adhesion ability were evaluated by flow cytometry and cell adhesion test respectively. The results showed that Met could inhibit the cell proliferation, induce the cell apoptosis and increase the ability of cell adhesion. The pretreatment of NB4 cells with 5 µmol/L U0126 could effectively inhibit the phosphorylation of ERK, and reduce cell apoptosis and adhesion induced by 5 mmol/L Met. It is concluded that Met can inhibit the proliferation and promote the apoptosis and adhesion of NB4 cells. MEK/ERK signaling pathway may be one of the molecular mechanisms of metformin on NB4 cells.

  9. Flow cytometric analysis of hemetopoietic progenitor cells in peripheral blood stem cell harvest from patients with CD34 positive acute leukemia.

    PubMed

    Miyazaki, T; Matsuda, I; Oguri, M; Amaya, H; Kiyosaki, M; Hamada, A; Tamaki, S; Tashiro, E; Kudo, Y; Taniguchi, O; Nakamura, T; Tomoyasu, S

    2001-01-01

    We analyzed CD34 positive cells in peripheral blood stem cell harvest (PBSCH) using flow cytometry. PBSCH from CD34 positive acute myelogeous leukemia (AML-M2) patient contained 1.87% CD34 positive cells, of which 1.21% was represented by MRD.PBSCH from CD34 positive acute lymphoblast leukemia (ALL) patient contained 3.14% CD34 positive cells, of which 0.11% was accounted for by minimal residual disease (MRD). If PBSCH from CD34 positive acute leukemia patient is analyzed for CD34 monoclonal antibody alone, the presence of CD34 positive MRD may escape attention so that CD34 positive hematopoietic progenitor cells may be overestimated. To avoid this risk, it is necessary to analyze PBSCH using both CD34 monoclonal antibody and characteristic markers of leukemia cells that were found pre-treatment.

  10. Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells.

    PubMed

    Zhang, JinFeng; Su, Le; Ye, Qing; Zhang, ShangLi; Kung, HsiangFu; Jiang, Fan; Jiang, GuoSheng; Miao, JunYing; Zhao, BaoXiang

    2017-01-31

    Nuclear factor-erythroid 2-related factor 2 (Nrf2) is persistently activated in many human tumors including acute myeloid leukemia (AML). Therefore, inhibition of Nrf2 activity may be a promising target in leukemia therapy. Here, we used an antioxidant response element-luciferase reporter system to identify a novel pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole-5-carboxamide (4f), that inhibited Nrf2 activity. 4f had a profound growth-inhibitory effect on three AML cell lines, THP-1, HL-60 and U937, and a similar anti-growth effect in a chick embryo model. Moreover, flow cytometry of AML cells revealed increased apoptosis with 4f (10 μM) treatment for 48 h. The protein levels of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase were enhanced in all three AML cell types. Furthermore, Nrf2 protein level was downregulated by 4f. Upregulation of Nrf2 by tert-butylhydroquinone (tBHQ) or Nrf2 overexpression could ameliorate 4f-induced growth inhibition and apoptosis. Treatment with 4f reduced both B-cell lymphoma-2 (Bcl-2) expression and Bcl-2/Bcl-2-associated X protein (Bax) ratio, which indicated that 4f induced apoptosis, at least in part, via mitochondrial-dependent signaling. Therefore, as an Nrf2 inhibitor, the pyrazolyl hydroxamic acid derivative 4f may be a promising agent in AML therapy.

  11. Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells

    PubMed Central

    Gao, Hui-er; Song, He-nan; Yang, Ming; Liu, Xiao-lei; Zhang, Zi-xiang; Li, Ying-hui; Gao, Ying-dai

    2016-01-01

    Leukemic stem cells (LSCs) greatly contribute to the initiation, relapse, and multidrug resistance of leukemia. Current therapies targeting the cell cycle and rapidly growing leukemic cells, including conventional chemotherapy, have little effect due to the self-renewal and differentiated malignant cells replenishment ability of LSCs despite their scarce supply in the bone marrow. Micheliolide (MCL) is a natural guaianolide sesquiterpene lactone (GSL) which was discovered in michelia compressa and michelia champaca plants, and has been shown to exert selective cytotoxic effects on CD34+CD38− LSCs. In this study, we demonstrate that DMAMCL significantly prolongs the lifespan of a mouse model of human acute myelogenous leukemia (AML). Mechanistic investigations further revealed that MCL exerted its cytotoxic effects via inhibition of NF-κB expression and activity, and by generating intracellular reactive oxygen species (ROS). These results provide valuable insight into the mechanisms underlying MCL-induced cytotoxicity of LSCs, and support further preclinical investigations of MCL-related therapies for the treatment of AML. PMID:27542251

  12. SYK as a New Therapeutic Target in B-Cell Precursor Acute Lymphoblastic Leukemia

    PubMed Central

    Uckun, Fatih M.; Qazi, Sanjive

    2014-01-01

    The identification of SYK as a master regulator of apoptosis controlling the activation of the PI3-K/AKT, NFκB, and STAT3 pathways—three major anti-apoptotic signaling pathways in B-lineage leukemia/lymphoma cells—prompts the hypothesis that rationally designed inhibitors targeting SYK may overcome the resistance of malignant B-lineage lymphoid cells to apoptosis and thereby provide the foundation for more effective multi-modality treatment regimens for poor prognosis B-precursor acute lymphoblastic leukemia (BPL). In recent preclinical proof-of-concept studies, a liposomal nanoparticle (LNP) formulation of a SYK substrate-binding site inhibitor, known as C61, has been developed as a nanomedicine candidate against poor prognosis and relapsed BPL. This nanoscale formulation of C61 exhibited a uniquely favorable pharmacokinetics and safety profile in mice, induced apoptosis in radiation-resistant primary leukemic cells taken directly from BPL patients as well as in vivo clonogenic BPL xenograft cells, destroyed the leukemic stem cell fraction of BPL blasts, and exhibited potent in vivo anti-leukemic activity in xenograft models of aggressive BPL. Further development of C61-LNP may provide the foundation for new and effective treatment strategies against therapy-refractory BPL. PMID:24851191

  13. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair

    PubMed Central

    Alcalay, Myriam; Meani, Natalia; Gelmetti, Vania; Fantozzi, Anna; Fagioli, Marta; Orleth, Annette; Riganelli, Daniela; Sebastiani, Carla; Cappelli, Enrico; Casciari, Cristina; Sciurpi, Maria Teresa; Mariano, Angela Rosa; Minardi, Simone Paolo; Luzi, Lucilla; Muller, Heiko; Di Fiore, Pier Paolo; Frosina, Guido; Pelicci, Pier Giuseppe

    2003-01-01

    Acute myelogenous leukemias (AMLs) are genetically heterogeneous and characterized by chromosomal rearrangements that produce fusion proteins with aberrant transcriptional regulatory activities. Expression of AML fusion proteins in transgenic mice increases the risk of myeloid leukemias, suggesting that they induce a preleukemic state. The underlying molecular and biological mechanisms are, however, unknown. To address this issue, we performed a systematic analysis of fusion protein transcriptional targets. We expressed AML1/ETO, PML/RAR, and PLZF/RAR in U937 hemopoietic precursor cells and measured global gene expression using oligonucleotide chips. We identified 1,555 genes regulated concordantly by at least two fusion proteins that were further validated in patient samples and finally classified according to available functional information. Strikingly, we found that AML fusion proteins induce genes involved in the maintenance of the stem cell phenotype and repress DNA repair genes, mainly of the base excision repair pathway. Functional studies confirmed that ectopic expression of fusion proteins constitutively activates pathways leading to increased stem cell renewal (e.g., the Jagged1/Notch pathway) and provokes accumulation of DNA damage. We propose that expansion of the stem cell compartment and induction of a mutator phenotype are relevant features underlying the leukemic potential of AML-associated fusion proteins. PMID:14660751

  14. Tipifarnib and Bortezomib in Treating Patients With Acute Leukemia or Chronic Myelogenous Leukemia in Blast Phase

    ClinicalTrials.gov

    2015-04-14

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Blastic Phase; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  15. Secondary Philadelphia chromosome and erythrophagocytosis in a relapsed acute myeloid leukemia after hematopoietic cell transplantation.

    PubMed

    Kelemen, Katalin; Galani, Komal; Conley, Christopher R; Greipp, Patricia T

    2014-06-01

    The acquisition of the Philadelphia chromosome (Ph) as a secondary change during the course of hematopoietic malignancies is rare and is associated with poor prognosis. Few cases of secondary Ph have been reported after hematopoietic cell transplantation (HCT). A secondary Ph at relapse is of clinical importance because it provides a therapeutic target for tyrosine kinase inhibitors along with or in replacement of chemotherapy. We describe a case of relapsed acute myeloid leukemia (AML) after HCT that developed a BCR-ABL1 translocation along with erythrophagocytosis by blasts as a secondary change at the time of relapse. The progression of this patient's myeloid neoplasm from myelodysplastic syndrome to AML to relapsed AML after HCT was accompanied by a stepwise cytogenetic evolution: A deletion 20q abnormality subsequently acquired a deletion 7q and, finally, at relapse after HCT, a secondary Ph was gained. The relationship between the secondary Ph and the erythrophagocytosis by blasts is not clear. We review the possible pathogenesis and cytogenetic associations of erythrophagocytosis by blasts, a rare feature in acute leukemias.

  16. Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells.

    PubMed

    Hartsink-Segers, Stefanie A; Exalto, Carla; Allen, Matthew; Williamson, Daniel; Clifford, Steven C; Horstmann, Martin; Caron, Huib N; Pieters, Rob; Den Boer, Monique L

    2013-10-01

    This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels.

  17. Treatment of Children with APL (Acute Promyelocytic Leukemia)

    MedlinePlus

    ... Childhood Leukemia Treatment of Children With Acute Promyelocytic Leukemia (APL) Treatment of acute promyelocytic leukemia (APL), the ... With Chronic Myelogenous Leukemia (CML) More In Childhood Leukemia About Childhood Leukemia Causes, Risk Factors, and Prevention ...

  18. PI-103 sensitizes acute myeloid leukemia stem cells to daunorubicin-induced cytotoxicity.

    PubMed

    Ding, Qian; Gu, Ran; Liang, Jiayi; Zhang, Xiangzhong; Chen, Yunxian

    2013-03-01

    To date, acute myeloid leukemia (AML) shows very poor outcome for conventional chemotherapy. Leukemia stem cells (LSCs) are insensitive to conventional chemotherapeutic drugs and play a central role in the pathogenesis of AML. Failure to effectively ablate these cells may lead to AML relapse following chemotherapy. Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constructively activated in LSCs. This pathway can be inhibited by PI-103, a novel synthesized molecule of the pyridofuropyrimidine class, resulting in the apoptosis of LSCs. Therefore, we investigate the influences of PI-103 in combination with daunorubicin (DNR) on the LSCs. Our data indicate that PI-103 synergistically sensitizes LSCs to DNR-induced cytotoxicity. In addition, the PI-103/DNR co-treatment can induce significant apoptosis in LSCs, but sparing hematopoietic stem cells. The synergistic effect and the LSCs-specific apoptosis mechanism may be associated with the inhibition of PI3K/Akt/mTOR signaling pathway. Our results suggest that PI-103 in combination with DNR may be a potent and less toxic therapy for targeting LSCs and deserve further preclinical and clinical studies in the treatment of AML.

  19. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation.

    PubMed

    Nasr, Rihab; Guillemin, Marie-Claude; Ferhi, Omar; Soilihi, Hassan; Peres, Laurent; Berthier, Caroline; Rousselot, Philippe; Robledo-Sarmiento, Macarena; Lallemand-Breitenbach, Valérie; Gourmel, Bernard; Vitoux, Dominique; Pandolfi, Pier Paolo; Rochette-Egly, Cécile; Zhu, Jun; de Thé, Hugues

    2008-12-01

    Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid-induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells.

  20. Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities

    PubMed Central

    Stahl, Maximilian; Kim, Tae Kon; Zeidan, Amer M

    2016-01-01

    The existence of cancer stem cells has been well established in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells (LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells (HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the self-renewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well. PMID:27822339

  1. Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia

    PubMed Central

    Goyal, Gaurav; Gundabolu, Krishna; Vallabhajosyula, Saraschandra; Silberstein, Peter T.; Bhatt, Vijaya Raj

    2016-01-01

    Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials. PMID:27247754

  2. Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities.

    PubMed

    Stahl, Maximilian; Kim, Tae Kon; Zeidan, Amer M

    2016-10-26

    The existence of cancer stem cells has been well established in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells (LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells (HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the self-renewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.

  3. Childhood Cancer: Leukemia (For Parents)

    MedlinePlus

    ... acute. Acute childhood leukemias are also divided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) , depending on ... Bone Marrow Childhood Cancer Neutropenia Stem Cell Transplants Acute Lymphoblastic Leukemia (ALL) Chemotherapy Radiation Therapy Chronic Myelogenous Leukemia (CML) ...

  4. Leydig-cell function in children after direct testicular irradiation for acute lymphoblastic leukemia

    SciTech Connect

    Brauner, R.; Czernichow, P.; Cramer, P.; Schaison, G.; Rappaport, R.

    1983-07-07

    To assess the effect of testicular irradiation on testicular endocrine function, we studied 12 boys with acute lymphoblastic leukemia who had been treated with direct testicular irradiation 10 months to 8 1/2 years earlier. Insufficient Leydig-cell function, manifested by a low response of plasma testosterone to chorionic gonadotropin or an increased basal level of plasma luteinizing hormone (or both), was observed in 10 patients, 7 of whom were pubertal. Two of these patients had a compensated testicular endocrine insufficiency with only high plasma concentrations of luteinizing hormone. Testosterone secretion was severely impaired in three pubertal boys studied more than four years after testicular irradiation. A diminished testicular volume indicating tubular atrophy was found in all pubertal patients, including three who had not received cyclophosphamide or cytarabine. These data indicate that testosterone insufficiency is a frequent complication of testicular irradiation, although some patients continue to have Leydig-cell activity for several years after therapy.

  5. Always expect the unexpected: lung abscess due to pseudomonas aeruginosa mimicking pulmonary aspergilloma in acute B-cell leukemia.

    PubMed

    Dieks, J-K; von Bueren, A O; Schaefer, I-M; Menke, J; Lex, C; Krause, U; Zenker, D; Kühnle, I; Kramm, C M

    2013-11-01

    We report on a case of Pseudomonas aeruginosa sepsis and consecutive lung abscess in a 13-year-old patient with acute B-cell leukemia. At first, radiographic findings strongly suggested presence of pulmonary aspergilloma and only microbiological testing of the surgically enucleated mass revealed the correct underlying pathogen and confirmed final diagnosis.

  6. Radiolabeled BC8 Antibody, Busulfan, Cyclophosphamide Followed by Donor Stem Cell Transplant in Treating Patients With Acute Myelogenous Leukemia in First Remission

    ClinicalTrials.gov

    2016-11-14

    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)

  7. The novel arylindolylmaleimide PDA-66 displays pronounced antiproliferative effects in acute lymphoblastic leukemia cells

    PubMed Central

    2014-01-01

    Background Prognosis of adult patients suffering from acute lymphoblastic leukemia (ALL) is still unsatisfactory. Targeted therapy via inhibition of deregulated signaling pathways appears to be a promising therapeutic option for the treatment of ALL. Herein, we evaluated the influence of a novel arylindolylmaleimide (PDA-66), a potential GSK3β inhibitor, on several ALL cell lines. Methods ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were exposed to different concentrations of PDA-66. Subsequently, proliferation, metabolic activity, apoptosis and necrosis, cell cycle distribution and protein expression of Wnt and PI3K/Akt signaling pathways were analyzed at different time points. Results PDA-66 inhibited the proliferation of ALL cells significantly by reduction of metabolic activity. The 72 h IC50 values ranged between 0.41 to 1.28 μM PDA-66. Additionally, caspase activated induction of apoptosis could be detected in the analyzed cell lines. PDA-66 influenced the cell cycle distribution of ALL cell lines differently. While RS4;11 and MOLT4 cells were found to be arrested in G2 phase, SEM cells showed an increased cell cycle in G0/1 phase. Conclusion PDA-66 displays significant antileukemic activity in ALL cells and classifies as candidate for further evaluation as a potential drug in targeted therapy of ALL. PMID:24502201

  8. Extracellular DNA traps released by acute promyelocytic leukemia cells through autophagy

    PubMed Central

    Ma, R; Li, T; Cao, M; Si, Y; Wu, X; Zhao, L; Yao, Z; Zhang, Y; Fang, S; Deng, R; Novakovic, V A; Bi, Y; Kou, J; Yu, B; Yang, S; Wang, J; Zhou, J; Shi, J

    2016-01-01

    Acute promyelocytic leukemia (APL) cells exhibit disrupted regulation of cell death and differentiation, and therefore the fate of these leukemic cells is unclear. Here, we provide the first evidence that a small percentage of APL cells undergo a novel cell death pathway by releasing extracellular DNA traps (ETs) in untreated patients. Both APL and NB4 cells stimulated with APL serum had nuclear budding of vesicles filled with chromatin that leaked to the extracellular space when nuclear and cell membranes ruptured. Using immunofluorescence, we found that NB4 cells undergoing ETosis extruded lattice-like structures with a DNA–histone backbone. During all-trans retinoic acid (ATRA)-induced cell differentiation, a subset of NB4 cells underwent ETosis at days 1 and 3 of treatment. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly elevated at 3 days, and combined treatment with TNF-α and IL-6 stimulated NB4 cells to release ETs. Furthermore, inhibition of autophagy by pharmacological inhibitors or by small interfering RNA against Atg7 attenuated LC3 autophagy formation and significantly decreased ET generation. Our results identify a previously unrecognized mechanism for death in promyelocytes and suggest that ATRA may accelerate ET release through increased cytokines and autophagosome formation. Targeting this cellular death pathway in addition to conventional chemotherapy may provide new therapeutic modalities for APL. PMID:27362801

  9. What Are the Key Statistics about Acute Myeloid Leukemia?

    MedlinePlus

    ... What Are the Key Statistics About Acute Myeloid Leukemia? The American Cancer Society’s estimates for leukemia in ... Leukemia Research and Treatment? More In Acute Myeloid Leukemia About Acute Myeloid Leukemia Causes, Risk Factors, and ...

  10. Expression of cellular oncogenes in primary cells from human acute leukemias.

    PubMed Central

    Mavilio, F; Sposi, N M; Petrini, M; Bottero, L; Marinucci, M; De Rossi, G; Amadori, S; Mandelli, F; Peschle, C

    1986-01-01

    The structure and the expression of 11 cellular oncogenes (protooncogenes) were analyzed in primary cells from 20 acute lymphocytic (ALL) and 31 acute myelogenous (AML) leukemia patients. Neoplastic cells, obtained prior to initiation of therapy, were purified and classified, on the basis of both surface antigen pattern and morphology, into pre-B, B, and T ALL and M1-M5 AML. RNA was extracted and analyzed for expression of cellular oncogenes coding for nuclear proteins (c-myc, c-myb, c-fos), the beta-chain of platelet-derived growth factor (c-sis), growth factor receptors or related proteins (c-src, c-abl, c-fes, c-erbB), or putative intermediate transducers of mitogenic signals (c-Ha-ras, c-Ki-ras, c-N-ras). Quantitative analysis of total RNA was carried out by dot blot hybridization to specific cDNA or genomic probes. Number and size of transcripts were evaluated by blot hybridization of electrophoretically fractionated poly(A)+ RNA. Expression of c-myc and c-myb was detected in all leukemic cells at variable levels and was characterized by well-defined patterns within ALL subtypes. Conversely, significant levels of c-fos transcripts were detected only in myelomonocytic (M4) and monocytic (M5) leukemias. Among the "src-family," c-fes was expressed more in AML than ALL, and c-abl was expressed at variable but not elevated levels in all leukemia types. c-Ha-ras was uniformly expressed at low levels, as in non-neoplastic cells. c-Ki-ras transcription was detected only in T ALL; N-ras expression was barely demonstrable. The structure of these protooncogenes was not grossly modified, as evaluated by Southern analysis, except for c-myc rearrangement in B ALL. These studies indicate that cellular oncogene expression in specific subtypes of leukemic cells may relate to either the proliferative activity (c-myc, c-myb) or the differentiation state (c-fos) of the cells, or possibly to expression of receptors for putative hemopoiesis-related growth factors (c-fes, c

  11. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.

    PubMed

    Herranz, Daniel; Ambesi-Impiombato, Alberto; Palomero, Teresa; Schnell, Stephanie A; Belver, Laura; Wendorff, Agnieszka A; Xu, Luyao; Castillo-Martin, Mireia; Llobet-Navás, David; Cordon-Cardo, Carlos; Clappier, Emmanuelle; Soulier, Jean; Ferrando, Adolfo A

    2014-10-01

    Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL.

  12. Genetic Inactivation of the PRC2 Complex in T-Cell Acute Lymphoblastic Leukemia

    PubMed Central

    Ntziachristos, Panagiotis; Tsirigos, Aristotelis; Van Vlierberghe, Pieter; Nedjic, Jelena; Trimarchi, Thomas; Flaherty, Maria Sol; Ferres-Marco, Dolors; da Ros, Vanina; Tang, Zuojian; Siegle, Jasmin; Asp, Patrik; Hadler, Michael; Rigo, Isaura; De Keersmaecker, Kim; Patel, Jay; Huynh, Tien; Utro, Filippo; Poglio, Sandrine; Samon, Jeremy B.; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M.; Rabadan, Raul; Levine, Ross L.; Brown, Stuart; Pflumio, Francoise; Dominguez, Maria; Ferrando, Adolfo; Aifantis, Iannis

    2011-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling1. In this study we report the presence of loss-of-function mutations and deletions of EZH2 and SUZ12 genes, encoding critical components of the Polycomb Repressive Complex 2 (PRC2) complex2,3, in 25% of T-ALLs. To further study the role of the PRC2 complex in T-ALL, we used NOTCH1-induced animal models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark lysine-27 tri-methylation of histone 3 (H3K27me3)4 by antagonizing the activity of the Polycomb Repressive Complex 2 (PRC2) complex. These studies demonstrate a tumor suppressor role for the PRC2 complex in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation. PMID:22237151

  13. Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia

    PubMed Central

    Sanghvi, Viraj R.; Mavrakis, Konstantinos J.; Van der Meulen, Joni; Boice, Michael; Wolfe, Andrew L.; Carty, Mark; Mohan, Prathibha; Rondou, Pieter; Socci, Nicholas D.; Benoit, Yves; Taghon, Tom; Van Vlierberghe, Pieter; Leslie, Christina S.; Speleman, Frank; Wendel, Hans-Guido

    2015-01-01

    The posttranscriptional control of gene expression by microRNAs (miRNAs) is highly redundant, and compensatory effects limit the consequences of the inactivation of individual miRNAs. This implies that only a few miRNAs can function as effective tumor suppressors. It is also the basis of our strategy to define functionally relevant miRNA target genes that are not under redundant control by other miRNAs. We identified a functionally interconnected group of miRNAs that exhibited a reduced abundance in leukemia cells from patients with T cell acute lymphoblastic leukemia (T-ALL). To pinpoint relevant target genes, we applied a machine learning approach to eliminate genes that were subject to redundant miRNA-mediated control and to identify those genes that were exclusively targeted by tumor-suppressive miRNAs. This strategy revealed the convergence of a small group of tumor suppressor miRNAs on the Myb oncogene, as well as their effects on HBP1, which encodes a transcription factor. The expression of both genes was increased in T-ALL patient samples, and each gene promoted the progression of T-ALL in mice. Hence, our systematic analysis of tumor suppressor miRNA action identified a widespread mechanism of oncogene activation in T-ALL. PMID:25406379

  14. Radotinib induces high cytotoxicity in c-KIT positive acute myeloid leukemia cells.

    PubMed

    Heo, Sook-Kyoung; Noh, Eui-Kyu; Kim, Jeong Yi; Jo, Jae-Cheol; Choi, Yunsuk; Koh, SuJin; Baek, Jin Ho; Min, Young Joo; Kim, Hawk

    2017-03-18

    Previously, we reported that radotinib, a BCR-ABL1 tyrosine kinase inhibitor, induced cytotoxicity in acute myeloid leukemia (AML) cells. However, the effects of radotinib in the subpopulation of c-KIT-positive AML cells were unclear. We observed that low-concentration radotinib had more potent cytotoxicity in c-KIT-positive cells than c-KIT-negative cells from AML patients. To address this issue, cell lines with high c-KIT expression, HEL92.1.7, and moderate c-KIT expression, H209, were selected. HEL92.1.7 cells were grouped into intermediate and high c-KIT expression populations. The cytotoxicity of radotinib against the HEL92.1.7 cell population with intermediate c-KIT expression was not different from that of the population with high c-KIT expression. When H209 cells were grouped into c-KIT expression-negative and c-KIT expression-positive populations, radotinib induced cytotoxicity in the c-KIT-positive population, but not the c-KIT-negative population. Thus, radotinib induces cytotoxicity in c-KIT-positive cells, regardless of the c-KIT expression intensity. Therefore, radotinib induces significant cytotoxicity in c-KIT-positive AML cells, suggesting that radotinib is a potential target agent for the treatment of c-KIT-positive malignancies including AML.

  15. ERG transcriptional networks in primary acute leukemia cells implicate a role for ERG in deregulated kinase signaling.

    PubMed

    Bock, Juliane; Mochmann, Liliana H; Schlee, Cornelia; Farhadi-Sartangi, Nasrin; Göllner, Stefanie; Müller-Tidow, Carsten; Baldus, Claudia D

    2013-01-01

    High expression of the E26 transforming sequence related gene (ERG) is associated with poor prognosis in a subgroup of leukemia patients with acute myeloid (AML) and acute T-lymphoblastic leukemia (T-ALL). In a previous study we proposed that ERG overexpression may deregulate several signaling cascades in acute leukemia. Herein, we further expand those studies by identifying a consensus of biological targets in primary blasts of newly diagnosed acute leukemia patients. Our findings of chromatin immunoprecipitation-on-chip of primary samples revealed 48 significantly enriched single genes including DAAM1 and NUMB. Significantly enriched signaling pathways included WNT/β-catenin, p53, and PI3K/AKT with ERG overexpression inducing dephosphorylation of AKT(Ser473) relative to non ERG expressing K562 cells. Cell based ERG overexpression studies also revealed drug resistance to multi-kinase inhibitor, BAY 43-9006 (Sorafenib) and to the tyrosine kinase inhibitor TKI258. Thus in primary leukemic cells, ERG may contribute to the dysregulation of kinase signaling, which results in resistance to kinase inhibitors.

  16. Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia.

    PubMed

    Peirs, S; Frismantas, V; Matthijssens, F; Van Loocke, W; Pieters, T; Vandamme, N; Lintermans, B; Dobay, M P; Berx, G; Poppe, B; Goossens, S; Bornhauser, B C; Bourquin, J-P; Van Vlierberghe, P

    2017-02-03

    Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.Leukemia advance online publication, 3 February 2017; doi:10.1038/leu.2017.10.

  17. [Genetic characteristics of human acute lymphoblastic leukemia cell line Molt-4].

    PubMed

    Ma, Xiao-Cai; Liu, Cong-Yan; Sun, Xue-Jing; He, Jing-Juan; Wan, Sui-Gui; Sun, Wan-Ling

    2014-04-01

    This study was aimed to investigate the genetic characteristics of human acute lymphoblastic leukemia cell line Molt-4, and evaluate its application in measuring telomere length by Flow-FISH. Molt-4 cell line was cultured in suspension and subcultured regularly. Eight different passages of Molt-4 cells in exponential stage were selected.The growth curves were drawn by cell counting method, meanwhile calculating the population doubling times of cells,DNA ploidies were determined by flow cytometry,karyotypes were analyzed by G-banding and telomere lengths were measured by Southern blot. The results showed that the population doubling time of Molt-4 cell line was (1.315 ± 0.062) d, DNA ploidy index was (2.085 ± 0.0093) , and the telomere length was (32.05 ± 5.27) kb. There were no significant difference among different passages (P = 0.931,0.888 and 0.935 separately). The karyotypes showed that the chromosome numbers of Molt-4 cell line were from 91 to 99 in different metaphases, and the majority of them were hypertetraploid, and stable and recurrent structural abnormalities of chromosomes could be kept. It is concluded that the stable genetic characteristics and the longer telomere length of Molt-4 cell line makes it be a feasible control cells in measurement of telomere length by Flow-FISH.

  18. Expression and functional roles of the chemokine receptor CXCR7 in acute myeloid leukemia cells

    PubMed Central

    Kim, Ha-Yon; Lee, So-Yeon; Kim, Deog-Young; Moon, Ji-Young; Choi, Yoon-Seok; Song, Ik-Chan; Lee, Hyo-Jin; Yun, Hwan-Jung; Kim, Samyong

    2015-01-01

    Background The C-X-C chemokine receptor 7 (CXCR7) has been shown to be a decoy receptor for CXCR4 in certain cell types. We investigated the expression status and functional roles of CXCR7 in acute myeloid leukemia (AML) cells in vitro. Methods CXCR7 mRNA was knocked down in AML cells by using small interfering RNA (siRNA) technology, and subsequent biological alterations in the cells were evaluated in vitro. Results All AML cell lines examined in this study (U937, K562, KG1a, HL-60, and MO7e) and primary CD34+ cells obtained from patients with AML expressed CXCR7 mRNA at various levels. Western blotting showed that all AML cells produced CXCR7. Furthermore, all AML cells expressed CXCR7 in both the cytoplasm and on the cell surface at various levels. Stromal cell-derived factor-1 (SDF-1; C-X-C motif ligand 12 (CXCL12)) induced internalization of cell surface CXCR7. However, neither hypoxia nor the examined hematopoietic growth factors (interleukin-1β (IL-1β), IL-3, IL-6, granulocyte-colony-stimulating factor, granulocyte, macrophage-colony-stimulating factor, and stem cell factor) and proinflammatory cytokines (interferon-γ, transforming growth factor-β, and tumor necrosis factor-α) were found to alter cell surface CXCR7 expression. The transfection of AML cells with CXCR4 siRNA, but not CXCR7 siRNA, significantly impaired the CXCL12-induced transmigration of the cells. The transfection of AML cells with CXCR7 siRNA did not affect the survival or proliferation of these cells. Knockdown of CXCR7, but not CXCR4, induced the upregulation of CXCL12 mRNA expression and CXCL12 production in AML cells. Conclusion CXCR7 is involved in the regulation of autocrine CXCL12 in AML cells. PMID:26770949

  19. Diagnosis of Large Granular Lymphocytic Leukemia in a Patient Previously Treated for Acute Myeloblastic Leukemia

    PubMed Central

    Bozdag, Sinem Civriz; Namdaroglu, Sinem; Kayikci, Omur; Kaygusuz, Gülsah; Demiriz, Itir; Cinarsoy, Murat; Tekgunduz, Emre; Altuntas, Fevzi

    2013-01-01

    Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disease characterized by the clonal expansion of cytotoxic T or natural killer cells. We report on a patient diagnosed with T-cell LGL leukemia two years after the achievement of hematologic remission for acute myeloblastic leukemia. PMID:24416499

  20. Hematuria and decreased kidney function as initial signs of acute B-cell lymphoblastic leukemia.

    PubMed

    Seo-Mayer, Patricia; Kenney, Barton; McNamara, Joseph; Stein, Jeffrey; Moeckel, Gilbert W

    2010-11-01

    We report the case of a 14-year-old boy who presented with hematuria and decreased kidney function as initial manifestations of acute lymphoblastic leukemia (ALL). Computed tomography of the abdomen showed extensive retroperitoneal lymphadenopathy and bilateral nephromegaly. The patient's kidney biopsy specimen showed a dense monomorphous interstitial infiltrate of small round blue cells with significant nuclear atypia. Immunohistochemical workup showed positive staining for CD20, CD10, and terminal deoxynucleotidyl transferase (TdT), consistent with ALL. The patient underwent induction chemotherapy, attained remission 4 weeks after induction, and presently is stable in the consolidation phase of chemotherapy. This is an unusual case of ALL involving both kidneys with initial presenting signs of hematuria and decreased kidney function.

  1. CAR therapy for hematological cancers: can success seen in the treatment of B-cell acute lymphoblastic leukemia be applied to other hematological malignancies?

    PubMed Central

    Pegram, Hollie J; Smith, Eric L; Rafq, Sarwish

    2016-01-01

    Chimeric antigen receptor (CAR) T-cell therapy has recently come into the spotlight due to impressive results in patients with B-cell acute lymphoblastic leukemia. By targeting CD19, a marker expressed most B-cell tumors, as well as normal B cells, CAR T-cell therapy has been investigated as a treatment strategy for B-cell leukemia and lymphoma. This review will discuss the successes of this therapy for the treatment of B-cell acute lymphoblastic leukemia and the challenges to this therapeutic strategy. We will also discuss application of CAR T-cell therapy to chronic lymphocytic leukemia and other B-cell malignancies including a follicular lymphoma, diffuse large B-cell lymphoma, as well as acute and plasma cell malignancies. PMID:26065479

  2. MN1–Fli1 oncofusion transforms murine hematopoietic progenitor cells into acute megakaryoblastic leukemia cells

    PubMed Central

    Wenge, D V; Felipe-Fumero, E; Angenendt, L; Schliemann, C; Schmidt, E; Schmidt, L H; Thiede, C; Ehninger, G; Berdel, W E; Arteaga, M-F; Mikesch, J-H

    2015-01-01

    Long-term outcome of acute megakaryoblastic leukemia (AMKL) patients without Down's syndrome remains poor. Founding mutations and chimeric oncogenes characterize various AMKL subtypes. However, for around one third of all cases the underlying mechanisms of AMKL leukemogenesis are still largely unknown. Recently, an in-frame fusion of meningeoma 1–friend leukemia virus integration 1 (MN1–Fli1) gene was detected in a child with AMKL. We intended to investigate the potential role of this oncofusion in leukemogenesis of acute myeloid leukemia. Strikingly, expression of MN1–Fli1 in murine hematopoietic progenitor cells was sufficient to induce leukemic transformation generating immature myeloid cells with cytomorphology and expression of surface markers typical for AMKL. Systematic structure function analyses revealed FLS and 3′ETS domains of Fli1 as decisive domains for the AMKL phenotype. Our data highlight an important role of MN1–Fli1 in AMKL leukemogenesis and provide a basis for research assessing the value of this oncofusion as a future diagnostic marker and/or therapeutic target in AMKL patients. PMID:26690545

  3. Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia

    ClinicalTrials.gov

    2014-10-23

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; 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); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  4. Repetitive genomic elements and overall DNA methylation changes in acute myeloid and childhood B-cell lymphoblastic leukemia patients.

    PubMed

    Bujko, Mateusz; Musialik, Ewa; Olbromski, Rafał; Przestrzelska, Marta; Libura, Marta; Pastwińska, Anna; Juszczyński, Przemysław; Zwierzchowski, Lech; Baranowski, Paweł; Siedlecki, Janusz Aleksander

    2014-07-01

    Aberrant epigenetic regulation is a hallmark of neoplastic cells. Increased DNA methylation of individual genes' promoter regions and decreases in overall DNA methylation level are both generally observed in cancer. In solid tumors, this global DNA hypomethylation is related to reduced methylation of repeated DNA elements (REs) and contributes to genome instability. The aim of the present study was to assess methylation level of LINE-1 and ALU REs and total 5-methylcytosine (5metC) content in adult acute myeloid leukemia (AML) (n = 58), childhood B-cell acute lymphoblastic leukemia (ALL) (n = 32), as the most frequent acute leukemias in two age categories and in normal adult bone marrow and children's blood samples. DNA pyrosequencing and ELISA assays were used, respectively. Global DNA hypomethylation was not observed in leukemia patients. Results revealed higher DNA methylation of LINE-1 in AML and ALL samples compared to corresponding normal controls. Elevated methylation of ALU and overall 5metC level were also observed in B-cell ALL patients. Differences of REs and global DNA methylation between AML cytogenetic-risk groups were observed, with the lowest methylation levels in intermediate-risk/cytogenetically normal patients. B-cell ALL is characterized by the highest DNA methylation level compared to AML and controls and overall DNA methylation is correlated with leukocyte count.

  5. Eradication of acute promyelocytic leukemia-initiating cells by PML/RARA-targeting.

    PubMed

    Nasr, Rihab; de Thé, Hugues

    2010-06-01

    Acute promyelocytic leukemia (APL) is characterized by a t(15;17) translocation that yields a PML/RARA fusion protein. Expression of PML/RARA, a potent transcriptional repressor, induces APL in mice. Both retinoic acid (RA) and arsenic trioxide directly target PML/RARA-mediated transcriptional repression and protein stability, inducing rapid differentiation of the promyelocytes and clinical remission in most APL patients. RA also triggers growth arrest and progressive clearance of leukemia initiating cells (LIC), both ex vivo and in vivo. Suboptimal RA concentrations or expression of the PLZF/RARA variant allows complete RA-induced differentiation, but neither LIC clearance nor disease remission. Thus, RA-induced differentiation and LIC clearance may be uncoupled. The RA/arsenic trioxide association, which dramatically synergizes for PML/RARA degradation but not for differentiation, rapidly clears LIC in a proteasome-dependent manner, resulting in APL eradication in murine models and patients. Collectively, these results demonstrate that LIC clearance, which mirrors PML/RARA degradation, is the primary basis for APL cure by the RA/arsenic trioxide association, rather than differentiation. Oncogene degradation could be a generally applicable therapeutic strategy to clear LICs in several types of tumors.

  6. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound

    PubMed Central

    Cabrera, Maia; Gomez, Natalia; Remes Lenicov, Federico; Echeverría, Emiliana; Shayo, Carina; Moglioni, Albertina; Fernández, Natalia; Davio, Carlos

    2015-01-01

    Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4’-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction) and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies. PMID:26360247

  7. Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia

    PubMed Central

    Uckun, Fatih M.; Myers, Dorothea E.; Qazi, Sanjive; Ozer, Zahide; Rose, Rebecca; D’Cruz, Osmond J.; Ma, Hong

    2015-01-01

    Patients with B cell precursor acute lymphoblastic leukemia (BPL) respond well to chemotherapy at initial diagnosis; however, therapeutic options are limited for individuals with BPL who relapse. Almost all BPL cells express CD19, and we recently cloned the gene encoding a natural ligand of the human CD19 receptor (CD19L). We hypothesized that fusion of CD19L to the soluble extracellular domain of proapoptotic TNF-related apoptosis-inducing ligand (sTRAIL) would markedly enhance the potency of sTRAIL and specifically induce BPL cell apoptosis due to membrane anchoring of sTRAIL and simultaneous activation of the CD19 and TRAIL receptor (TRAIL-R) apoptosis signaling pathways. Here, we demonstrate that recombinant human CD19L-sTRAIL was substantially more potent than sTRAIL and induced apoptosis in primary leukemia cells taken directly from BPL patients. CD19L-sTRAIL effectively targeted and eliminated in vivo clonogenic BPL xenograft cells, even at femtomolar-picomolar concentrations. In mice, CD19L-sTRAIL exhibited a more favorable pharmacokinetic (PK) profile than sTRAIL and was nontoxic at doses ranging from 32 fmol/kg to 3.2 pmol/kg. CD19L-sTRAIL showed potent in vivo antileukemic activity in NOD/SCID mouse xenograft models of relapsed and chemotherapy-resistant BPL at nontoxic fmol/kg dose levels. Together, these results suggest that recombinant human CD19L-sTRAIL has clinical potential as a biotherapeutic agent against BPL. PMID:25621496

  8. BMS-214662 in Treating Patients With Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myeloid Leukemia

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  9. What Should You Ask Your Doctor about Acute Lymphocytic Leukemia?

    MedlinePlus

    ... Types What Should You Ask Your Doctor About Acute Lymphocytic Leukemia? It is important to have frank, honest discussions ... Your Doctor About Acute Lymphocytic Leukemia? More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

  10. HLA-G Expression on Blasts and Tolerogenic Cells in Patients Affected by Acute Myeloid Leukemia

    PubMed Central

    Tomasoni, Daniela; Ciceri, Fabio

    2014-01-01

    Human Leukocyte Antigen-G (HLA-G) contributes to cancer cell immune escape from host antitumor responses. The clinical relevance of HLA-G in several malignancies has been reported. However, the role of HLA-G expression and functions in Acute Myeloid Leukemia (AML) is still controversial. Our group identified a subset of tolerogenic dendritic cells, DC-10 that express HLA-G and secrete IL-10. DC-10 are present in the peripheral blood and are essential in promoting and maintaining tolerance via the induction of adaptive T regulatory (Treg) cells. We investigated HLA-G expression on blasts and the presence of HLA-G-expressing DC-10 and CD4+ T cells in the peripheral blood of AML patients at diagnosis. Moreover, we explored the possible influence of the 3′ untranslated region (3′UTR) of HLA-G, which has been associated with HLA-G expression, on AML susceptibility. Results showed that HLA-G-expressing DC-10 and CD4+ T cells are highly represented in AML patients with HLA-G positive blasts. None of the HLA-G variation sites evaluated was associated with AML susceptibility. This is the first report describing HLA-G-expressing DC-10 and CD4+ T cells in AML patients, suggesting that they may represent a strategy by which leukemic cells escape the host's immune system. Further studies on larger populations are required to verify our findings. PMID:24741612

  11. CD93 marks a non-quiescent human leukemia stem cell population and is required for development of MLL-rearranged acute myeloid leukemia

    PubMed Central

    Iwasaki, Masayuki; Liedtke, Michaela; Gentles, Andrew J.; Cleary, Michael L.

    2015-01-01

    SUMMARY Leukemia stem cells (LSCs) are thought to share several properties with hematopoietic stem cells, including cell cycle quiescence and a capacity for self-renewal. These features are hypothesized to underlie leukemic initiation, progression, and relapse, and also complicate efforts to eradicate leukemia through therapeutic targeting of LSCs without adverse effects on HSCs. Here, we show that acute myeloid leukemias with genomic rearrangements of the MLL gene contain a non-quiescent LSC population. Although human CD34+CD38− LSCs are generally highly quiescent, the C-type lectin CD93 is expressed on a subset of actively cycling, non-quiescent AML cells enriched for LSC activity. CD93 expression is functionally required for engraftment of primary human AML LSCs and leukemogenesis, and regulates LSC self-renewal predominantly by silencing CDKN2B, a major tumor suppressor in AML. Thus, CD93 expression identifies a predominantly cycling, non-quiescent leukemia-initiating cell population in MLL-rearranged AML, providing opportunities for selective targeting and eradication of LSCs. PMID:26387756

  12. Discrimination and classification of acute lymphoblastic leukemia cells by Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Managò, Stefano; Valente, Carmen; Mirabelli, Peppino; De Luca, Anna Chiara

    2015-05-01

    Currently, a combination of technologies is typically required to identify and classify leukemia cells. These methods often lack the specificity and sensitivity necessary for early and accurate diagnosis. Here, we demonstrate the use of Raman spectroscopy to identify normal B cells, collected from healthy patients, and three ALL cell lines (RS4;11, REH and MN60 at different differentiation level, respectively). Raman markers associated with DNA and protein vibrational modes have been identified that exhibit excellent discriminating power for leukemia cell identification. Principal Component Analysis was finally used to confirm the significance of these markers for identify leukemia cells and classifying the data. The obtained results indicate a sorting accuracy of 96% between the three leukemia cell lines.

  13. Th17 cells and interleukin-17 increase with poor prognosis in patients with acute myeloid leukemia.

    PubMed

    Han, Yixiang; Ye, Aifang; Bi, Laixi; Wu, Jianbo; Yu, Kang; Zhang, Shenghui

    2014-08-01

    Although Th17 cells play crucial roles in the pathogenesis of many autoimmune and inflammatory disorders, their roles in malignancies are currently under debate. The role and mechanism of Th17 cells in patients with acute myeloid leukemia (AML) remain poorly understood. Here we demonstrated that the frequency of Th17 cells was significantly increased in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells from AML patients compared with healthy donors. Plasma levels of interleukin (IL)-17, IL-22, IL-23, IL-1β, IL-6, and transforming growth factor (TGF)-β1 were significantly increased in blood and bone marrow in AML patients compared with healthy donors. The in vitro experiments demonstrated that IL-1β, IL-6, IL-23, but not TGF-β1 promoted the generation and differentiation of Th17 cells from naive CD4(+) T cells in humans. IL-17A, a signature cytokine secreted by Th17 cells, induced the proliferation of IL-17 receptor (IL-17R)-positive AML cells via IL-17R, in which activation of PI3K/Akt and Jak/Stat3 signaling pathway may play important roles. In addition, combination of IL-17A and IL-22 significantly reduced the generation of Th1 cells and the production of interferon (IFN)-γ from healthy donor or AML patient peripheral blood mononuclear cells. Patients with high Th17 cell frequency had poor prognosis, whereas patients with high Th1 cell frequency had prolonged survival. Combined analysis of Th1 and Th17 cell frequencies improved the ability to predict patient outcomes. In conclusion, Th17 cells play a crucial role in the pathogenesis of AML and may be an important therapeutic target and prognostic predictor.

  14. Family directed umbilical cord blood banking for acute leukemia: usage rate in hematopoietic stem cell transplantation.

    PubMed

    Screnci, M; Murgi, E; Tamburini, A; Pecci, M R; Ballatore, G; Cusanno, A; Valle, V; Luciani, P; Corona, F; Girelli, G

    2015-04-01

    Family-directed umbilical cord blood (UCB) collection and banking is indicated in women delivering healthy babies who already have a member of their own family with a disease potentially treatable with an allogeneic hematopoietic stem cell (HSCs) transplantation (HSCT). The rapid availability of UCB is an important issue in HSCs procurement particularly for recipients with acute leukemia who urgently need HSCT. The aims of this study were to assess the usage rate of family UCB collections directed to patients with acute leukemia and to investigate the factors influencing the usage rate. A total of 113 families were enrolled, 118 UCB units were successfully collected and one collection failed due to emergency occurred during delivery. Among these, 7 collections were required for children who were in urgent need of a transplant: three HLA-matched units were successfully transplanted, respectively after 2, 5 and 6 months from collection; three collections resulted HLA-mismatched, while HLA-typing is pending for one unit. The remaining collections were mostly required for potential future use, among these units only one was transplanted in a HLA compatible sibling after 3 years and 4 months from collection. After a median time of storage of 8.5 years (range 0.1-20 years) a total of 4/118 (3.4 %) collection has been transplanted. During this time interval, considering only patients who have had the need of a transplant, the main factor influencing low utilization rate of UCB collections was due to HLA disparity, indeed among typed UCB unit mostly (77 %) resulted HLA mismatched with the intended recipient.

  15. Targeting PDK1 with dichloroacetophenone to inhibit acute myeloid leukemia (AML) cell growth.

    PubMed

    Qin, Lijun; Tian, Yun; Yu, Zhenlong; Shi, Dingbo; Wang, Jingshu; Zhang, Changlin; Peng, Ruoyu; Chen, Xuezhen; Liu, Congcong; Chen, Yiming; Huang, Wenlin; Deng, Wuguo

    2016-01-12

    Pyruvate dehydrogenase kinase-1 (PDK1), a key metabolic enzyme involved in aerobic glycolysis, is highly expressed in many solid tumors. Small molecule compound DAP (2,2-dichloroacetophenone) is a potent inhibitor of PDK1. Whether targeting PDK1 with DAP can inhibit acute myeloid leukemia (AML) and how it works remains unknown. In this study, we evaluated the effect of inhibition of PDK1 with DAP on cell growth, apoptosis and survival in AML cells and identified the underlying mechanisms. We found that treatment with DAP significantly inhibited cell proliferation, increased apoptosis induction and suppressed autophagy in AML cells in vitro, and inhibited tumor growth in an AML mouse model in vivo. We also showed that inhibition of PDK1 with DAP increased the cleavage of pro-apoptotic proteins (PARP and Caspase 3) and decreased the expression of the anti-apoptotic proteins (BCL-xL and BCL-2) and autophagy regulators (ULK1, Beclin-1 and Atg). In addition, we found that DAP inhibited the PI3K/Akt signaling pathway. Furthermore, we demonstrated that PDK1 interacted with ULK1, BCL-xL and E3 ligase CBL-b in AML cells, and DPA treatment could inhibit the interactions. Collectively, our results indicated that targeting PDK1 with DAP inhibited AML cell growth via multiple signaling pathways and suggest that targeting PDK1 may be a promising therapeutic strategy for AMLs.

  16. In Vitro Apoptotic Effects of Farnesyltransferase blockade in Acute Myeloid Leukemia Cells

    PubMed Central

    Giudice, V; Ricci, P; Marino, L; Rocco, M; Villani, G; Langella, M; Manente, L; Seneca, E; Ferrara, I; Pezzullo, L; Serio, B; Selleri, C

    2016-01-01

    Farnesyltransferase inhibitors (FTIs) are a class of oral anti-cancer drugs currently tested in phase I-II clinical trials for treatment of hematological malignancies. The in vitro effects of various FTIs (alpha-hydroxyfarnesylphosphonic acid, manumycin-A and SCH66336) were tested on CD34+ KG1a cell line and in primary acute myeloid leukemia (AML) cells from 64 patients. By cell viability and clonogeneic methylcellulose assays, FTIs showed a significant inhibitory activity in CD34+ KG1a and primary bone marrow (BM) leukemic cells from 56% of AML patients. FTIs also induced activation of caspase-3 and Fas-independent apoptosis, confirmed by the finding that inhibition of caspase-8 was not associated with the rescue of FTI-treated cells. We concluded that other cellular events induced by FTIs may trigger activation of caspase-3 and subsequent apoptosis, but the expression of proapoptotic molecules, as Bcl-2 and Bcl-XL, and antiapoptotic, as Bcl-X(s), were not modified by FTIs. By contrast, expression of inducible nitric oxide synthase (iNOS) was increased in FTI-treated AML cells. Our results suggest a very complex mechanism of action of FTIs that require more studies for a better clinical use of the drugs alone or in combination in the treatment of hematological malignancies. PMID:27896224

  17. Selenite promotes all-trans retinoic acid-induced maturation of acute promyelocytic leukemia cells

    PubMed Central

    Misra, Sougat; Selvam, Arun Kumar; Wallenberg, Marita; Ambati, Aditya; Matolcsy, András; Magalhaes, Isabelle; Lauter, Gilbert; Björnstedt, Mikael

    2016-01-01

    Selective targeting of the PML/RARα oncoprotein demonstrates a successful molecular targeted therapy in acute promyelocytic leukemia (APL) with a typical t(15:17) chromosomal translocation. The zinc-thiolate coordination is critical for structural stability of zinc finger proteins, including the PML moiety of PML/RARα. Based on the known interaction of redox-active selenium compounds with thiolate ligands of zinc, we herein have investigated the abrogatory effects of selenite alone or in combination with all-trans retinoic acid on PML/RARα and the possible effects on differentiation in these cells. At pharmacological concentrations, selenite inhibited the proliferation and survival of APL originated NB4 cells. In combination with ATRA, it potentiated the differentiation of NB4 cells without any differentiating effects of its own as a single agent. Concordant with our hypothesis, PML/RARα oncoprotein expression was completely abrogated by selenite. Increased expression of RAR, PU.1 and FOXO3A transcription factors in the combined treatment suggested the plausible basis for increased differentiation in these cells. We show that selenite at clinically achievable dose targets PML/RARα oncoprotein for degradation and potentiates differentiation of promyelocytic leukemic cells in combination with ATRA. The present investigation reveals the hitherto unknown potential of selenite in targeted abrogation of PML/RARα in APL cells with prospective therapeutic value. PMID:27732960

  18. A Comparison of Azacitidine and Decitabine Activities in Acute Myeloid Leukemia Cell Lines

    PubMed Central

    Hollenbach, Paul W.; Nguyen, Aaron N.; Brady, Helen; Williams, Michelle; Ning, Yuhong; Richard, Normand; Krushel, Leslie; Aukerman, Sharon L.; Heise, Carla; MacBeth, Kyle J.

    2010-01-01

    Background The cytidine nucleoside analogs azacitidine (AZA) and decitabine (DAC) are used for the treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Few non-clinical studies have directly compared the mechanisms of action of these agents in a head-to-head fashion, and the agents are often viewed as mechanistically similar DNA hypomethylating agents. To better understand the similarities and differences in mechanisms of these drugs, we compared their in vitro effects on several end points in human AML cell lines. Methodology/Principal Findings Both drugs effected DNA methyltransferase 1 depletion, DNA hypomethylation, and DNA damage induction, with DAC showing equivalent activity at concentrations 2- to 10-fold lower than AZA. At concentrations above 1 µM, AZA had a greater effect than DAC on reducing cell viability. Both drugs increased the sub-G1 fraction and apoptosis markers, with AZA decreasing all cell cycle phases and DAC causing an increase in G2-M. Total protein synthesis was reduced only by AZA, and drug-modulated gene expression profiles were largely non-overlapping. Conclusions/Significance These data demonstrate shared mechanisms of action of AZA and DAC on DNA-mediated markers of activity, but distinctly different effects in their actions on cell viability, protein synthesis, cell cycle, and gene expression. The differential effects of AZA may be mediated by RNA incorporation, as the distribution of AZA in nucleic acid of KG-1a cells was 65∶35, RNA∶DNA. PMID:20126405

  19. Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia.

    PubMed

    Liu, Hudan; Chiang, Mark Y; Pear, Warren S

    2011-08-01

    NOTCH1 plays a central role in T-cell development and, when aberrantly activated, in acute T-cell lymphoblastic leukemia (T-ALL). As a transmembrane receptor that is ultimately converted into a transcription factor, NOTCH1 directly activates a spectrum of target genes, which function to mediate NOTCH1 signaling in normal or transformed T cells. During physiologic T-cell development, NOTCH1 has important functions in cell fate determination, proliferation, survival and metabolism. Activating NOTCH1 mutations occur in more than half of human patients with T-ALL, suggesting an important role for aberrant NOTCH1 signaling in the pathogenesis of this disease. Inhibiting NOTCH1 signaling in patient-derived cell lines and murine T-ALLs leads to growth arrest and/or apoptosis suggesting that NOTCH1 inhibitors can improve T-ALL treatment. However, there are challenges to translate NOTCH1 inhibitors to the clinic because of toxicity and resistance. This review focuses on molecular mechanisms of oncogenic NOTCH1 signaling, molecular and functional analysis of NOTCH1 transcriptional targets in T-ALL, and recent advances in therapeutic targeting of NOTCH1.

  20. Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells

    PubMed Central

    Cornet-Masana, Josep Maria; Moreno-Martínez, Daniel; Lara-Castillo, María Carmen; Nomdedeu, Meritxell; Etxabe, Amaia; Tesi, Niccolò; Pratcorona, Marta; Esteve, Jordi; Risueño, Ruth M.

    2016-01-01

    Acute myeloid leukemia (AML) is an hematologic neoplasia characterized by the accumulation of transformed immature myeloid cells in bone marrow. Although the response rate to induction therapy is high, survival rate 5-year after diagnosis is still low, highlighting the necessity of new novel agents. To identify agents with the capability to abolish the self-renewal capacity of AML blasts, an in silico screening was performed to search for small molecules that induce terminal differentiation. Emetine, a hit compound, was validated for its anti-leukemic effect in vitro, ex vivo and in vivo. Emetine, a second-line anti-protozoa drug, differentially reduced cell viability and clonogenic capacity of AML primary patient samples, sparing healthy blood cells. Emetine treatment markedly reduced AML burden in bone marrow of xenotransplanted mice and decreased self-renewal capacity of the remaining engrafted AML cells. Emetine also synergized with commonly used chemotherapeutic agents such as ara-C. At a molecular level, emetine treatment was followed by a reduction in HIF-1α protein levels. This study validated the anti-leukemiceffect of emetine in AML cell lines, a group of diverse AML primary samples, and in a human AML-transplanted murine model, sparing healthy blood cells. The selective anti-leukemic effect of emetine together with the safety of the dose range required to exert this effect support the development of this agent in clinical practice. PMID:26992240

  1. Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-18

    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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  2. Lenalidomide in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-07-25

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  3. Upregulation of miR-99a is associated with poor prognosis of acute myeloid leukemia and promotes myeloid leukemia cell expansion

    PubMed Central

    Si, Xiaohui; Zhang, Xiaoyun; Hao, Xing; Li, Yunan; Chen, Zizhen; Ding, Yahui; Shi, Hui; Bai, Jie; Gao, Yingdai; Cheng, Tao; Yang, Feng-Chun; Zhou, Yuan

    2016-01-01

    Leukemia stem cells (LSCs) can resist available treatments that results in disease progression and/or relapse. To dissect the microRNA (miRNA) expression signature of relapse in acute myeloid leukemia (AML), miRNA array analysis was performed using enriched LSCs from paired bone marrow samples of an AML patient at different disease stages. We identified that miR-99a was significantly upregulated in the LSCs obtained at relapse compared to the LSCs collected at the time of initial diagnosis. We also found that miR-99a was upregulated in LSCs compared to non-LSCs in a larger cohort of AML patients, and higher expression levels of miR-99a were significantly correlated with worse overall survival and event-free survival in these AML patients. Ectopic expression of miR-99a led to increased colony forming ability and expansion in myeloid leukemia cells after exposure to chemotherapeutic drugs in vitro and in vivo, partially due to overcoming of chemotherapeutic agent-mediated cell cycle arrest. Gene profiling and bioinformatic analyses indicated that ectopic expression of miR-99a significantly upregulated genes that are critical for LSC maintenance, cell cycle, and downstream targets of E2F and MYC. This study suggests that miR-99a has a novel role and potential use as a biomarker in myeloid leukemia progression. PMID:27801668

  4. Novel strategies of adoptive immunotherapy: How natural killer cells may change the treatment of elderly patients with acute myeloblastic leukemia.

    PubMed

    Lemoli, Roberto M; Parisi, Sarah; Curti, Antonio

    2017-01-01

    Although many attempts have been made to identify novel molecular-targeted therapies for patients with acute myeloid leukemia, their translation into the clinic have had limited impact. In particular, the question of effective and curative treatments for elderly patients, who are not eligible for stem cell transplantation, remains an unmet medical need. To answer this question, a wide range of immunologic therapeutic strategies, mostly T cell based, have been proposed and investigated. At present, however, the clinical results have been largely unsatisfactory. Natural killer cells have recently been used as a means of adoptive immunotherapy with promising clinical results. On the basis of recent clinical reports and moving from the basic immunobiology of natural killer cells, here we discuss some open issues in the clinical translation of natural killer-based adoptive immunotherapy for the management of elderly patients with acute myeloid leukemia.

  5. Liposomal daunorubicin, fludarabine, and cytarabine (FLAD) as bridge therapy to stem cell transplant in relapsed and refractory acute leukemia.

    PubMed

    De Astis, Enrico; Clavio, Marino; Raiola, Anna Maria; Ghiso, Anna; Guolo, Fabio; Minetto, Paola; Galaverna, Federica; Miglino, Maurizio; Di Grazia, Carmen; Ballerini, Filippo; Marani, Carlo; Pastori, Giordana; Mitscheunig, Laura; Cruciani, Fabio; Lovera, Davide; Varaldo, Riccardo; Ghiggi, Chiara; Lemoli, Roberto Massimo; Bacigalupo, Andrea; Gobbi, Marco

    2014-12-01

    Therapeutic options for patients with relapsed or refractory acute leukemia are still undefined and often unsatisfactory. We report the outcome of 79 patients with relapsed-refractory acute leukemia treated with fludarabine, cytarabine, and liposomal daunorubicin (FLAD regimen) followed by hematopoietic stem cell transplantation (HSCT), when clinically indicated, between May 2000 and January 2013. Forty-one patients had acute myeloid leukemia (AML), and 38 had acute lymphoblastic leukemia (ALL). Two patients with myeloid blast crises of CML and three with lymphoid blast crises were included in the AML and ALL subgroups, respectively. Median age was 48 years (range 13-77). FLAD was well tolerated with negligible, nonhematological toxicity. Six patients (7.5 %) died before response evaluation. Forty-seven patients achieved hematologic complete response (CR). Complete remission rate was 53 and 65 % among AML and ALL patients, respectively. No CR was recorded among 11 refractory AML patients. Twenty-four patients (30 %) underwent HSCT. Nine patients received stem cells from an HLA identical sibling, and 15 from an alternative donor (3 unrelated matched, 12 haploidentical sibling). Median overall survival in AML and ALL patients receiving FLAD therapy was 9 and 8 months, respectively. A 5-year projected OS for patients receiving the whole program (FLAD + HSCT) was 24 % for AML patients (median survival 43 months), 28 % for ALL patients treated in relapse (median survival 15 months), and 0 % for ALL patients treated for refractory disease. In this paper, we show that FLAD seems to be an effective bridge therapy to HSCT for a part of poor prognosis acute leukemia patients. However, prospective studies are needed to confirm our results.

  6. Conditioning with targeted busulfan for autologous peripheral blood stem cells transplantation for acute myelogenous leukemia in an XYY male.

    PubMed

    Sada, Eriko; Henzan, Hideho; Ohtani, Ryoko; Takase, Ken; Miyamoto, Toshihiro; Fukuda, Takahiro; Nagafuji, Koji; Yamauchi, Keita; Takamatsu, Yasushi; Inaba, Shoichi; Harada, Mine

    2005-01-01

    We report herein a 19-year-old Japanese male with XYY syndrome who developed acute myelogenous leukemia. During three courses of cytotoxic chemotherapy, he suffered repeated hepatic and renal insufficiencies, possibly related to latent dysfunction from the XYY syndrome. The patient was treated with granulocyte colony-stimulating factor combined with etoposide, cytarabine, and busulfan (the latter adjusted to a targeting dose) followed by autologous peripheral blood stem cell transplantation. He had no severe regimen-related toxicities and is now free of leukemia.

  7. Flavopiridol and Vorinostat in Treating Patients With Relapsed or Refractory Acute Leukemia or Chronic Myelogenous Leukemia or Refractory Anemia

    ClinicalTrials.gov

    2013-04-01

    Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Relapsing Chronic Myelogenous Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  8. WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells.

    PubMed

    Brigger, D; Proikas-Cezanne, T; Tschan, M P

    2014-07-03

    Members of the WD-repeat protein interacting with phosphoinositides (WIPI) family are phosphatidylinositol 3-phosphate (PI3P) effectors that are essential for the formation of autophagosomes. Autophagosomes, unique double-membraned organelles, are characteristic for autophagy, a bulk degradation mechanism with cytoprotective and homeostatic function. Both, WIPI-1 and WIPI-2 are aberrantly expressed in several solid tumors, linking these genes to carcinogenesis. We now found that the expression of WIPI-1 was significantly reduced in a large cohort of 98 primary acute myeloid leukemia (AML) patient samples (complex karyotypes; t(8;21); t(15,17); inv(16)). In contrast, the expression of WIPI-2 was only reduced in acute promyelocytic leukemia (APL), a distinct subtype of AML (t(15,17)). As AML cells are blocked in their differentiation, we tested if the expression levels of WIPI-1 and WIPI-2 increase during all-trans retinoic acid (ATRA)-induced neutrophil differentiation of APL. According to the higher WIPI-1 expression in granulocytes compared with immature blast cells, WIPI-1 but not WIPI-2 expression was significantly induced during neutrophil differentiation of NB4 APL cells. Interestingly, the induction of WIPI-1 expression was dependent on the transcription factor PU.1, a master regulator of myelopoiesis, supporting our notion that WIPI-1 expression is reduced in AML patients lacking proper PU-1 activity. Further, knocking down WIPI-1 in NB4 cells markedly attenuated the autophagic flux and significantly reduced neutrophil differentiation. This result was also achieved by knocking down WIPI-2, suggesting that both WIPI-1 and WIPI-2 are functionally required and not redundant in mediating the PI3P signal at the onset of autophagy in NB4 cells. In line with these data, downregulation of PI3KC3 (hVPS34), which generates PI3P upstream of WIPIs, also inhibited neutrophil differentiation. In conclusion, we demonstrate that both WIPI-1 and WIPI-2 are required for the

  9. 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.

  10. Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

    PubMed Central

    Gutierrez, Alejandro; Pan, Li; Groen, Richard W.J.; Baleydier, Frederic; Kentsis, Alex; Marineau, Jason; Grebliunaite, Ruta; Kozakewich, Elena; Reed, Casie; Pflumio, Francoise; Poglio, Sandrine; Uzan, Benjamin; Clemons, Paul; VerPlank, Lynn; An, Frank; Burbank, Jason; Norton, Stephanie; Tolliday, Nicola; Steen, Hanno; Weng, Andrew P.; Yuan, Huipin; Bradner, James E.; Mitsiades, Constantine; Look, A. Thomas; Aster, Jon C.

    2014-01-01

    T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug’s antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential. PMID:24401270

  11. Role of low density lipoprotein-bound cholesterol esters in acute lymphoblastic leukemia cells

    SciTech Connect

    Cutts, J.L.; Madden, E.A.; Melnykovych, G.

    1986-05-01

    The glucocorticoid sensitive CEM-C7 T-cell line was derived from human acute lymphoblastic leukemia cells by Norman and Thompson. Madden et al. have demonstrated that this growth inhibitory effect is due in part to a glucocorticoid-mediated inhibition of cholesterol synthesis and can be partially reversed by cholesterol dispersions. To further delineate the role of cholesterol in this growth inhibition, they have examined the ability of low density lipoprotein (LDL)-bound (/sup 3/H)cholesterol linoleate to reverse the growth inhibitory effect of 1 ..mu..M dexamethasone (Dex) on the CEM-C7 cells. LDL-bound cholesterol linoleate was unable to reverse the Dex-mediated growth inhibition, although incorporation of (/sup 14/C) acetate into free cholesterol was inhibited by 29%, following the Brown and Goldstein model. The presence of Dex further inhibited acetate incorporation into free cholesterol in the LDL-treated cells. Under all conditions, more than 99% of the acetate incorporated into cholesterol was present as free cholesterol, while over 87% of the LDL-bound cholesterol linoleate taken up remained in the ester compartment. These results indicate that CEM-C7 cells are unable to utilize LDL-bound cholesterol esters as a source of free cholesterol and rely on endogenous synthesis for their free cholesterol requirements.

  12. Mechanisms of resistance to apoptosis in the human acute promyelocytic leukemia cell line NB4.

    PubMed

    Gañán-Gómez, I; Estañ-Omaña, M C; Sancho, P; Aller, P; Boyano-Adánez, M C

    2015-03-01

    Current frontline therapies have improved overall survival in acute promyelocytic leukemia (APL) patients to exceptional rates; however, relapse is still a problem among high-risk and old patients. Therefore, the development of better and safer therapies continues to be a goal in the treatment of this disease. In the present work, we examined three different pathways that hinder cell death in the APL cell line NB4, shedding light on the mechanisms that underlie resistance to apoptosis in these cells and that might help provide them with a proliferative advantage. We found that the proteasome inhibitor MG-132 specifically induces in NB4 cells an Nrf2-mediated antioxidant response which counteracts mitochondria-dependent apoptosis induced by the lipophilic cation dequalinium. More importantly, we also demonstrated that high basal autophagy levels and the gain-of-function of mutant p53 are intrinsic mechanisms of resistance to apoptosis in this cell line. According to our results, the pharmacological inhibition of autophagy and p53 mutants are useful tools to explore resistance to apoptosis in APL and other types of cancer and could be the bases of new therapeutic approaches that improve the efficiency and allow dose reduction of the current treatments.

  13. Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia

    SciTech Connect

    Yamazaki, Hiroto; Wilson Xu, C.; Naito, Motohiko; Nishida, Hiroko; Okamoto, Toshihiro; Ghani, Farhana Ishrat; Iwata, Satoshi; Inukai, Takeshi; Sugita, Kanji; Morimoto, Chikao

    2011-05-27

    Highlights: {yields} We performed more detailed analysis of CD9 function for CSC properties in B-ALL. {yields} Leukemogenic fusion/Src family proteins were markedly regulated in the CD9{sup +} cells. {yields} Proliferation of B-ALL cells was inhibited by anti-CD9 monoclonal antibody. {yields} Knockdown of CD9 by RNAi remarkably reduced the leukemogenic potential. {yields} CD9-knockdown affected the expression and phosphorylation of Src family and USP22. -- Abstract: Although the prognosis of acute lymphoblastic leukemia (ALL) has improved considerably in recent years, some of the cases still exhibit therapy-resistant. We have previously reported that CD9 was expressed heterogeneously in B-ALL cell lines and CD9{sup +} cells exhibited an asymmetric cell division with greater tumorigenic potential than CD9{sup -} cells. CD9{sup +} cells were also serially transplantable in immunodeficient mice, indicating that CD9{sup +} cell possess self-renewal capacity. In the current study, we performed more detailed analysis of CD9 function for the cancer stem cell (CSC) properties. In patient sample, CD9 was expressed in the most cases of B-ALL cells with significant correlation of CD34-expression. Gene expression analysis revealed that leukemogenic fusion proteins and Src family proteins were significantly regulated in the CD9{sup +} population. Moreover, CD9{sup +} cells exhibited drug-resistance, but proliferation of bulk cells was inhibited by anti-CD9 monoclonal antibody. Knockdown of CD9 remarkably reduced the leukemogenic potential. Furthermore, gene ablation of CD9 affected the expression and tyrosine-phosphorylation of Src family proteins and reduced the expression of histone-deubiquitinase USP22. Taken together, our results suggest that CD9 links to several signaling pathways and epigenetic modification for regulating the CSC properties of B-ALL.

  14. PU.1 affects proliferation of the human acute myeloid leukemia U937 cell line by directly regulating MEIS1

    PubMed Central

    ZHOU, JING; ZHANG, XIAOFENG; WANG, YUHUA; GUAN, YINGHUI

    2015-01-01

    The transcription factor PU.1 is a member of the ETS family, which is expressed in a wide variety of hematopoietic lineages. Accumulating evidence has indicated that PU.1 plays a key role in hematopoiesis, and reduced expression of PU.1 leads to the pathogenesis of human myeloid leukemia. As a multi-functional factor, PU.1 is also required for mixed lineage leukemia (MLL) stem cell potential and the development of MLL. However, the function of PU.1 in human non-MLL leukemia and its molecular mechanism remains poorly understood. In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation. Using electrophoretic mobility shift assay, chromatin immunoprecipitation analysis and luciferase reporter assay, previously unexplored evidence that PU.1 activated the MEIS1 promoter through a conserved binding motif in vitro and in vivo was further defined. Overall, the present study provides insight into the molecular mechanism of the contribution of PU.1 to the pathogenesis of non-MLL U937 cells, which is mediated by direct regulation of MEIS1 transcription. The present data reveal the possibility of developing an alternative therapy for non-MLL leukemia by targeting PU.1-mediated MEIS1 gene activation. PMID:26622774

  15. Attenuated A20 expression of acute myeloid leukemia-derived dendritic cells increased the anti-leukemia immune response of autologous cytolytic T cells.

    PubMed

    Zhang, Xiaoying; Su, Yongfeng; Song, Haifeng; Yu, Zhiyong; Zhang, Bin; Chen, Hu

    2014-06-01

    Previous studies reported leukemic cells from acute myeloid leukemia (AML) patients can differentiate into dendritic cells (DCs), which had some immunoregulatory dysfunctions to effectively stimulate autologous CTLs' anti-leukemia immune response. The zinc-finger protein A20, a negative regulator of the nuclear factor (NF)-κB pathway, was found to play a crucial role in controlling the maturation and function of human monocyte-derived DCs. However, the effects of A20 in AML derived DCs (AML-DCs) have not yet been evaluated. In this study, A20 expression was up-regulated in AML-DCs activated with tumor necrosis factor (TNF)-α. Then, A20 attenuation with siRNA in AML-DC enhanced the expression of several co-stimulatory molecules and proinflammatory cytokines. Furthermore, after A20 attenuation in AML-DCs, the autologous cytolytic T cells (CTLs) induced by AML-DCs had higher killing capability and specificity for primary AML cells. Additionally, receptor-interacting protein (RIP) and the NF-κBp65 pathway were elevated in AML-DCs when A20 was reduced. Hence, this study identified A20 as a negative regulator for controlling AML-DC maturation and immunostimulatory potency, as A20 down-regulation resulted in AML-DCs with enhanced autologous CTLs immune capacity through the NF-κB pathway.

  16. Ganoderma lucidum polysaccharide exerts anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

    PubMed

    Yang, Guohua; Yang, Lei; Zhuang, Yun; Qian, Xifeng; Shen, Yunfeng

    2016-01-01

    In this study, we investigated the anti-tumor activity both in vitro and in vivo of a polysaccharide obtained from Ganoderma lucidum on HL-60 acute myeloid leukemia cells, and focused on its targeting effect on mitogen-activated protein kinase (MAPK) pathways. It was found by the methods such as western blot and flow cytometry (FCM), that G. lucidum polysaccharide (GLP) blocked the extracellular signal-regulated kinase/MAPK signaling pathway, simultaneously activated p38 and JNK MAPK pathways, and therefore regulated their downstream genes and proteins, including p53, c-myc, c-fos, c-jun, Bcl-2, Bax, cleaved caspase-3 and cyclin D1. As a result, cycle arrest and apoptosis of HL-60 cells were induced. Therefore, GLP exerted anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

  17. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-08-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); Blastic Phase Chronic Myelogenous Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma

  18. Cooperative antiproliferative and differentiation-enhancing activity of medicinal plant extracts in acute myeloid leukemia cells.

    PubMed

    Zhamanbayeva, Gulzhan T; Aralbayeva, Araylim N; Murzakhmetova, Maira K; Tuleukhanov, Sultan T; Danilenko, Michael

    2016-08-01

    Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with poor prognosis and limited treatment options. Sea buckthorn (Hippophae rhamnoides) berries, dog rose (Rosa canina) rosehips, and garden sage (Salvia officinalis) and oregano (Origanum vulgare) aerial parts are widely used in traditional medicine and exhibit antitumor effects in preclinical models. However, these plants remain scarcely tested for antileukemic activity. Here, we show that their water-ethanol leaf extracts reduced the growth and viability of AML cells and, at non-cytotoxic doses, potentiated cell differentiation induced by a low concentration of 1α,25-dihydroxyvitamin D3, the hormonal form of vitamin D, in a cell type-dependent manner. The latter effect was accompanied by upregulation of the vitamin D receptor protein components and its transcriptional activity. Furthermore, at minimally effective doses the extracts cooperated with one another to produce marked cytostatic effects associated with a partial S-phase arrest and a modest induction of apoptosis. In contrast, these combinations only slightly affected the growth and viability of proliferating normal human peripheral blood mononuclear cells. In addition, the extracts strongly inhibited microsomal lipid peroxidation and protected normal erythrocytes against hypoosmotic shock. Our results suggest that further exploration of the enhanced antileukemic effects of the combinations tested here may lead to the development of alternative therapeutic and preventive approaches against AML.

  19. Altered neutrophil immunophenotypes in childhood B-cell precursor acute lymphoblastic leukemia

    PubMed Central

    Oliveira, Elen; Bacelar, Thiago S.; Ciudad, Juana; Ribeiro, Maria Cecília M.; Garcia, Daniela R.N.; Sedek, Lukasz; Maia, Simone F.; Aranha, Daniel B.; Machado, Indyara C.; Ikeda, Arissa; Baglioli, Bianca F.; Lopez-Duarte, Nathalia; Teixeira, Lisandra A. C.; Szczepanski, Tomasz; Silva, Maria Luiza M.; Land, Marcelo G.P.

    2016-01-01

    An increasing number of evidences suggest a genetic predisposition in acute lymphoblastic leukemia (ALL) that might favor the occurrence of the driver genetic alterations. Such genetic background might also translate into phenotypic alterations of residual hematopoietic cells. Whether such phenotypic alterations are present in bone marrow (BM) cells from childhood B-cell precursor (BCP)-ALL remains to be investigated. Here we analyzed the immunophenotypic profile of BM and peripheral blood (PB) maturing/matured neutrophils from 118 children with BCP-ALL and their relationship with the features of the disease. Our results showed altered neutrophil phenotypes in most (77%) BCP-ALL cases. The most frequently altered marker was CD10 (53%), followed by CD33 (34%), CD13 (15%), CD15/CD65 (10%) and CD123 (7%). Of note, patients with altered neutrophil phenotypes had younger age (p = 0.03) and lower percentages of BM maturing neutrophils (p = 0.004) together with greater BM lymphocyte (p = 0.04), and mature B-cell (p = 0.03) counts. No significant association was found between an altered neutrophil phenotype and other disease features. These findings point out the potential existence of an altered residual hematopoiesis in most childhood BCP-ALL cases. PMID:27028865

  20. Clonal Architecture of Secondary Acute Myeloid Leukemia Defined by Single-Cell Sequencing

    PubMed Central

    Hughes, Andrew E. O.; Magrini, Vincent; Demeter, Ryan; Miller, Christopher A.; Fulton, Robert; Fulton, Lucinda L.; Eades, William C.; Elliott, Kevin; Heath, Sharon; Westervelt, Peter; Ding, Li; Conrad, Donald F.; White, Brian S.; Shao, Jin; Link, Daniel C.; DiPersio, John F.; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.; Walter, Matthew J.; Graubert, Timothy A.

    2014-01-01

    Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions—the population frequency of individual clones, their genetic composition, and their evolutionary relationships—which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells. PMID:25010716

  1. Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing.

    PubMed

    Hughes, Andrew E O; Magrini, Vincent; Demeter, Ryan; Miller, Christopher A; Fulton, Robert; Fulton, Lucinda L; Eades, William C; Elliott, Kevin; Heath, Sharon; Westervelt, Peter; Ding, Li; Conrad, Donald F; White, Brian S; Shao, Jin; Link, Daniel C; DiPersio, John F; Mardis, Elaine R; Wilson, Richard K; Ley, Timothy J; Walter, Matthew J; Graubert, Timothy A

    2014-07-01

    Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells.

  2. Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations

    PubMed Central

    Spinella, Jean-François; Cassart, Pauline; Richer, Chantal; Saillour, Virginie; Ouimet, Manon; Langlois, Sylvie; St-Onge, Pascal; Sontag, Thomas; Healy, Jasmine; Minden, Mark D.; Sinnett, Daniel

    2016-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Using an integrative approach combining genomic and transcriptomic data, we molecularly characterized 30 pediatric T-ALLs and identified common recurrent T-ALL targets such as FBXW7, JAK1, JAK3, PHF6, KDM6A and NOTCH1 as well as novel candidate T-ALL driver mutations including the p.R35L missense mutation in splicesome factor U2AF1 found in 3 patients and loss of function mutations in the X-linked tumor suppressor genes MED12 (frameshit mutation p.V167fs, splice site mutation g.chrX:70339329T>C, missense mutation p.R1989H) and USP9X (nonsense mutation p.Q117*). In vitro functional studies further supported the putative role of these novel T-ALL genes in driving transformation. U2AF1 p.R35L was shown to induce aberrant splicing of downstream target genes, and shRNA knockdown of MED12 and USP9X was shown to confer resistance to apoptosis following T-ALL relevant chemotherapy drug treatment in Jurkat leukemia cells. Interestingly, nearly 60% of novel candidate driver events were identified among immature T-ALL cases, highlighting the underlying genomic complexity of pediatric T-ALL, and the need for larger integrative studies to decipher the mechanisms that contribute to its various subtypes and provide opportunities to refine patient stratification and treatment. PMID:27602765

  3. YKL-40 in allogeneic hematopoietic cell transplantation after acute myeloid leukemia and myelodysplastic syndrome

    PubMed Central

    Kornblit, Brian; Wang, Tao; Lee, Stephanie J.; Spellman, Stephen R.; Zhu, Xiaochun; Fleischhauer, Katharina; Müller, Carlheinz; Verneris, Michael R.; Müller, Klaus; Johansen, Julia S.; Vindelov, Lars; Garred, Peter

    2016-01-01

    YKL-40, also called chitinase3-like-1 protein, is an inflammatory biomarker which has been associated with disease severity in inflammatory and malignant diseases, including acute myeloid leukemia (AML), multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pre-transplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (MDS) (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ≥5 (p=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age adjusted 95th percentile a trend towards increased grade II-IV acute graft versus host disease in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00–1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available. PMID:27427920

  4. How Is Acute Myeloid Leukemia Diagnosed?

    MedlinePlus

    ... Detection, Diagnosis, and Types How Is Acute Myeloid Leukemia Diagnosed? Certain signs and symptoms might suggest that ... of samples used to test for acute myeloid leukemia If signs and symptoms and/or the results ...

  5. CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia.

    PubMed

    Davila, Marco L; Brentjens, Renier J

    2016-10-01

    Immunotherapy has demonstrated significant potential for the treatment of patients with chemotherapy-resistant hematologic malignancies and solid tumors. One type of immunotherapy involves the adoptive transfer of T cells that have been genetically modified with a chimeric antigen receptor (CAR) to target a tumor. These hybrid proteins are composed of the antigen-binding domains of an antibody fused to T-cell receptor signaling machinery. CAR T cells that target CD19 recently have made the jump from the laboratory to the clinic, and the results have been remarkable. CD19-targeted CAR T cells have induced complete remissions of disease in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), who have an expected complete response rate of 30% in response to chemotherapy. The high efficacy of CAR T cells in B-ALL suggests that regulatory approval of this therapy for this routinely fatal leukemia is on the horizon. We review the preclinical development of CAR T cells and their early clinical application for lymphoma. We also provide a comprehensive analysis of the use of CAR T cells in patients with B-ALL. In addition, we discuss the unique toxicities associated with this therapy and the management schemes that have been developed.

  6. Differential cytotoxic effects of arsenic compounds in human acute promyelocytic leukemia cells

    SciTech Connect

    Charoensuk, Vichaya; Gati, Wendy P. Weinfeld, Michael; Le, X. Chris

    2009-08-15

    Arsenic trioxide, As{sub 2}O{sub 3}, has successfully been used to treat acute promyelocytic leukemia (APL). Induction of apoptosis in cancerous cells has been proposed to be the underlying mechanism for the therapeutic efficacy of arsenic. To further understand the cytotoxicity of arsenic compounds in APL cells, HL-60 cells were exposed to graded concentrations of the following arsenicals for up to 48 h: arsenic trioxide (As{sup III}), sodium arsenate (As{sup V}), phenylarsine oxide (PAO{sup III}), monomethylarsonous acid (MMA{sup III}), monomethylarsonic acid (MMA{sup V}) and dimethylarsinic acid (DMA{sup V}), and the viability and modes of cell death assessed. The arsenic-exposed cells were stained with annexin V-PE and 7-aminoactinomycin D (7-AAD) and analyzed by flow cytometry in order to detect apoptotic and viable cells while cell morphology was visualized using scanning and transmission electron microscopy. Acridine orange staining and microtubule-associated protein 1 light chain 3 (MAP-LC3) detection were used to recognize autophagic cell death. The results showed that the compounds reduced viable HL-60 cells by inducing apoptosis in a concentration-dependent manner. None of the compounds tested caused a significant change in binding of acridine orange or redistribution of MAP-LC3. Potencies of the six different arsenic compounds tested were ranked as PAO{sup III} > MMA{sup III} {>=} As{sup III} > As{sup V} > MMA{sup V} > DMA{sup V}. An increase in caspase-3 activity by PAO{sup III}, MMA{sup III} and DMA{sup V} implied that these compounds induced apoptosis in HL-60 cells through a caspase-dependent mechanism, but the other arsenic compounds failed to activate caspase-3, suggesting that they induce apoptosis by an alternative pathway.

  7. Ras activation in normal white blood cells and childhood acute lymphoblastic leukemia.

    PubMed

    von Lintig, F C; Huvar, I; Law, P; Diccianni, M B; Yu, A L; Boss, G R

    2000-05-01

    Ras is an important cellular switch, relaying growth-promoting signals from the plasma membrane to the nucleus. In cultured cells, Ras is activated by various hematopoietic cytokines and growth factors, but the activation state of Ras in peripheral WBCs and bone marrow cells has not been studied nor has Ras activation been assessed in cells from patients with acute lymphoblastic leukemia (ALL). Using an enzyme-based method, we assessed Ras activation in peripheral WBCs, lymphocytes, and bone marrow cells from normal subjects and from children with T-cell ALL (T-ALL) and B-lineage ALL (B-ALL). In normal subjects, we found mean Ras activations of 14.3, 12.5, and 17.2% for peripheral blood WBCs, lymphocytes, and bone marrow cells, respectively. All three of these values are higher than we have found in other normal human cells, compatible with constitutive activation of Ras by cytokines and growth factors present in serum and bone marrow. In 9 of 18 children with T-ALL, Ras activation exceeded two SDs above the mean of the corresponding cells from normal subjects, whereas in none of 11 patients with B-ALL did Ras show increased activation; activating genetic mutations in ras occur in less than 10% of ALL patients. Thus, Ras is relatively activated in peripheral blood WBCs, lymphocytes, and bone marrow cells compared with other normal human cells, and Ras is activated frequently in T-ALL but not in B-ALL. Increased Ras activation in T-ALL compared with B-ALL may contribute to the more aggressive nature of the former disease.

  8. PROGRESS IN ACUTE MYELOID LEUKEMIA

    PubMed Central

    Kadia, Tapan M.; Ravandi, Farhad; O’Brien, Susan; Cortes, Jorge; Kantarjian, Hagop M.

    2014-01-01

    Significant progress has been made in the treatment of acute myeloid leukemia (AML). Steady gains in clinical research and a renaissance of genomics in leukemia have led to improved outcomes. The recognition of tremendous heterogeneity in AML has allowed individualized treatments of specific disease entities within the context of patient age, cytogenetics, and mutational analysis. The following is a comprehensive review of the current state of AML therapy and a roadmap of our approach to these distinct disease entities. PMID:25441110

  9. Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia/lymphoma.

    PubMed Central

    McGuire, E A; Rintoul, C E; Sclar, G M; Korsmeyer, S J

    1992-01-01

    T-cell translocation gene 1 (Ttg-1), also called rhombotin, is deregulated upon translocation into the alpha/delta T-cell receptor loci in acute lymphoblastic leukemias bearing the t(11;14)(p15;q11). Ttg-1 encodes a nuclear protein, expressed predominantly in neuronal cells, which belongs to a novel family of transcription factors possessing LIM domains. We utilized the lck proximal promoter to overexpress this candidate oncogene in immature thymocytes of transgenic mice. lckPr Ttg-1 mice develop immature, aggressive T-cell leukemia/lymphomas. Tumor incidence is proportional to the level of Ttg-1 expression. Most tumors contain CD4+8+ cells as well as CD4-8+ cells, which have an immature rather than a mature peripheral phenotype. Ttg-1-induced tumorigenesis preferentially affects a minority population of thymocytes representing an immature CD4-8+ intermediate stage between double-negative CD4-8- cells and double-positive CD4+8+ cells. This model indicates that the aberrant expression of putative transcription factors plays a primary role in the genesis of T-cell acute lymphoblastic leukemias. Images PMID:1508213

  10. T-cell-replete haploidentical transplantation versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis.

    PubMed

    Gorin, Norbert-Claude; Labopin, Myriam; Piemontese, Simona; Arcese, William; Santarone, Stella; Huang, He; Meloni, Giovanna; Ferrara, Felicetto; Beelen, Dietrich; Sanz, Miguel; Bacigalupo, Andrea; Ciceri, Fabio; Mailhol, Audrey; Nagler, Arnon; Mohty, Mohamad

    2015-04-01

    Adult patients with acute leukemia in need of a transplant but without a genoidentical donor are usually considered upfront for transplantation with stem cells from any other allogeneic source, rather than autologous stem cell transplantation. We used data from the European Society for Blood and Marrow Transplantation and performed a matched pair analysis on 188 T-cell-replete haploidentical and 356 autologous transplants done from January 2007 to December 2012, using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. "Haploidentical expert" centers were defined as having reported more than five haploidentical transplants for acute leukemia (median value for the study period). The median follow-up was 28 months. Multivariate analyses, including type of transplant categorized into three classes ("haploidentical regular", "haploidentical expert" and autologous), conditioning intensity (reduced intensity versus myeloablative conditioning) and the random effect taking into account associations related to matching, showed that non-relapse mortality was higher following haploidentical transplants in expert (HR: 4.7; P=0.00004) and regular (HR: 8.98; P<10(-5)) centers. Relapse incidence for haploidentical transplants was lower in expert centers (HR:0.39; P=0.0003) but in regular centers was similar to that for autologous transplants. Leukemia-free survival and overall survival rates were higher following autologous transplantation than haploidentical transplants in regular centers (HR: 1.63; P=0.008 and HR: 2.31; P=0.0002 respectively) but similar to those following haploidentical transplants in expert centers. We conclude that autologous stem cell transplantation should presently be considered as a possible alternative to haploidentical transplantation in regular centers that have not developed a specific expert program.

  11. Risk-Based Classification System of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2017-02-13

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  12. A novel 2,6-diisopropylphenyl-docosahexaenoamide conjugate induces apoptosis in T cell acute lymphoblastic leukemia cell lines

    SciTech Connect

    Altenburg, Jeffrey D.; Harvey, Kevin A.; McCray, Sharon; Xu, Zhidong; Siddiqui, Rafat A.

    2011-07-29

    Highlights: {yields} 2,6-Diisopropylphenyl-docosahexaenoamide conjugates (DIP-DHA) inhibits the proliferation of T-cell leukemic cell lines. {yields} DIP-DHA resulted in increased activation of caspase-3, and caspase-7. {yields} DIP-DHA significantly downregulated CXCR4 surface expression. -- Abstract: We have previously characterized the effects of 2,6-diisopropylphenyl-docosahexaenoamide (DIP-DHA) conjugates and their analogs on the proliferation and progression of breast cancer cell lines. For this study, we investigated the effects of the DIP-DHA conjugate on 2 representative T cell acute lymphoblastic leukemia (T-ALL) cell lines: CEM and Jurkat. Treatment of both cell lines with DIP-DHA resulted in significantly greater inhibition of proliferation and induction of apoptosis than that of parent compounds, 2,6-diisopropylphenol (DIP) or docosahexaenoate (DHA). Treatment of the cells with DIP-DHA resulted in increased activation of caspase-3, and caspase-7. Furthermore, induction of apoptosis in both cell lines was reversed in the presence of a caspase family inhibitor. Treatment with DIP-DHA reduced mitochondrial membrane potential. These observations suggest that the effects are driven by intrinsic apoptotic pathways. DIP-DHA treatment also downregulated surface CXCR4 expression, an important chemokine receptor involved in cancer metastasis that is highly expressed in both CEM and Jurkat cells. In conclusion, our data suggest that the DIP-DHA conjugate exhibits significantly more potent effects on CEM and Jurkat cells than that of DIP or DHA alone. These conjugates have potential use for treatment of patients with T cell acute lymphoblastic leukemia.

  13. Rosmarinic acid potentiates ATRA-induced macrophage differentiation in acute promyelocytic leukemia NB4 cells.

    PubMed

    Heo, Sook-Kyoung; Noh, Eui-Kyu; Yoon, Dong-Joon; Jo, Jae-Cheol; Koh, SuJin; Baek, Jin Ho; Park, Jae-Hoo; Min, Young Joo; Kim, Hawk

    2015-01-15

    Rosmarinic acid (RA, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid) has a number of biological activities, but little is known about anti-leukemic activities of RA combined with all-trans retinoic acid (ATRA) against acute promyelocytic leukemia (APL) cells. We examined the differentiation marker, CD11b, in bone marrow cells (BMC) of an APL patient, in NB4 cells (APL cell line), and in normal BMC and peripheral blood mononuclear cells (PBMC) of healthy subjects by flow cytometric analysis. ATRA/RA induced expression of CD11b in the BMC of the APL patient and in NB4 cells, but not in normal BMC or PBMC. Therefore, we realized that RA potentiated ATRA-induced macrophage differentiation in APL cells. Further characterization of the induced macrophages showed that they exhibited morphological changes and were able to phagocytose and generate reactive oxygen species. Th also had typical expression of C-C chemokine receptor type 1 (CCR1), CCR2, and intercellular adhesion molecule-1 (ICAM-1). Moreover, the expression of CD11b(+) and CD14(+) cells depended on ERK-NF-κB axis activation. Together, these results indicate that RA potentiates ATRA-induced macrophage differentiation in APL cells. Thus, RA may play an important role as an appurtenant differentiation agent for functional macrophage differentiation in APL. Additionally, the differentiated macrophages might have a normal life span and, they could die. These data indicate that co-treatment with RA and ATRA has potential as an anti-leukemic therapy in APL.

  14. ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer.

    PubMed

    Thoms, Julie A I; Birger, Yehudit; Foster, Sam; Knezevic, Kathy; Kirschenbaum, Yael; Chandrakanthan, Vashe; Jonquieres, Georg; Spensberger, Dominik; Wong, Jason W; Oram, S Helen; Kinston, Sarah J; Groner, Yoram; Lock, Richard; MacKenzie, Karen L; Göttgens, Berthold; Izraeli, Shai; Pimanda, John E

    2011-06-30

    The Ets-related gene (ERG) is an Ets-transcription factor required for normal blood stem cell development. ERG expression is down-regulated during early T-lymphopoiesis but maintained in T-acute lymphoblastic leukemia (T-ALL), where it is recognized as an independent risk factor for adverse outcome. However, it is unclear whether ERG is directly involved in the pathogenesis of T-ALL and how its expression is regulated. Here we demonstrate that transgenic expression of ERG causes T-ALL in mice and that its knockdown reduces the proliferation of human MOLT4 T-ALL cells. We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. This enhancer is not active in normal T cells but in transgenic mice targets expression to fetal liver c-kit(+) cells, adult bone marrow stem/progenitors and early CD4(-)CD8(-) double-negative thymic progenitors. Taken together, these data illustrate that ERG promotes T-ALL and that failure to extinguish activity of stem cell enhancers associated with regulatory transcription factors such as ERG can contribute to the development of leukemia.

  15. CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells

    SciTech Connect

    Yamazaki, Hiroto; Nishida, Hiroko; Iwata, Satoshi; Dang, Nam H.; Morimoto, Chikao

    2009-05-29

    Although cancer stem cells (CSCs) have been recently identified in myeloid leukemia, published data on lymphoid malignancy have been sparse. T-acute lymphoblastic leukemia (T-ALL) is characterized by the abnormal proliferation of T-cell precursors and is generally aggressive. As CD34 is the only positive-selection marker for CSCs in T-ALL, we performed extensive analysis of CD markers in T-ALL cell lines. We found that some of the tested lines consisted of heterogeneous populations of cells with various levels of surface marker expression. In particular, a small subpopulation of CD90 (Thy-1) and CD110 (c-Mpl) were shown to correlate with stem cell properties both in vitro and in transplantation experiments. As these markers are expressed on hematopoietic stem cells, our results suggest that stem cell-like population are enriched in CD90+/CD110+ fraction and they are useful positive-selection markers for the isolation of CSCs in some cases of T-ALL.

  16. Anti-leukemic effects of HDACi Belinostat and HMTi 3-Deazaneplanocin A on human acute promyelocytic leukemia cells.

    PubMed

    Valiulienė, Giedrė; Stirblytė, Ieva; Jasnauskaitė, Monika; Borutinskaitė, Veronika; Navakauskienė, Rūta

    2017-03-15

    Development of acute myeloid leukemia is usually sustained by deregulated epigenome. Alterations in DNA methylation and histone modifications are common manifestations of the disease. Acute promyelocytic leukemia (APL) is not an exception. Therefore, drugs that target epigenetic processes suggest an appealing strategy for APL treatment. In this study we tested the anti-leukemic activity of histone deacetylase inhibitor (HDACi) Belinostat (PXD101, (2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide), and histone methyltransferase inhibitor (HMTi) 3-Deazaneplanocin A (DZNep, 5R-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-cyclopentene-1S,2R-diol) combined with retinoic acid (RA) in APL cells NB4 and HL-60. We demonstrated that APL cell treatment with combinations of differentiation inductor RA, HDACi Belinostat and HMTi DZNep caused a depletion of leukemia cell growth and viability, initiated apoptosis and exaggerated RA induced granulocytic differentiation. Also an increased expression of transcription factors C/EBPε and PPARγ was demonstrated, while no significant reduction in C/EBPα gene level was detected. Furthermore, combined treatment depleted gene expression levels of EZH2 and SUZ12, especially in HL-60 cells, and diminished protein levels of Polycomb Repressive Complex 2 (PRC2) components EZH2, SUZ12 and EED. In addition, our study has shown that Belinostat and DZNep together with RA caused a depletion in HDAC1 and HDAC2 protein levels, HDAC2 gene expression and increased hyperacetylation of histone H4 in both leukemia cell lines. Using ChIP method we also demonstrated the increased association of hyperacetylated histone H4 with the C/EBPα and C/EBPε promoter regions in HL-60 cells. Summarizing, these findings indicate that combined treatment with RA, Belinostat and 3-Deazaneplanocin A is an effective epigenetic inducer for leukemia cell differentiation.

  17. Heterogeneity in mechanisms of emergent resistance in pediatric T-cell acute lymphoblastic leukemia

    PubMed Central

    Sutton, Rosemary; Venn, Nicola C.; Bendak, Katerina; Anderson, Denise; Marshall, Glenn M.; Cole, Catherine H.

    2016-01-01

    Relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem and is thought to be associated with clonal selection during treatment. In this study we used an established pre-clinical model of induction therapy to increase our understanding of the effect of engraftment and chemotherapy on clonal selection and acquisition of drug resistance in vivo. Immune-deficient mice were engrafted with patient diagnostic specimens and exposed to a repeated combination therapy consisting of vincristine, dexamethasone, L-asparaginase and daunorubicin. Any re-emergence of disease following therapy was shown to be associated with resistance to dexamethasone, no resistance was observed to the other three drugs. Immunoglobulin/T-cell receptor gene rearrangements closely matched those in respective diagnosis and relapse patient specimens, highlighting that these clonal markers do not fully reflect the biological changes associated with drug resistance. Gene expression profiling revealed the significant underlying heterogeneity of dexamethasone-resistant xenografts. Alterations were observed in a large number of biological pathways, yet no dominant signature was common to all lines. These findings indicate that the biological changes associated with T-ALL relapse and resistance are stochastic and highly individual, and underline the importance of using sophisticated molecular techniques or single cell analyses in developing personalized approaches to therapy. PMID:27623214

  18. Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia

    PubMed Central

    Demarest, Renée M.; Dahmane, Nadia

    2011-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic neoplasm characterized by malignant expansion of immature T cells. Activated NOTCH (NotchIC) and c-MYC expression are increased in a large percentage of human T-ALL tumors. Furthermore, c-MYC has been shown to be a NOTCH target gene. Although activating mutations of Notch have been found in human T-ALL tumors, there is little evidence that the c-MYC locus is altered in this neoplasm. It was previously demonstrated that Notch and c-Myc–regulated genes have a broadly overlapping profile, including genes involved in cell cycle progression and metabolism. Given that Notch and c-Myc appear to function similarly in T-ALL, we sought to determine whether these two oncogenes could substitute for each other in T-ALL tumors. Here we report that NOTCHIC is able to maintain T-ALL tumors formed in the presence of exogenous NOTCHIC and c-MYC when exogenous c-MYC expression is extinguished. In contrast, c-MYC is incapable of maintaining these tumors in the absence of NOTCHIC. We propose that failure of c-MYC to maintain these tumors is the result of p53-mediated apoptosis. These results demonstrate that T-ALL maintenance is dependent on NOTCHIC, but not c-MYC, demonstrating that NOTCH is oncogenic dominant in T-ALL tumors. PMID:21217079

  19. Heterogeneity in mechanisms of emergent resistance in pediatric T-cell acute lymphoblastic leukemia.

    PubMed

    Yadav, Babasaheb D; Samuels, Amy L; Wells, Julia E; Sutton, Rosemary; Venn, Nicola C; Bendak, Katerina; Anderson, Denise; Marshall, Glenn M; Cole, Catherine H; Beesley, Alex H; Kees, Ursula R; Lock, Richard B

    2016-09-13

    Relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem and is thought to be associated with clonal selection during treatment. In this study we used an established pre-clinical model of induction therapy to increase our understanding of the effect of engraftment and chemotherapy on clonal selection and acquisition of drug resistance in vivo. Immune-deficient mice were engrafted with patient diagnostic specimens and exposed to a repeated combination therapy consisting of vincristine, dexamethasone, L-asparaginase and daunorubicin. Any re-emergence of disease following therapy was shown to be associated with resistance to dexamethasone, no resistance was observed to the other three drugs. Immunoglobulin/T-cell receptor gene rearrangements closely matched those in respective diagnosis and relapse patient specimens, highlighting that these clonal markers do not fully reflect the biological changes associated with drug resistance. Gene expression profiling revealed the significant underlying heterogeneity of dexamethasone-resistant xenografts. Alterations were observed in a large number of biological pathways, yet no dominant signature was common to all lines. These findings indicate that the biological changes associated with T-ALL relapse and resistance are stochastic and highly individual, and underline the importance of using sophisticated molecular techniques or single cell analyses in developing personalized approaches to therapy.

  20. Interactions between acute lymphoblastic leukemia and bone marrow stromal cells influence response to therapy.

    PubMed

    Tesfai, Yordanos; Ford, Jette; Carter, Kim W; Firth, Martin J; O'Leary, Rebecca A; Gottardo, Nicholas G; Cole, Catherine; Kees, Ursula R

    2012-03-01

    The cure rate for pediatric patients with B precursor acute lymphoblastic leukemia (pre-B ALL) is steadily improving, however relapses do occur despite initial response to therapy. To identify links between drug resistance and gene deregulation we used oligonucleotide microarray technology and determined in 184 pre-B ALL specimen genes differentially expressed compared to normal CD34(+) specimens. We identified 20 signature genes including CTGF, BMP-2, CXCR4 and IL7R, documented to regulate interactions in the bone marrow. We recorded remarkably similar levels of expression in three independent patient cohorts, and found distinct patterns in cytogenetically defined subgroups of pre-B ALL. The canonical pathways that were affected are involved in inter- and intra-cellular communication, regulating signaling within the microenvironment. We tested experimentally whether interaction with stromal cells conferred protection to four drugs used in current ALL therapy, and demonstrated that bone marrow stromal cells significantly influenced resistance to vincristine and cytosine arabinoside. Compounds designed to block the identified cellular interactions within the bone marrow microenvironment are expected to mobilise the leukemic cells and make them more accessible to contemporary antileukemic agents. The data provide novel insight into the pathobiology of ALL and indicate new therapeutic targets for patients with ALL.

  1. XIAP inhibitors induce differentiation and impair clonogenic capacity of acute myeloid leukemia stem cells

    PubMed Central

    Moreno-Martínez, Daniel; Nomdedeu, Meritxell; Lara-Castillo, María Carmen; Etxabe, Amaia; Pratcorona, Marta; Tesi, Niccolò; Díaz-Beyá, Marina; Rozman, María; Montserrat, Emili; Urbano-Ispizua, Álvaro; Esteve, Jordi; Risueño, Ruth M.

    2014-01-01

    Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials. PMID:24952669

  2. Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-03-19

    Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  3. Tanespimycin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-09-27

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  4. Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia

    PubMed Central

    Theunissen, Prisca; Mejstrikova, Ester; Sedek, Lukasz; van der Sluijs-Gelling, Alita J.; Gaipa, Giuseppe; Bartels, Marius; Sobral da Costa, Elaine; Kotrová, Michaela; Novakova, Michaela; Sonneveld, Edwin; Buracchi, Chiara; Bonaccorso, Paola; Oliveira, Elen; te Marvelde, Jeroen G.; Szczepanski, Tomasz; Lhermitte, Ludovic; Hrusak, Ondrej; Lecrevisse, Quentin; Grigore, Georgiana Emilia; Froňková, Eva; Trka, Jan; Brüggemann, Monika; Orfao, Alberto; van der Velden, Vincent H. J.

    2017-01-01

    A fully-standardized EuroFlow 8–color antibody panel and laboratory procedure was stepwise designed to measure minimal residual disease (MRD) in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) patients with a sensitivity of ≤10−5, comparable to real-time quantitative polymerase chain reaction (RQ-PCR)–based MRD detection via antigen-receptor rearrangements. Leukocyte markers and the corresponding antibodies and fluorochromes were selected based on their contribution in separating BCP-ALL cells from normal/regenerating BCP cells in multidimensional principal component analyses. After 5 multicenter design-test-evaluate-redesign phases with a total of 319 BCP-ALL patients at diagnosis, two 8-color antibody tubes were selected, which allowed separation between normal and malignant BCP cells in 99% of studied patients. These 2 tubes were tested with a new erythrocyte bulk-lysis protocol allowing acquisition of high cell numbers in 377 bone marrow follow-up samples of 178 BCP-ALL patients. Comparison with RQ-PCR–based MRD data showed a clear positive relation between the percentage concordant cases and the number of cells acquired. For those samples with >4 million cells acquired, concordant results were obtained in 93% of samples. Most discordances were clarified upon high-throughput sequencing of antigen-receptor rearrangements and blind multicenter reanalysis of flow cytometric data, resulting in an unprecedented concordance of 98% (97% for samples with MRD < 0.01%). In conclusion, the fully standardized EuroFlow BCP-ALL MRD strategy is applicable in >98% of patients with sensitivities at least similar to RQ-PCR (≤10−5), if sufficient cells (>4 × 106, preferably more) are evaluated. PMID:27903527

  5. Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia.

    PubMed

    Theunissen, Prisca; Mejstrikova, Ester; Sedek, Lukasz; van der Sluijs-Gelling, Alita J; Gaipa, Giuseppe; Bartels, Marius; Sobral da Costa, Elaine; Kotrová, Michaela; Novakova, Michaela; Sonneveld, Edwin; Buracchi, Chiara; Bonaccorso, Paola; Oliveira, Elen; Te Marvelde, Jeroen G; Szczepanski, Tomasz; Lhermitte, Ludovic; Hrusak, Ondrej; Lecrevisse, Quentin; Grigore, Georgiana Emilia; Froňková, Eva; Trka, Jan; Brüggemann, Monika; Orfao, Alberto; van Dongen, Jacques J M; van der Velden, Vincent H J

    2017-01-19

    A fully-standardized EuroFlow 8-color antibody panel and laboratory procedure was stepwise designed to measure minimal residual disease (MRD) in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) patients with a sensitivity of ≤10(-5), comparable to real-time quantitative polymerase chain reaction (RQ-PCR)-based MRD detection via antigen-receptor rearrangements. Leukocyte markers and the corresponding antibodies and fluorochromes were selected based on their contribution in separating BCP-ALL cells from normal/regenerating BCP cells in multidimensional principal component analyses. After 5 multicenter design-test-evaluate-redesign phases with a total of 319 BCP-ALL patients at diagnosis, two 8-color antibody tubes were selected, which allowed separation between normal and malignant BCP cells in 99% of studied patients. These 2 tubes were tested with a new erythrocyte bulk-lysis protocol allowing acquisition of high cell numbers in 377 bone marrow follow-up samples of 178 BCP-ALL patients. Comparison with RQ-PCR-based MRD data showed a clear positive relation between the percentage concordant cases and the number of cells acquired. For those samples with >4 million cells acquired, concordant results were obtained in 93% of samples. Most discordances were clarified upon high-throughput sequencing of antigen-receptor rearrangements and blind multicenter reanalysis of flow cytometric data, resulting in an unprecedented concordance of 98% (97% for samples with MRD < 0.01%). In conclusion, the fully standardized EuroFlow BCP-ALL MRD strategy is applicable in >98% of patients with sensitivities at least similar to RQ-PCR (≤10(-5)), if sufficient cells (>4 × 10(6), preferably more) are evaluated.

  6. Characterization of arsenic-induced cytogenetic alterations in acute promyelocytic leukemia cell line, NB4.

    PubMed

    Yaghmaie, Marjan; Mozdarani, Hossein; Alimoghaddam, Kamran; Ghaffari, Seyed Hamidullah; Ghavamzadeh, Ardeshir; Hajhashemi, Marjan

    2012-06-01

    Gain or loss of genes plays important roles in leukemogenesis of APL via cooperation with PML-RARA. Fluorescence in situ hybridization (FISH) was applied to investigate the DNA copy number changes of hTERT, ERG, CDKN1B (P27), CDKN2A (P16), and TP53 genes in an acute promyelocytic leukemia (APL) cell line (NB4). Five bacterial artificial chromosome probes (BAC) for 9p21.3, 17p13.1, 12p13.2, 5p15.33, 21q22.2 regions were prepared using sequence independent amplification (SIA) and were hybridized to NB4 cells treated with different doses of arsenic trioxide (As(2)O(3); ATO) at various time intervals. NB4 cells were also karyotyped by G-banded chromosome analysis 24 h after culture initiation. FISH analysis prior to treatment showed CDKN1B, CDKN2A, and TP53 gene deletion but ERG and hTERT gene amplification. After treatment with ATO, the number of the NB4 cells with deleted CDKN1B and CDKN2A as well as the counts of the cells with hTERT amplification was significantly reduced in time- and does-dependent manners. In addition, we observed expressive increase in signal patterns of CDKN1B and CDKN2A along with significant decline in hTERT signal patterns in ATO-treated cells as compared with the control group (in time- and dose-dependent manners). On the other hand, no difference in signal patterns for Erg and p53 was observed in response to ATO exposure. The results of the present study show the cytogenetic alteration in hTERT, CDKN1B, and CDKN2A in NB4 cells after treatment with ATO might introduce a new mechanism of antitumor activities of ATO in APL cell line, NB4.

  7. Acute Lymphoblastic Leukemia (ALL) (For Parents)

    MedlinePlus

    ... 1- to 2-Year-Old Acute Lymphoblastic Leukemia (ALL) KidsHealth > For Parents > Acute Lymphoblastic Leukemia (ALL) Print A A A What's in this article? ... child will develop acute lymphoblastic, or lymphoid, leukemia (ALL). This is the most common type of childhood ...

  8. Acute Lymphoblastic Leukemia (ALL) (For Parents)

    MedlinePlus

    ... 1- to 2-Year-Old Acute Lymphoblastic Leukemia (ALL) KidsHealth > For Parents > Acute Lymphoblastic Leukemia (ALL) A A A What's in this article? About ... child will develop acute lymphoblastic, or lymphoid, leukemia (ALL). This is the most common type of childhood ...

  9. 47,XYY karyotype in acute myeloid leukemia.

    PubMed

    Palanduz, S; Aktan, M; Ozturk, S; Tutkan, G; Cefle, K; Pekcelen, Y

    1998-10-01

    A case of acute myelomonocytic leukemia (AMMoL; M4) with a 47,XYY karyotype is reported. This chromosome aneuploidy was found in both bone marrow cells and mitogen-stimulated lymphocytes. The contribution of XYY chromosomal constitution in the pathogenesis of AMMoL is controversial.

  10. Acute Lymphoblastic Leukemia Cells Inhibit the Differentiation of Bone Mesenchymal Stem Cells into Osteoblasts In Vitro by Activating Notch Signaling

    PubMed Central

    Yang, Gui-Cun; Xu, You-Hua; Chen, Hong-Xia; Wang, Xiao-Jing

    2015-01-01

    The disruption of normal hematopoiesis has been observed in leukemia, but the mechanism is unclear. Osteoblasts originate from bone mesenchymal stem cells (BMSCs) and can maintain normal hematopoiesis. To investigate how leukemic cells inhibit the osteogenic differentiation of BMSCs and the role of Notch signaling in this process, we cocultured BMSCs with acute lymphoblastic leukemia (ALL) cells in osteogenic induction medium. The expression levels of Notch1, Hes1, and the osteogenic markers Runx2, Osteopontin (OPN), and Osteocalcin (OCN) were assessed by real-time RT-PCR and western blotting on day 3. Alkaline phosphatase (ALP) activity was analyzed using an ALP kit, and mineralization deposits were detected by Alizarin red S staining on day 14. And then we treated BMSCs with Jagged1 and anti-Jagged1 neutralizing Ab. The expression of Notch1, Hes1, and the abovementioned osteogenic differentiation markers was measured. Inhibition of the expression of Runx2, OPN, and OCN and reduction of ALP activity and mineralization deposits were observed in BMSCs cocultured with ALL cells, while Notch signal inhibiting rescued these effects. All these results indicated that ALL cells could inhibit the osteogenic differentiation of BMSCs by activating Notch signaling, resulting in a decreased number of osteoblastic cells, which may impair normal hematopoiesis. PMID:26339248

  11. Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia.

    PubMed

    Quotti Tubi, L; Canovas Nunes, S; Brancalion, A; Doriguzzi Breatta, E; Manni, S; Mandato, E; Zaffino, F; Macaccaro, P; Carrino, M; Gianesin, K; Trentin, L; Binotto, G; Zambello, R; Semenzato, G; Gurrieri, C; Piazza, F

    2017-02-01

    Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory β subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.

  12. Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells*

    PubMed Central

    Liu, Li; Liu, Liang; Leung, Lai-Han; Cooney, Austin J.; Chen, Changyi; Rosengart, Todd K.; Ma, Yupo; Yang, Jianchang

    2015-01-01

    All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia. However, it has not been useful for other types of acute myeloid leukemia (AML). Here we explored the effect of SALL4, a stem cell factor, on ATRA-induced AML differentiation in both ATRA-sensitive and ATRA-resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases, whereas, in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells. We reason that, in AMLs, SALL4 activation may prevent cell differentiation and/or protect self-renewal that is seen in normal hematopoietic stem/progenitor cells. Indeed, our studies show that ATRA-mediated myeloid differentiation can be largely blocked by exogenous expression of SALL4, whereas ATRA plus SALL4 knockdown causes significantly increased AML differentiation and cell death. Mechanistic studies indicate that SALL4 directly associates with retinoic acid receptor α and modulates ATRA target gene expression. SALL4 is shown to recruit lysine-specific histone demethylase 1 (LSD1) to target genes and alter the histone methylation status. Furthermore, coinhibition of LSD1 and SALL4 plus ATRA treatment exhibited the strongest anti-AML effect. These findings suggest that SALL4 plays an unfavorable role in ATRA-based regimes, highlighting an important aspect of leukemia therapy. PMID:25737450

  13. MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia

    PubMed Central

    Correia, Nádia C.; Fragoso, Rita; Carvalho, Tânia; Enguita, Francisco J.; Barata, João T.

    2016-01-01

    Previous results indicated that miR-146b-5p is downregulated by TAL1, a transcription factor critical for early hematopoiesis that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL) where it has an oncogenic role. Here, we confirmed that miR-146b-5p expression is lower in TAL1-positive patient samples than in other T-ALL cases. Furthermore, leukemia T-cells display decreased levels of miR-146b-5p as compared to normal T-cells, thymocytes and other hematopoietic progenitors. MiR-146b-5p silencing enhances the in vitro migration and invasion of T-ALL cells, associated with increased levels of filamentous actin and chemokinesis. In vivo, miR-146b overexpression in a TAL1-positive cell line extends mouse survival in a xenotransplant model of human T-ALL. In contrast, knockdown of miR-146b-5p results in leukemia acceleration and decreased mouse overall survival, paralleled by faster tumor infiltration of the central nervous system. Our results suggest that miR-146b-5p is a functionally relevant microRNA gene in the context of T-ALL, whose negative regulation by TAL1 and possibly other oncogenes contributes to disease progression by modulating leukemia cell motility and disease aggressiveness. PMID:27550837

  14. Acute myeloid leukemia

    MedlinePlus

    ... types of leukemia, including AML: Blood disorders, including polycythemia vera , essential thrombocythemia , and myelodysplasia Certain chemicals (for ... More Anemia Bone marrow transplant Chemotherapy Immunodeficiency disorders Polycythemia vera Patient Instructions Bone marrow transplant - discharge Review ...

  15. Outcome of B-Cell Acute Lymphoblastic Leukemia in Brazilian Children: Immunophenotypical, Hematological, and Clinical Evaluation.

    PubMed

    Cézar, Rodrigo S; Cerqueira, Bruno A V; da Paz, Silvana de Souza; Barbosa, Cynara G; de Moura Neto, José P; Barreto, José H de S; Goncalves, Marilda de S

    2015-08-01

    The aim of this study is to investigate the clinical, hematological, and immunophenotypic characteristics of Brazilian children with B-cell acute lymphoblastic leukemia (B-ALL) to identify prognostic biomarkers of the disease. Thirty-three children newly diagnosed with B-ALL were followed between March 2004 and December 2009. Information about the demographic profile, diagnosis, immunophenotype, clinical manifestations, and disease outcome were gathered from the patients' medical records. Of the 33 patients with B-ALL, 18 were male and 15 female. Eighteen patients were classified as high risk; 13 as low risk, and 2 as true low risk. The frequencies of cluster of differentiation (CD)10, CD19, and CD20 antigens were 69.7%, 81.8%, and 18.2%, respectively. Six patients (18.2%) had aberrant expression of myeloid antigens. At diagnosis, patients immunopositive for CD20 had elevated white blood cell counts (P = 0.018) and lower platelet counts (P = 0.017). The 6-year overall survival was 67.5%± 3.47%. Our results demonstrate the distinct immunophenotypic and prognostic characteristics of patients with B-ALL, which can be related to the Brazilian racial admixture. Consequently, these results will most likely aid in the selection of additional prognostic markers and their use in monitoring the clinical manifestations and treatment response among B-ALL patients.

  16. PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia.

    PubMed

    Kleppe, Maria; Soulier, Jean; Asnafi, Vahid; Mentens, Nicole; Hornakova, Tekla; Knoops, Laurent; Constantinescu, Stefan; Sigaux, François; Meijerink, Jules P; Vandenberghe, Peter; Tartaglia, Marco; Foa, Robin; Macintyre, Elizabeth; Haferlach, Torsten; Cools, Jan

    2011-06-30

    We have recently reported inactivation of the tyrosine phosphatase PTPN2 (also known as TC-PTP) through deletion of the entire gene locus in ∼ 6% of T-cell acute lymphoblastic leukemia (T-ALL) cases. T-ALL is an aggressive disease of the thymocytes characterized by the stepwise accumulation of chromosomal abnormalities and gene mutations. In the present study, we confirmed the strong association of the PTPN2 deletion with TLX1 and NUP214-ABL1 expression. In addition, we found cooperation between PTPN2 deletion and activating JAK1 gene mutations. Activating mutations in JAK1 kinase occur in ∼ 10% of human T-ALL cases, and aberrant kinase activity has been shown to confer proliferation and survival advantages. Our results reveal that some JAK1 mutation-positive T-ALLs harbor deletions of the tyrosine phosphatase PTPN2, a known negative regulator of the JAK/STAT pathway. We provide evidence that down-regulation of Ptpn2 sensitizes lymphoid cells to JAK1-mediated transformation and reduces their sensitivity to JAK inhibition.

  17. Promoter DNA Methylation Pattern Identifies Prognostic Subgroups in Childhood T-Cell Acute Lymphoblastic Leukemia

    PubMed Central

    Borssén, Magnus; Palmqvist, Lars; Karrman, Kristina; Abrahamsson, Jonas; Behrendtz, Mikael; Heldrup, Jesper; Forestier, Erik; Roos, Göran; Degerman, Sofie

    2013-01-01

    Background Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided. Design and Methods Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32). Results Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP− (low methylation). CIMP− T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes. Conclusions We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL. PMID:23762353

  18. Gene copy number alteration profile and its clinical correlation in B-cell acute lymphoblastic leukemia.

    PubMed

    Gupta, Sanjeev Kumar; Bakhshi, Sameer; Kumar, Lalit; Kamal, Vineet Kumar; Kumar, Rajive

    2017-02-01

    The genes related to B-cell development are frequently altered in B-cell acute lymphoblastic leukemia (B-ALL). One hundred sixty-two newly diagnosed B-ALL cases, median age 8.5 years (2 months-67 years), were prospectively analyzed for copy number alterations (CNAs) in CDKN2A/B, IKZF1, PAX5, RB1, ETV6, BTG1, EBF1, and pseudoautosomal region genes (CRLF2, CSF2RA, IL3RA) using multiplex ligation-dependent probe amplification. The CNAs were detected in 114 (70.4%) cases; most commonly affected genes being CDKN2A/B-55 (34%), PAX5-51 (31.5%), and IKZF1-43 (26.5%). IKZF1 and RB1 deletions correlated with higher induction failure. Patients classified as good-risk, according to the integrated CNA profile and cytogenetic criteria, had lower induction failure [5 (8.6%) vs. 20 (25.3%); p = 0.012]. Those classified as good-risk, based on CNA profile irrespective of cytogenetics, also showed lower induction failure [6 (9.4%) vs. 19 (26%); p = 0.012]. The CNA profile identified patients with better induction outcome and has a potential role in better risk stratification of B-ALL.

  19. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

  20. Nivolumab in Treating Patients With HTLV-Associated T-Cell Leukemia/Lymphoma

    ClinicalTrials.gov

    2017-02-20

    Acute Adult T-Cell Leukemia/Lymphoma; Adult T-Cell Leukemia/Lymphoma; CD3 Positive; CD4-Positive Neoplastic Cells Present; Chronic Adult T-Cell Leukemia/Lymphoma; HTLV-1 Infection; Hypercalcemia; Lymphomatous Adult T-Cell Leukemia/Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Smoldering Adult T-Cell Leukemia/Lymphoma

  1. 8-Chloro-Adenosine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-11-08

    Recurrent Adult Acute Myeloid Leukemia; Relapsed Adult Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia Arising From Previous Myeloproliferative Disorder

  2. CD34⁺/CD38⁻ acute myelogenous leukemia cells aberrantly express Aurora kinase A.

    PubMed

    Yang, Jing; Ikezoe, Takayuki; Nishioka, Chie; Nobumoto, Atsuya; Udaka, Keiko; Yokoyama, Akihito

    2013-12-01

    We previously showed that Aurora kinase A (AURKA) is aberrantly expressed in acute myelogenous leukemia (AML) cells when compared to bone marrow mononuclear cells isolated from healthy volunteers. We have also shown that CD34(+) /CD38(-) AML cells, one of compartments enriched for leukemia stem cells in most leukemia subgroups, were relatively resistant to cytarabine-mediated growth inhibition when compared to their CD34(+) /CD38(+) counterparts. Our study attempted to identify therapeutic targets in CD34(+) /CD38(-) AML cells and found that CD34(+) /CD38(-) AML cells isolated from patients (n = 26) expressed larger amounts of AURKA than their CD34(+) /CD38(+) counterparts and CD34(+) normal hematopoietic stem/progenitor cells isolated from healthy volunteers (n = 6), as measured by real-time reverse-transcriptase polymerase chain reaction. Blockade of AURKA by the specific inhibitor MLN8237 or a short hairpin RNA (shRNA) against AURKA significantly inhibited proliferation, impaired self-renewal capability and induced apoptosis of CD34(+) /CD38(-) AML cells, in association with modulation of levels of Bcl-2 family member proteins. Importantly, inhibition of AURKA in CD34(+) /CD38(-) AML cells by MLN8237 or an shRNA significantly impaired engraftment of these cells in severely immunocompromised mice and appeared to prolong their survival. These results suggest that AURKA is a promising molecular target to eliminate chemotherapy-resistant CD34(+) /CD38(-) AML cells.

  3. Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2015-07-09

    Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma

  4. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    PubMed

    Scott, Bart L; Pasquini, Marcelo C; Logan, Brent R; Wu, Juan; Devine, Steven M; Porter, David L; Maziarz, Richard T; Warlick, Erica D; Fernandez, Hugo F; Alyea, Edwin P; Hamadani, Mehdi; Bashey, Asad; Giralt, Sergio; Geller, Nancy L; Leifer, Eric; Le-Rademacher, Jennifer; Mendizabal, Adam M; Horowitz, Mary M; Deeg, H Joachim; Horwitz, Mitchell E

    2017-04-10

    Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

  5. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

    PubMed Central

    Bond, Jonathan; Marchand, Tony; Touzart, Aurore; Cieslak, Agata; Trinquand, Amélie; Sutton, Laurent; Radford-Weiss, Isabelle; Lhermitte, Ludovic; Spicuglia, Salvatore; Dombret, Hervé; Macintyre, Elizabeth; Ifrah, Norbert; Hamel, Jean-François; Asnafi, Vahid

    2016-01-01

    Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently

  6. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia.

    PubMed

    Nakamura, Satoki; Hirano, Isao; Okinaka, Keiji; Takemura, Tomonari; Yokota, Daisuke; Ono, Takaaki; Shigeno, Kazuyuki; Shibata, Kiyoshi; Fujisawa, Shinya; Ohnishi, Kazunori

    2010-11-01

    FOXM1 is an important cell cycle regulator and regulates cell proliferation. In addition, FOXM1 has been reported to contribute to oncogenesis in various cancers. However, it is not clearly understood how FOXM1 contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of FOXM1 in AML cells. The FOXM1 messenger RNA (mRNA) expressed in AML cell lines was predominantly the FOXM1B isoform, and its levels were significantly higher than in normal high aldehyde dehydrogenase activity (ALDH(hi)) cells. Reduction of FOXM1 expression in AML cells inhibited cell proliferation compared with control cells, through induction of G(2)/M cell cycle arrest, a decrease in the protein expression of Aurora kinase B, Survivin, Cyclin B1, S-phase kinase-associated protein 2 and Cdc25B and an increase in the protein expression of p21(Cip1) and p27(Kip1). FOXM1 messenger RNA (mRNA) was overexpressed in all 127 AML clinical specimens tested (n = 21, 56, 32 and 18 for M1, M2, M4 and M5 subtypes, respectively). Compared with normal ALDH(hi) cells, FOXM1 gene expression was 1.65- to 2.26-fold higher in AML cells. Moreover, the FOXM1 protein was more strongly expressed in AML-derived ALDH(hi) cells compared with normal ALDH(hi) cells. In addition, depletion of FOXM1 reduced colony formation of AML-derived ALDH(hi) cells due to inhibition of Cdc25B and Cyclin B1 expression. In summary, we found that FOXM1B mRNA is predominantly expressed in AML cells and that aberrant expression of FOXM1 induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of FOXM1 expression represents an attractive target for AML therapy.

  7. Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia

    PubMed Central

    Morrow, K; Hernandez, CP; Raber, P; Valle, L Del; Wilk, AM; Majumdar, S; Wyczechowska, D; Reiss, K; Rodriguez, PC

    2013-01-01

    New treatments for adults with acute lymphoblastic T-cell leukemia (T-ALL) are urgently needed, as the current rate of overall remission in these patients is only about 40 percent. We recently showed the potential therapeutic benefit of the pegylated-human-arginase I (peg-Arg I) in T-ALL. However, the mechanisms by which peg-Arg I induces an anti-T-ALL effect remained unknown. Our results show the induction of T-ALL cell apoptosis by peg-Arg I, which associated with a global arrest in protein synthesis and with the phosphorylation of the eukaryotic-translation-initiation factor 2 alpha (eIF2α). Inhibition of eIF2α phosphorylation in T-ALL cells prevented the apoptosis induced by peg-Arg I, whereas the expression of a phosphomimetic eIF2α form increased the sensibility of T-ALL cells to peg-Arg I. Phosphorylation of eIF2α by peg-Arg I was mediated through kinases PERK and GCN2 and down-regulation of phosphatase GADD34. GCN2 and decreased GADD34 promoted T-ALL cell apoptosis after treatment with peg-Arg I, whereas PERK had an unexpected anti-apoptotic role. Additional results showed that phospho-eIF2α signaling further increased the anti-leukemic effects induced by peg-Arg I in T-ALL-bearing mice. These results suggest the central role of phospho-eIF2α in the anti-T-ALL effects induced by peg-Arg I and support its study as a therapeutic target. PMID:22926702

  8. High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia

    ClinicalTrials.gov

    2016-11-14

    Acute Leukemia of Ambiguous Lineage; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  9. SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

    PubMed Central

    Leal, Paulo C.; Bhasin, Manoj K.; Zenatti, Priscila Pini; Nunes, Ricardo J.; Yunes, Rosendo A.; Nowill, Alexandre E.; Libermann, Towia A.; Zerbini, Luiz Fernando; Yunes, José Andrés

    2015-01-01

    Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002. PMID:26302043

  10. TFDP3 confers chemoresistance in minimal residual disease within childhood T-cell acute lymphoblastic leukemia

    PubMed Central

    Chu, Ming; Yin, Kailin; Dong, Yujun; Wang, Pingzhang; Xue, Yun; Zhou, Peng; Wang, Yuqi; Wang, Yuedan

    2017-01-01

    Acquired drug resistance in childhood T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. In this study, a novel gene therapy target for childhood T-ALL to overcome chemoresistance was discovered: TFDP3 increased in the minimal residual disease (MRD) positive childhood T-ALL patients. Then, we established a preclinical model of resistance to induction therapy to examine the functional relevance of TFDP3 to chemoresistance in MRD derived from Jurkat/E6-1. Jurkat xenografts in NOD/SCID mice were exposed to a four drug combination (VXLD) of vincristine (VCR), dexamethasone (DEX), L-asparaginase (L-asp) and daunorubicin (DNR). During the 4-week VXLD treatment, the level of TFDP3 increased 4-fold. High expression of TFDP3 was identified in the re-emerging lines (Jurkat/MRD) with increased chemoresistance, which is correlated with partially promoter demethylation of TFDP3. Downregulation of TFDP3 by RNA interference reversed chemoresistance in Jurkat/MRD accompanied by reinstated E2F1 activity that coincided with increased levels of p53, p73, and associated proapoptotic target genes. Importantly, TFDP3 silencing in vivo induced apparent benefit to overcome chemoresistance in combination with VXLD treatment. Collectively, TFDP3 confers chemoresistance in MRD within childhood T-ALL, indicating that TFDP3 is a potential gene therapy target for residual cancer. PMID:27902457

  11. Iron overload in patients with acute leukemia or MDS undergoing myeloablative stem cell transplantation.

    PubMed

    Armand, Philippe; Kim, Haesook T; Rhodes, Joanna; Sainvil, Marie-Michele; Cutler, Corey; Ho, Vincent T; Koreth, John; Alyea, Edwin P; Hearsey, Doreen; Neufeld, Ellis J; Fleming, Mark D; Steen, Hanno; Anderson, Damon; Kwong, Raymond Y; Soiffer, Robert J; Antin, Joseph H

    2011-06-01

    Patients with hematologic malignancies undergoing allogeneic stem cell transplantation (HSCT) commonly have an elevated serum ferritin prior to HSCT, which has been associated with increased mortality after transplantation. This has led to the suggestion that iron overload is common and deleterious in this patient population. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. We report a prospective study of 48 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS) undergoing myeloablative HSCT, using magnetic resonance imaging (MRI) to estimate liver iron content (LIC) and cardiac iron. The median (and range) pre-HSCT value of serum ferritin was 1549 ng/mL (20-6989); serum hepcidin, 59 ng/mL (10-468); labile plasma iron, 0 LPI units (0.0-0.9). Eighty-five percent of patients had hepatic iron overload (HIO), and 42% had significant HIO (LIC ≥5.0 mg/gdw). Only 1 patient had cardiac iron overload. There was a strong correlation between pre-HSCT serum ferritin and estimated LIC (r = .75), which was mostly dependent on prior transfusion history. Serum hepcidin was appropriately elevated in patients with HIO. Labile plasma iron elevation was rare. A regression calibration analysis supported the hypothesis that elevated pre-HSCT LIC is significantly associated with inferior post-HSCT survival. These results contribute to our understanding of the prevalence, mechanism, and consequences of iron overload in HSCT.

  12. Clonal evolution of preleukemic hematopoietic stem cells in acute myeloid leukemia.

    PubMed

    Sykes, Stephen M; Kokkaliaris, Konstantinos D; Milsom, Michael D; Levine, Ross L; Majeti, Ravindra

    2015-12-01

    Acute myeloid leukemia (AML) is an aggressive blood cancer that results from an abnormal expansion of uncontrollably proliferating myeloid progenitors that have lost the capacity to differentiate. AML encompasses many genetically distinct subtypes that predominantly develop de novo. However, AML can also arise from premalignant myeloid conditions, such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs), or develop as the result of exposure to genotoxic agents used to treat unrelated malignancies. Although numerous distinct cytogenetic and molecular abnormalities associated with AML were discovered prior to the turn of the millennium, recent advances in whole genome sequencing and global genomic approaches have resulted in an explosion of newly identified molecular abnormalities. However, even with these advances, our understanding of how these mutations contribute to the etiology, pathogenesis, and therapeutic responses of AML remains largely unknown. Recently the International Society for Experimental Hematology (ISEH) hosted a webinar entitled "Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells (HSCs) in AML" in which two AML mavens, Ross Levine, MD, and Ravindra Majeti, MD, PhD, discussed some of their recent, groundbreaking studies that have shed light on how many of these newly identified mutations contribute to leukemogenesis and therapy resistance in AML. Here, we provide a brief overview of this webinar and discuss the basic scientific and clinical implications of the data presented.

  13. Segmentation of White Blood Cell from Acute Lymphoblastic Leukemia Images Using Dual-Threshold Method

    PubMed Central

    Cao, Yihui; Yao, Di

    2016-01-01

    We propose a dual-threshold method based on a strategic combination of RGB and HSV color space for white blood cell (WBC) segmentation. The proposed method consists of three main parts: preprocessing, threshold segmentation, and postprocessing. In the preprocessing part, we get two images for further processing: one contrast-stretched gray image and one H component image from transformed HSV color space. In the threshold segmentation part, a dual-threshold method is proposed for improving the conventional single-threshold approaches and a golden section search method is used for determining the optimal thresholds. For the postprocessing part, mathematical morphology and median filtering are utilized to denoise and remove incomplete WBCs. The proposed method was tested in segmenting the lymphoblasts on a public Acute Lymphoblastic Leukemia (ALL) image dataset. The results show that the performance of the proposed method is better than single-threshold approach independently performed in RGB and HSV color space and the overall single WBC segmentation accuracy reaches 97.85%, showing a good prospect in subsequent lymphoblast classification and ALL diagnosis. PMID:27313659

  14. Up-front allogeneic hematopoietic cell transplantation in acute myeloid leukemia arising from the myelodysplastic syndrome.

    PubMed

    Choi, Yunsuk; Kim, Sung-Doo; Park, Young-Hoon; Lee, Jae Seok; Kim, Dae-Young; Lee, Jung-Hee; Lee, Kyoo-Hyung; Seol, Miee; Lee, Young-Shin; Kang, Young-Ah; Jeon, Mijin; Jung, Ah Rang; Lee, Je-Hwan

    2015-01-01

    In patients with secondary acute myeloid leukemia (s-AML) arising from the myelodysplastic syndrome (MDS), treatment outcome is unsatisfactory. We compared up-front allogeneic hematopoietic cell transplantation (HCT) to induction chemotherapy (IC) as an initial treatment in patients with s-AML arising from MDS. This retrospective study included 85 patients who were diagnosed with s-AML arising from MDS; 11 patients proceeded to up-front HCT without IC (HCT group) and 74 received IC (IC group) as an initial treatment for s-AML, 28 of whom subsequently underwent HCT. In the IC group, 41.9% achieved complete remission (CR) compared to 81.8% in the HCT group (p = 0.013). The HCT group showed a significantly longer event-free survival (EFS) than the IC group (median 29.2 vs. 5.2 months, p = 0.042). Overall survival of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, p = 0.149). After adjustment for other clinical factors, outcome in the HCT group was significantly better than in the IC group in terms of CR rate (hazard ratio, HR, 11.195; p = 0.007) and EFS (HR, 0.384; p = 0.029). Up-front HCT is a viable option in s-AML arising from MDS if an appropriate donor is available.

  15. Important milestones in acute leukemia in 2013.

    PubMed

    Rowe, Jacob M

    2013-09-01

    This year marked the occurrence of several important milestones in the treatment of acute leukemias. First, the standard 7 + 3 protocol for acute myeloid leukemia (AML) was developed 40 years ago, and with some adaptations, has stood the test of time. Second, the 1 millionth hematopoietic cell transplant was recorded this year. Stem cell transplant, the first reported by Dr E. Donnall Thomas in 1957, had been considered a rare procedure until about a decade ago. Today, it has become a proven and often life-saving therapy for patients with acute leukemia. Advances in the treatment of patients with AML continue to take place, many of which relate to an increased understanding of the clinical heterogeneity of known subtypes. Forty years ago, the regimen that has come to be known as 7+3 for acute myeloid leukemia (AML) was born [1,2]. Cytosine arabinoside, or arabinosylcytosine as it was then called, was given as a continuous intravenous infusion of 100 mg/m(2) for 7 days, and the anthracycline, daunorubicin, was administered at 45 mg/m(2) intravenously for 3 days. Sixteen patients were originally treated on this protocol, and 5 of 8 previously untreated and 2 of 8 previously treated patients achieved a complete response (CR). This regimen has withstood the test of time. Attempts to add or substitute other agents have not yielded superior results. The only major contemporary change is that a higher dose of daunorubicin is safe and has become the standard of care [3].

  16. A rapid culture technique produces functional dendritic-like cells from human acute myeloid leukemia cell lines.

    PubMed

    Ning, Jian; Morgan, David; Pamphilon, Derwood

    2011-01-01

    Most anti-cancer immunotherapeutic strategies involving dendritic cells (DC) as vaccines rely upon the adoptive transfer of DC loaded with exogenous tumour-peptides. This study utilized human acute myeloid leukemia (AML) cells as progenitors from which functional dendritic-like antigen presenting cells (DLC) were generated, that constitutively express tumour antigens for recognition by CD8(+) T cells. DLC were generated from AML cell lines KG-1 and MUTZ-3 using rapid culture techniques and appropriate cytokines. DLC were evaluated for their cell-surface phenotype, antigen uptake and ability to stimulate allogeneic responder cell proliferation, and production of IFN-γ; compared with DC derived from normal human PBMC donors. KG-1 and MUTZ-3 DLC increased expression of CD80, CD83, CD86, and HLA-DR, and MUTZ-3 DLC downregulated CD14 and expressed CD1a. Importantly, both KG-1 and MUTZ-3-derived DLC promoted proliferation of allogeneic responder cells more efficiently than unmodified cells; neither cells incorporated FITC-labeled dextran, but both stimulated IFN-γ production from responding allogeneic CD8(+) T cells. Control DC produced from PBMC using the FastDC culture also expressed high levels of critical cell surface ligands and demonstrated good APC function. This paper indicates that functional DLC can be cultured from the AML cell lines KG-1 and MUTZ-3, and FastDC culture generates functional KG-1 DLC.

  17. Biomarkers in Bone Marrow Samples From Pediatric Patients With High-Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-17

    Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Childhood Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  18. Wntless (GPR177) expression correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia via Wnt signaling.

    PubMed

    Chiou, Shyh-Shin; Wang, Li-Ting; Huang, Shih-Bo; Chai, Chee-Yin; Wang, Shen-Nien; Liao, Yu-Mei; Lin, Pei-Chin; Liu, Kwei-Yan; Hsu, Shih-Hsien

    2014-10-01

    B-cell precursor acute lymphoblastic leukemia (BCP ALL) is the most common childhood leukemia, with a cure rate of 80%. Nevertheless, disease relapse is the most important prognostic factor for the disease outcome. We aimed to elucidate the role of Wnt secretion-regulating protein, Wntless (Wls)/GPR177, on disease outcome in pediatric patients with BCP ALL, and assess its pathogenetic role in the regulation of the disease. Wls expression was characterized and correlated with Wnt pathway signaling in the bone marrow leukemia cells isolated from 44 pediatric patients with BCP ALL. The overexpression of Wls was detected in leukemia cells and was significantly correlated with the disease relapse and poor survival in the patients. The high expression of Wls also correlated with the Wnt expression and consequent downstream signaling activation, which was shown to provide essential proliferation, transformation and anti-apoptotic activity during leukemogenesis. These results indicated that Wls played an essential role in disease relapse and poor survival in patients with BCP ALL. Therefore, Wls may provide a potential future therapeutic target, particularly for patients who do not respond to existing therapies and suffer relapse.

  19. Acute Appendicitis Secondary to Acute Promyelocytic Leukemia

    PubMed Central

    Rodriguez, Eduardo A.; Lopez, Marvin A.; Valluri, Kartik; Wang, Danlu; Fischer, Andrew; Perdomo, Tatiana

    2015-01-01

    Patient: Female, 43 Final Diagnosis: Myeloid sarcoma appendicitis Symptoms: Abdominal pain • chills • fever Medication: — Clinical Procedure: Laparoscopic appendectomy, bone marrow biopsy Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: The gastrointestinal tract is a rare site for extramedullary involvement in acute promyelocytic leukemia (APL). Case Report: A 43-year-old female with no past medical history presented complaining of mild abdominal pain, fever, and chills for the past day. On examination, she was tachycardic and febrile, with mild tenderness of her right lower quadrant and without signs of peritoneal irritation. Laboratory examination revealed pancytopenia and DIC, with a fibrinogen level of 290 mg/dL. CT of the abdomen showed a thickened and hyperemic appendix without perforation or abscess, compatible with acute appendicitis. The patient was given IV broad-spectrum antibiotics and was transfused with packed red blood cells and platelets. She underwent uncomplicated laparoscopic appendectomy and bone marrow biopsy, which revealed neo-plastic cells of 90% of the total bone marrow cellularity. Flow cytometry indicated presence of 92.4% of immature myeloid cells with t (15: 17) and q (22: 12) mutations, and FISH analysis for PML-RARA demonstrated a long-form fusion transcript, positive for APL. Appendix pathology described leukemic infiltration with co-expression of myeloperoxidase and CD68, consistent with myeloid sarcoma of the appendix. The patient completed a course of daunorubicin, cytarabine, and all trans-retinoic acid. Repeat bone marrow biopsy demonstrated complete remission. She will follow up with her primary care physician and hematologist/oncologist. Conclusions: Myeloid sarcoma of the appendix in the setting of APL is very rare and it might play a role in the development of acute appendicitis. Urgent management, including bone marrow biopsy for definitive diagnosis and urgent surgical intervention

  20. Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells.

    PubMed

    Tabe, Yoko; Yamamoto, Shinichi; Saitoh, Kaori; Sekihara, Kazumasa; Monma, Norikazu; Ikeo, Kazuho; Mogushi, Kaoru; Shikami, Masato; Ruvolo, Vivian; Ishizawa, Jo; Hail, Numsen; Kazuno, Saiko; Igarashi, Mamoru; Matsushita, Hiromichi; Yamanaka, Yasunari; Arai, Hajime; Nagaoka, Isao; Miida, Takashi; Hayashizaki, Yoshihide; Konopleva, Marina; Andreeff, Michael

    2017-03-15

    Leukemia cells in the bone marrow must meet the biochemical demands of increased cell proliferation and also survive by continually adapting to fluctuations in nutrient and oxygen availability. Thus, targeting metabolic abnormalities in leukemia cells located in the bone marrow is a novel therapeutic approach. In this study, we investigated the metabolic role of bone marrow adipocytes in supporting the growth of leukemic blasts. Prevention of nutrient starvation-induced apoptosis of leukemic cells by bone marrow adipocytes, as well as the metabolic and molecular mechanisms involved in this process, was investigated using various analytic techniques. In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by bone marrow adipocytes was associated with an increase in fatty acid β-oxidation (FAO) along with the upregulation of PPARγ, FABP4, CD36, and BCL2 genes. In AMoL cells, bone marrow adipocyte coculture increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38 MAPK with autophagy activation, and upregulated antiapoptotic chaperone HSPs. Inhibition of FAO disrupted metabolic homeostasis, increased reactive oxygen species production, and induced the integrated stress response mediator ATF4 and apoptosis in AMoL cells cocultured with bone marrow adipocytes. Our results suggest that bone marrow adipocytes support AMoL cell survival by regulating their metabolic energy balance and that the disruption of FAO in bone marrow adipocytes may be an alternative, novel therapeutic strategy for AMoL therapy. Cancer Res; 77(6); 1453-64. ©2017 AACR.

  1. Acute lymphocytic leukemia (ALL)

    MedlinePlus

    ... made. Life-threatening symptoms can occur as normal blood counts drop. Causes Most of the time, no clear cause can be found for ALL. The following factors may play a role in the development of all types of leukemia: Certain chromosome problems Exposure to radiation, ...

  2. BIRC3 alterations in chronic and B-cell acute lymphocytic leukemia patients

    PubMed Central

    ALHOURANI, EYAD; OTHMAN, MONEEB A.K.; MELO, JOANA B.; CARREIRA, ISABEL M.; GRYGALEWICZ, BEATA; VUJIĆ, DRAGANA; ZECEVIĆ, ZELJKO; JOKSIĆ, GORDANA; GLASER, ANITA; POHLE, BEATE; SCHLIE, CORDULA; HAUKE, SVEN; LIEHR, THOMAS

    2016-01-01

    Deletions within chromosome 11q22-23, are considered among the most common chromosomal aberrations in chronic lymphocytic leukemia (CLL), and are associated with a poor outcome. In addition to the ataxia telangiectasia mutated (ATM) gene, the baculoviral IAP repeat-containing 3 (BIRC3) gene is also located in the region. BIRC3 encodes a negative regulator of the non-canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein. Disruption of BIRC3 is known to be restricted to CLL fludarabine-refractory patients. The aim of the present study was to determine the frequency of copy number changes of BIRC3 and to assess its association with two known predictors of negative CLL outcome, ATM and tumor protein 53 (TP53) gene deletions. To evaluate the specificity of BIRC3 alterations to CLL, BIRC3 copy numbers were assessed in 117 CLL patients in addition to 45 B-cell acute lymphocytic leukemia (B-ALL) patients. A commercially available multiplex ligation dependent probe amplification kit, which includes four probes for the detection of TP53 and four probes for ATM gene region, was applied. Interphase-directed fluorescence in situ hybridization was used to apply commercially available probes for BIRC3, ATM and TP53. High resolution array-comparative genomic hybridization was conducted in selected cases. Genetic abnormalities of BIRC3 were detected in 23/117 (~20%) of CLL and 2/45 (~4%) of B-ALL cases. Overall, 20 patients with CLL and 1 with B-ALL possessed a BIRC3 deletion, whilst 3 patients with CLL and 1 with B-ALL harbored a BIRC3 duplication. All patients with an ATM deletion also carried a BIRC3 deletion. Only 2 CLL cases possessed deletions in BIRC3, ATM and TP53 simultaneously. Evidently, the deletion or duplication of BIRC3 may be observed rarely in B-ALL patients. BIRC3 duplication may occur in CLL patients, for which the prognosis requires additional studies in the future. The likelihood that TP53 deletions occur simultaneously with

  3. VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice

    PubMed Central

    Gentner, Eva; Vegi, Naidu M.; Mulaw, Medhanie A.; Mandal, Tamoghna; Bamezai, Shiva; Claus, Rainer; Tasdogan, Alpaslan; Quintanilla-Martinez, Leticia; Grunenberg, Alexander; Döhner, Konstanze; Döhner, Hartmut; Bullinger, Lars; Haferlach, Torsten; Buske, Christian

    2016-01-01

    Homeobox genes are key regulators in normal and malignant hematopoiesis. The human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus laevis Xvent-2 gene, was shown to be highly expressed in normal myeloid cells and in patients with acute myeloid leukemia. We now demonstrate that constitutive expression of VENTX suppresses expression of genes responsible for terminal erythroid differentiation in normal CD34+ stem and progenitor cells. Transplantation of bone marrow progenitor cells retrovirally engineered to express VENTX caused massive expansion of primitive erythroid cells and partly acute erythroleukemia in transplanted mice. The leukemogenic potential of VENTX was confirmed in the AML1-ETO transplantation model, as in contrast to AML1-ETO alone co-expression of AML1-ETO and VENTX induced acute myeloid leukemia, partly expressing erythroid markers, in all transplanted mice. VENTX was highly expressed in patients with primary human erythroleukemias and knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked cell growth. In summary, these data indicate that VENTX is able to perturb erythroid differentiation and to contribute to myeloid leukemogenesis when co-expressed with appropriate AML oncogenes and point to its potential significance as a novel therapeutic target in AML. PMID:27888632

  4. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplant for Patients with Acute Leukemia

    PubMed Central

    Holter-Chakrabarty, Jennifer L.; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D.; Artz, Andrew S.; Baron, Frédéric; Bredeson, Christopher N.; Dvorak, Christopher C.; Epstein, Robert B.; Lazarus, Hillard M.; Olsson, Richard F.; Selby, George B.; Williams, Kirsten M.; Cooke, Kenneth R.; Pasquini, Marcelo C.; McCarthy, Philip L.

    2015-01-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI N=948, TBICy N=821) recipients of related or unrelated hematopoietic cell transplantation (HCT) who received TBI (1200-1500cGY) for acute leukemia from 2003 to 2010. The two cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Ph+ ALL, HLA matched siblings, stem cell source, anti-thymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect TRM (24% vs. 23% at 3y, p=0.67; relative risk [RR] 1.01, p=0.91), leukemia relapse (27% vs. 29% at 3y, p=0.34; RR 0.89, p=0.18), leukemia-free survival (49% vs. 48% at3y, p=0.27; RR 0.93, p=0.29), chronic GVHD (45% vs. 47% at 1y, p=0.39; RR 0.9, p=0.11) or overall survival (53% vs. 52% at 3y, p=0.62; RR 0.96, p=0.57) for CyTBI and TBICy respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (p=0.08). This study demonstrates that the sequence of Cy and TBI does not impact transplant outcomes and complications in patients with acute leukemia undergoing HCT with myeloablative conditioning. PMID:25840335

  5. Idarubicin and Cytarabine With or Without Bevacizumab in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-01-23

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  6. Up-regulated A20 promotes proliferation, regulates cell cycle progression and induces chemotherapy resistance of acute lymphoblastic leukemia cells.

    PubMed

    Chen, Shuying; Xing, Haiyan; Li, Shouyun; Yu, Jing; Li, Huan; Liu, Shuang; Tian, Zheng; Tang, Kejing; Rao, Qing; Wang, Min; Wang, Jianxiang

    2015-09-01

    A20, also known as tumor necrosis factor-α (TNFα)-induced protein 3 (TNFAIP3), has been identified as a key regulator of cell survival in many solid tumors. However, little is known about the protein expression level and function of A20 in acute lymphoblastic leukemia (ALL). In this study, we found that A20 is up-regulated in ALL patients and several cell lines. Knockdown of A20 in Jurkat, Nalm-6, and Reh cells resulted in reduced cell proliferation, which was associated with cell cycle arrest. Phospho-ERK (p-ERK) was also down-regulated, while p53 and p21 were up-regulated in A20 knockdown cells. In addition, A20 knockdown induced apoptosis in Jurkat and Reh cells and enhanced the sensitivity of these cell lines to chemotherapeutic drugs. These results indicate that A20 may stimulate cell proliferation by regulating cell cycle progression. A20 inhibited apoptosis in some types of ALL cells, thereby enhancing their resistance to chemotherapy. This effect was abolished through A20 silencing. These findings suggest that A20 may contribute to the pathogenesis of ALL and that it may be used as a new therapeutic target for ALL treatment.

  7. Effect of Graft Source on Unrelated Donor Haemopoietic Stem-Cell Transplantation in Adults with Acute Leukemia: A Retrospective Analysis

    PubMed Central

    Eapen, Mary; Rocha, Vanderson; Sanz, Guillermo; Scaradavou, Andromachi; Zhang, Mei-Jie; Arcese, William; Sirvent, Anne; Champlin, Richard E.; Chao, Nelson; Gee, Adrian P.; Isola, Luis; Laughlin, Mary J.; Marks, David I.; Nabhan, Samir; Ruggeri, Annalisa; Soiffer, Robert; Horowitz, Mary M.; Gluckman, Eliane; Wagner, John E.

    2011-01-01

    SUMMARY Background Umbilical cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPC) or bone marrow (BM), especially when a HLA-matched adult unrelated donor is not available. Methods In order to establish the appropriateness of current graft selection practices, we retrospectively compared leukemia-free survival and other outcomes for each graft source in patients aged >16 years transplanted for acute leukemia using Cox regression. Data were available on 1525 patients transplanted between 2002 and 2006 using UCB (n=165), PBPC (n=888) and BM (n=472). UCB units were matched at HLA-A and B at antigen level and DRB1 at allele level (n=10) or mismatched at one (n=40) or two antigens (n=115). PBPC and BM grafts from unrelated adult donors were matched for allele-level HLA-A, B, C and DRB1 (n=632; n=332) or mismatched at one locus (n=256; n=140). Findings Leukemia-free survival after UCB transplantation was comparable to that observed after 8/8 and 7/8 allele-matched PBPC or BM transplantation. Transplant-related mortality, however, was higher after UCB transplantation compared to 8/8 allele-matched PBPC (HR 1.62, p<0.01) or BM (HR 1.69, p<0.01). Grades 2–4 acute and chronic graft-versus-host disease were lower in UCB recipients compared to allele-matched PBPC (HR 0.57, p<0.01 and HR 0.38, p<0.01, respectively), while chronic and not acute graft-versus-host disease was lower after UCB compared to allele-matched BM transplantation (HR 0.63, p=0.01). Interpretation Together, these data support the use of UCB for adults with acute leukemia when an HLA-matched unrelated adult donor is lacking and when transplant is urgently needed. PMID:20558104

  8. Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts.

    PubMed

    Aliperta, R; Cartellieri, M; Feldmann, A; Arndt, C; Koristka, S; Michalk, I; von Bonin, M; Ehninger, A; Bachmann, J; Ehninger, G; Bornhäuser, M; Bachmann, M P

    2015-09-18

    Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.

  9. Immunotherapy with natural killer cells: a possible approach for the treatment of Acute Myeloid Leukemia also in Brazil.

    PubMed

    Silla, Lúcia

    2016-10-01

    The allogeneic hematopoietic stem cell transplantation (HSCT) can cure intermediate and high-risk acute myeloid leukemia. Even with the development of strategies to reduce HSCT toxicity, this is still a complex treatment with high morbidity and mortality. Knowledge of the graft versus leukemia effect of HSCT has prepared the way for the development of Adoptive Immunotherapy or in vitro expansion of activated lymphocytes without alloreactivity, with subsequent intravenous infusion. The infusion of genetically modified T lymphocytes and haploidentical natural killer cells has been tested as an alternative to HSCT with very interesting results worldwide and in Brazil, as we not only have the technology of in vitro expansion of clinical grade lymphocytes available, but also do it according to the Good Manufacturing Practices that have been determined internationally.

  10. Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing.

    PubMed

    Kearney, Conor J; Ramsbottom, Kelly M; Voskoboinik, Ilia; Darcy, Phillip K; Oliaro, Jane

    2016-08-01

    Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit. However, the receptor-ligand interactions that critically dictate NK cell function in AML remain undefined. Here, we demonstrate that CD112/CD155 expression is required for DNAM-1-dependent killing of AML cells. Indeed, the low, or absent, expression of CD112/CD155 on multiple AML cell lines resulted in failure to stimulate optimal NK cell function. Importantly, isolated clones with low CD112/155 expression were resistant to NK cell killing while those expressing abundant levels of CD112/155 were highly susceptible. Attenuated NK cell killing in the absence of CD112/CD155 originated from decreased NK-target cell conjugation. Furthermore, we reveal by time-lapse microscopy, a significant increase in NK cell 'failed killing' in the absence of DNAM-1 ligands. Consequently, NK cells preferentially lysed ligand-expressing cells within heterogeneous populations, driving clonal selection of CD112/CD155-negative blasts upon NK cell attack. Taken together, we identify reduced CD155 expression as a major NK cell escape mechanism in AML and an opportunity for targeted immunotherapy.

  11. Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma.

    PubMed

    Yamasaki, S; Suzuki, R; Hatano, K; Fukushima, K; Iida, H; Morishima, S; Suehiro, Y; Fukuda, T; Uchida, N; Uchiyama, H; Ikeda, H; Yokota, A; Tsukasaki, K; Yamaguchi, H; Kuroda, J; Nakamae, H; Adachi, Y; Matsuoka, K-I; Nakamura, Y; Atsuta, Y; Suzumiya, J

    2017-04-03

    Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.Bone Marrow Transplantation advance online publication, 3 April 2017; doi:10.1038/bmt.2017.52.

  12. Rebeccamycin Analog in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  13. How Is Acute Lymphocytic Leukemia Diagnosed?

    MedlinePlus

    ... Adults Early Detection, Diagnosis, and Types How Is Acute Lymphocytic Leukemia Diagnosed? Certain signs and symptoms can suggest that ... described below. Tests used to diagnose and classify ALL If your doctor thinks you have leukemia, he ...

  14. Alloreactive Natural Killer Cells for the Treatment of Acute Myeloid Leukemia: From Stem Cell Transplantation to Adoptive Immunotherapy

    PubMed Central

    Ruggeri, Loredana; Parisi, Sarah; Urbani, Elena; Curti, Antonio

    2015-01-01

    Natural killer (NK) cells express activating and inhibitory receptors, which recognize MHC class-I alleles, termed “Killer cell Immunoglobulin-like Receptors” (KIRs). Preclinical and clinical data from haploidentical T-cell-depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched NK cells play a major role as effectors against acute myeloid leukemia (AML). Outside the transplantation setting, several reports have proven the safety and feasibility of NK cell infusion in AML patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. The aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts at exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against AML. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of AML. PMID:26528283

  15. Targeting MTHFD2 in acute myeloid leukemia

    PubMed Central

    Pikman, Yana; Puissant, Alexandre; Alexe, Gabriela; Furman, Andrew; Chen, Liying M.; Frumm, Stacey M.; Ross, Linda; Fenouille, Nina; Bassil, Christopher F.; Lewis, Caroline A.; Ramos, Azucena; Gould, Joshua; Stone, Richard M.; DeAngelo, Daniel J.; Galinsky, Ilene; Clish, Clary B.; Kung, Andrew L.; Hemann, Michael T.; Vander Heiden, Matthew G.; Banerji, Versha

    2016-01-01

    Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decreased leukemia burden and prolonged survival. Based upon primary patient AML data and functional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppression. Mechanistically, MYC regulates the expression of MTHFD2, and MTHFD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTHFD2 in AML. PMID:27325891

  16. Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-05-13

    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 Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myelomonocytic Leukemia (M4); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  17. SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-01-10

    Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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(15;17)(q22;q12); 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 Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  18. [Oncogenes and the origin of leukemia. Acute avian leukemia viruses].

    PubMed

    Graf, T

    1988-03-01

    Oncogenes have been intimately associated with the genesis of human neoplasms. A particularly useful system to study the mechanism of tumorigenesis is a small group of avian retroviruses that carry two oncogenes. These viruses causes acute leukemias and can transform hematopoietic cells in vitro. The mechanisms by which viral oncogenes affect the growth control and differentiation of their target cells is now understood in fair detail for two of these virus strains. In the avian erythroblastosis virus AEV, the v-erbB oncogene deregulates the growth control of erythroid precursors, while verbA blocks their terminal differentiation into erythrocytes. Based on the findings that v-erbB oncogene corresponds to a mutated growth factor receptor gene and that v-erbA corresponds to a mutated hormone receptor gene, models have been developed that explain the function of these two oncogenes on a molecular basis. The myelomonocytic leukemia virus MH2 acts by a completely different mechanism. In this case, the v-myc oncogene stimulates the proliferation of macrophage-like cells, while the v-mil gene stimulates them to produce their own growth factor, thus leading to autocrine growth. It will be interesting to determine whether the type of mechanisms of oncogene cooperativity elucidated for acute leukemia viruses are also operative during leukemogenesis in humans.

  19. New Strategies in Acute Myelogenous Leukemia: Leukemogenesis and Personalized Medicine

    PubMed Central

    Gojo, Ivana; Karp, Judith E.

    2014-01-01

    Recent advances in molecular technology have unraveled the complexity of leukemogenesis and provided the opportunity to design more personalized and pathophysiology-targeted therapeutic strategies. Despite the use of intensive chemotherapy, relapse remains the most common cause for therapeutic failure in acute myelogenous leukemia (AML). The interactions between leukemia stem cells (LSC) and marrow microenvironment appear to be critical in promoting therapeutic resistance through progressive acquisition of genetic and epigenetic changes within leukemia cells and immune evasion, resulting in leukemia cell survival. With advances in genomic sequencing efforts, epigenetic and phenotypic characterization, personalized therapeutic strategies aimed at critical leukemia survival mechanisms may be feasible in the near future. Here, we review select novel approaches to therapy of AML such as targeting LSC, altering leukemia/marrow microenvironment interactions, inhibiting DNA repair or cell cycle checkpoints, and augmenting immune-based anti-leukemia activity. PMID:25324141

  20. Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells.

    PubMed

    Ash, Dipankar; Subramanian, Manikandan; Surolia, Avadhesha; Shaha, Chandrima

    2015-01-01

    Nitric oxide (NO) has been shown to be effective in cancer chemoprevention and therefore drugs that help generate NO would be preferable for combination chemotherapy or solo use. This study shows a new evidence of NO as a mediator of acute leukemia cell death induced by fisetin, a promising chemotherapeutic agent. Fisetin was able to kill THP-1 cells in vivo resulting in tumor shrinkage in the mouse xenograft model. Death induction in vitro was mediated by an increase in NO resulting in double strand DNA breaks and the activation of both the extrinsic and the intrinsic apoptotic pathways. Double strand DNA breaks could be reduced if NO inhibitor was present during fisetin treatment. Fisetin also inhibited the downstream components of the mTORC1 pathway through downregulation of levels of p70 S6 kinase and inducing hypo-phosphorylation of S6 Ri P kinase, eIF4B and eEF2K. NO inhibition restored phosphorylation of downstream effectors of mTORC1 and rescued cells from death. Fisetin induced Ca(2+) entry through L-type Ca(2+) channels and abrogation of Ca(2+) influx reduced caspase activation and cell death. NO increase and increased Ca(2+) were independent phenomenon. It was inferred that apoptotic death of acute monocytic leukemia cells was induced by fisetin through increased generation of NO and elevated Ca(2+) entry activating the caspase dependent apoptotic pathways. Therefore, manipulation of NO production could be viewed as a potential strategy to increase efficacy of chemotherapy in acute monocytic leukemia.

  1. Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells

    PubMed Central

    Ash, Dipankar; Subramanian, Manikandan; Surolia, Avadhesha; Shaha, Chandrima

    2015-01-01

    Nitric oxide (NO) has been shown to be effective in cancer chemoprevention and therefore drugs that help generate NO would be preferable for combination chemotherapy or solo use. This study shows a new evidence of NO as a mediator of acute leukemia cell death induced by fisetin, a promising chemotherapeutic agent. Fisetin was able to kill THP-1 cells in vivo resulting in tumor shrinkage in the mouse xenograft model. Death induction in vitro was mediated by an increase in NO resulting in double strand DNA breaks and the activation of both the extrinsic and the intrinsic apoptotic pathways. Double strand DNA breaks could be reduced if NO inhibitor was present during fisetin treatment. Fisetin also inhibited the downstream components of the mTORC1 pathway through downregulation of levels of p70 S6 kinase and inducing hypo-phosphorylation of S6 Ri P kinase, eIF4B and eEF2K. NO inhibition restored phosphorylation of downstream effectors of mTORC1 and rescued cells from death. Fisetin induced Ca2+ entry through L-type Ca2+ channels and abrogation of Ca2+ influx reduced caspase activation and cell death. NO increase and increased Ca2+ were independent phenomenon. It was inferred that apoptotic death of acute monocytic leukemia cells was induced by fisetin through increased generation of NO and elevated Ca2+ entry activating the caspase dependent apoptotic pathways. Therefore, manipulation of NO production could be viewed as a potential strategy to increase efficacy of chemotherapy in acute monocytic leukemia. PMID:25973292

  2. Infection Rates among Acute Leukemia Patients Receiving Alternative Donor Hematopoietic Cell Transplantation.

    PubMed

    Ballen, Karen; Woo Ahn, Kwang; Chen, Min; Abdel-Azim, Hisham; Ahmed, Ibrahim; Aljurf, Mahmoud; Antin, Joseph; Bhatt, Ami S; Boeckh, Michael; Chen, George; Dandoy, Christopher; George, Biju; Laughlin, Mary J; Lazarus, Hillard M; MacMillan, Margaret L; Margolis, David A; Marks, David I; Norkin, Maxim; Rosenthal, Joseph; Saad, Ayman; Savani, Bipin; Schouten, Harry C; Storek, Jan; Szabolcs, Paul; Ustun, Celalettin; Verneris, Michael R; Waller, Edmund K; Weisdorf, Daniel J; Williams, Kirsten M; Wingard, John R; Wirk, Baldeep; Wolfs, Tom; Young, Jo-Anne H; Auletta, Jeffrey; Komanduri, Krishna V; Lindemans, Caroline; Riches, Marcie L

    2016-09-01

    Alternative graft sources (umbilical cord blood [UCB], matched unrelated donors [MUD], or mismatched unrelated donors [MMUD]) enable patients without a matched sibling donor to receive potentially curative hematopoietic cell transplantation (HCT). Retrospective studies demonstrate comparable outcomes among different graft sources. However, the risk and types of infections have not been compared among graft sources. Such information may influence the choice of a particular graft source. We compared the incidence of bacterial, viral, and fungal infections in 1781 adults with acute leukemia who received alternative donor HCT (UCB, n= 568; MUD, n = 930; MMUD, n = 283) between 2008 and 2011. The incidences of bacterial infection at 1 year were 72%, 59%, and 65% (P < .0001) for UCB, MUD, and MMUD, respectively. Incidences of viral infection at 1 year were 68%, 45%, and 53% (P < .0001) for UCB, MUD, and MMUD, respectively. In multivariable analysis, bacterial, fungal, and viral infections were more common after either UCB or MMUD than after MUD (P < .0001). Bacterial and viral but not fungal infections were more common after UCB than MMUD (P = .0009 and <.0001, respectively). The presence of viral infection was not associated with an increased mortality. Overall survival (OS) was comparable among UCB and MMUD patients with Karnofsky performance status (KPS) ≥ 90% but was inferior for UCB for patients with KPS < 90%. Bacterial and fungal infections were associated with poorer OS. Future strategies focusing on infection prevention and treatment are indicated to improve HCT outcomes.

  3. T-cell receptor excision circle levels after allogeneic stem cell transplantation are predictive of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Uzunel, Mehmet; Sairafi, Darius; Remberger, Mats; Mattsson, Jonas; Uhlin, Michael

    2014-07-15

    In this retrospective study, 209 patients with malignant disease were analyzed for levels of T-cell receptor excision circles (TRECs) for the first 24 months after allogeneic stem cell transplantation. CD3(+) cells were separated by direct antibody-coupled magnetic beads, followed by DNA extraction according to a standard protocol. The δRec-ψJα signal joint TREC was measured with real-time quantitative PCR. Patients were grouped based on malignant disease: chronic myeloid leukemia, chronic lymphatic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Patients were further subdivided based on TREC levels below (low-TREC) or above (high-TREC) median at each time point. TREC levels were then correlated to relapse incidence and relapse-free survival (RFS). For patients with AML, low TREC levels 2 months post-transplantation were correlated to high relapse incidence at 5 years (P<0.05). In patients with chronic leukemia, high TREC levels were correlated with improved RFS (P<0.05). For patients with MDS, high TREC levels at 9 months post-transplantation were associated with higher RFS at 5 years (P<0.02) and lower relapse incidence (P<0.02). This study shows the potential use of TREC measurement in blood to predict relapse in patients with AML and MDS after allogeneic hematopoietic stem cell transplantation.

  4. Allogeneic hematopoietic cell transplantation in adult patients with acute lymphoblastic leukemia.

    PubMed

    Marks, David I; Alonso, Laura; Radia, Rohini

    2014-12-01

    This review discusses the use of prognostic factors, patient and donor selection, choice of conditioning regimens, and timing of transplant. It also describes the management of Philadelphia-positive acute lymphocytic leukemia (ALL) and central nervous system disease. All aggressively treated adults with ALL should be considered for allogeneic transplantation and tissue typed at diagnosis. We further suggest that eligible patients be entered into clinical trials (that incorporate transplantation); these unselected prospective outcome data are essential to evaluate the true value of allogeneic transplantation in adults with ALL.

  5. Decitabine With or Without Bortezomib in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-08-30

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  6. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia.

    PubMed

    Vicente, Carmen; Schwab, Claire; Broux, Michaël; Geerdens, Ellen; Degryse, Sandrine; Demeyer, Sofie; Lahortiga, Idoya; Elliott, Alannah; Chilton, Lucy; La Starza, Roberta; Mecucci, Cristina; Vandenberghe, Peter; Goulden, Nicholas; Vora, Ajay; Moorman, Anthony V; Soulier, Jean; Harrison, Christine J; Clappier, Emmanuelle; Cools, Jan

    2015-10-01

    T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia.

  7. Somatic inactivation of ATM in hematopoietic cells predisposes mice to cyclin D3 dependent T cell acute lymphoblastic leukemia.

    PubMed

    Ehrlich, Lori A; Yang-Iott, Katherine; DeMicco, Amy; Bassing, Craig H

    2015-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of immature T cells that exhibits heterogeneity of oncogenic lesions, providing an obstacle for development of more effective and less toxic therapies. Inherited deficiency of ATM, a regulator of the cellular DNA damage response, predisposes young humans and mice to T-ALLs with clonal chromosome translocations. While acquired ATM mutation or deletion occurs in pediatric T-ALLs, the role of somatic ATM alterations in T-ALL pathogenesis remains unknown. We demonstrate here that somatic Atm inactivation in haematopoietic cells starting as these cells differentiate in utero predisposes mice to T-ALL at similar young ages and harboring analogous translocations as germline Atm-deficient mice. However, some T-ALLs from haematopoietic cell specific deletion of Atm were of more mature thymocytes, revealing that the developmental timing and celluar origin of Atm inactivation influences the phenotype of ATM-deficient T-ALLs. Although it has been hypothesized that ATM suppresses cancer by preventing deletion and inactivation of TP53, we find that Atm inhibits T-ALL independent of Tp53 deletion. Finally, we demonstrate that the Cyclin D3 protein that drives immature T cell proliferation is essential for transformation of Atm-deficient thymocytes. Our study establishes a pre-clinical model for pediatric T-ALLs with acquired ATM inactivation and identifies the cell cycle machinery as a therapeutic target for this aggressive childhood T-ALL subtype.

  8. RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

    PubMed Central

    Gianfelici, Valentina; Chiaretti, Sabina; Demeyer, Sofie; Di Giacomo, Filomena; Messina, Monica; La Starza, Roberta; Peragine, Nadia; Paoloni, Francesca; Geerdens, Ellen; Pierini, Valentina; Elia, Loredana; Mancini, Marco; De Propris, Maria Stefania; Apicella, Valerio; Gaidano, Gianluca; Testi, Anna Maria; Vitale, Antonella; Vignetti, Marco; Mecucci, Cristina; Guarini, Anna; Cools, Jan; Foà, Robin

    2016-01-01

    Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways. PMID:27151993

  9. Mycobacterium kansasii Pneumonia with Mediastinal Lymphadenitis in a Patient with Acute Myeloid Leukemia: Successful Treatment to Stem Cell Transplantation

    PubMed Central

    Choi, Yeon-Geun; Lee, Dong-Gun; Yim, Eunjung; Joo, Hyonsoo; Ryu, Seongyul; Choi, Jae-Ki; Kim, Hee-Je

    2017-01-01

    Non-tuberculous mycobacterial (NTM) disease is a relatively rare cause of neutropenic fever in patients with hematologic malignancies. During the neutropenic period, performing invasive procedures for microbiological or pathological confirmation is difficult. In addition, the optimal treatment duration for NTM disease in patients with leukemia, especially prior to stem cell transplantation (SCT), has not been documented. Therefore, we report a case of pneumonia with necrotizing lymphadenitis caused by Mycobacterium kansasii diagnosed during chemotherapy being performed for acute myeloid leukemia. The radiologic findings were similar to those of invasive fungal pneumonia; however, a bronchoalveolar washing fluid culture confirmed that the pathogen was M. kansasii. After 70 days from starting NTM treatment, allogeneic SCT was performed without any complications. The patient fully recovered after 12 months of NTM treatment, and neither reactivation of M. kansasii infection nor related complications were reported. PMID:28271647

  10. Natural killer cell (NK) subsets and NK-like T-cell populations in acute myeloid leukemias and myelodysplastic syndromes.

    PubMed

    Aggarwal, N; Swerdlow, S H; TenEyck, S P; Boyiadzis, M; Felgar, R E

    2016-07-01

    The impact of the immune microenvironment on the behavior and therapeutic strategies for hematopoietic and lymphoid neoplasms is being increasingly recognized. Many functional studies of natural killer (NK) cell cytotoxic responses in myelodysplasia (MDS) and acute myeloid leukemia (AML) exist, but with limited data on these lymphocyte proportions and related T-cell subsets. The proportions of these cells and their prognostic implications were therefore investigated in 89 AML, 51 MDS, and 20 control marrows by flow cytometry. The median proportion of NK cells (relative to the total lymphocytes) was lower in AML versus controls (P = 0.01). Among AML, a lower proportion of NK cells predicted better survival, whereas a higher NK cell proportion was associated with the poor prognostic AML category (P = 0.002). NK cell proportions were similar in MDS, MDS subgroups, and control marrows. The relative proportion of the mature NK cell subset (CD56(dim) CD16/57(bright) ) was lower in AML and MDS versus controls (P = 0.006, P = 0.0002, respectively). The proportion of mature NK cells was not a prognostic indicator although fewer were seen in poor prognosis AML. In contrast, a lower proportion of mature NK cells correlated with worse survival in MDS (P = 0.027). A higher proportion of NK-like T-cells (of total lymphoid cells) was found in MDS compared to controls (P = 0.01). A lower proportion of NK-like T-cells predicted better survival in AML but not in MDS. Thus, the proportions of NK, NK-cell subsets, and NK-like T-cells vary in myeloid neoplasms, may potentially impact immunomodulatory therapies, and may impact outcome. © 2016 International Clinical Cytometry Society.

  11. Age and Modified European LeukemiaNet Classification to Predict Transplant Outcomes: An Integrated Approach for Acute Myelogenous Leukemia Patients Undergoing Allogeneic Stem Cell Transplantation.

    PubMed

    Oran, Betül; Jimenez, Antonio M; De Lima, Marcos; Popat, Uday R; Bassett, Roland; Andersson, Borje S; Borthakur, Gautam; Bashir, Qaiser; Chen, Julianne; Ciurea, Stefan O; Jabbour, Elias; Cortes, Jorge; Kebriaei, Partow; Khouri, Issa F; Qazilbash, Muzaffar H; Ravandi, Farhad; Rondon, Gabriela; Lu, Xinyan; Shpall, Elizabeth J; Champlin, Richard E

    2015-08-01

    We evaluated the prognostic significance of a modified European LeukemiaNet (ELN) classification for patients with acute myelogenous leukemia (AML) undergoing hematopoietic stem cell transplantation (HSCT) while in first complete remission (CR1). We analyzed 464 AML patients with matched related (n = 211, 45.5%), matched unrelated (n = 176, 37.9%), and mismatched donors (n = 77, 16.6%). Patients were classified into 4 modified ELN risk groups (favorable, intermediate-I, intermediate-II, and adverse) separately for 354 patients age < 60 years and 110 patients age ≥ 60 years. In this modified version of ELN classification, patients with normal cytogenetic were classified by FLT3-ITD mutational status: favorable risk if FLT3-ITDwild and intermediate-I if FLT3-ITDmut. The best outcomes occurred in the ELN favorable and intermediate-II groups in younger AML patients and in the favorable and intermediate-I groups in older AML patients. Older AML patients had worse transplant outcomes within each modified ELN risk group except intermediate-I when compared with younger patients; leukemia-free survival at 3 years was 67.8% versus 49.8% in favorable, 53.4% versus 50.7% in intermediate-I, 65.7% versus 20.2% in intermediate-II, and 44.6% versus 23.8% in adverse group younger and older patients, respectively. Among lesion-specific abnormalities, del5q/-5 and abnl(17p) had the worse transplant outcomes, with 3-year leukemia-free survival rates of 18.4% and 20% in younger CR1 patients. In conclusion, the modified ELN prognostic classification developed for chemotherapy outcomes also identifies prognostic groups for HSCT, which is useful for a selection of patients for post-transplant strategies to improve outcomes.

  12. Preservation of high glycolytic phenotype by establishing new acute lymphoblastic leukemia cell lines at physiologic oxygen concentration

    SciTech Connect

    Sheard, Michael A.; Ghent, Matthew V.; Cabral, Daniel J.; Lee, Joanne C.; Khankaldyyan, Vazgen; Ji, Lingyun; Wu, Samuel Q.; Kang, Min H.; and others

    2015-05-15

    Cancer cells typically exhibit increased glycolysis and decreased mitochondrial oxidative phosphorylation, and they continue to exhibit some elevation in glycolysis even under aerobic conditions. However, it is unclear whether cancer cell lines employ a high level of glycolysis comparable to that of the original cancers from which they were derived, even if their culture conditions are changed to physiologically relevant oxygen concentrations. From three childhood acute lymphoblastic leukemia (ALL) patients we established three new pairs of cell lines in both atmospheric (20%) and physiologic (bone marrow level, 5%) oxygen concentrations. Cell lines established in 20% oxygen exhibited lower proliferation, survival, expression of glycolysis genes, glucose consumption, and lactate production. Interestingly, the effects of oxygen concentration used during cell line initiation were only partially reversible when established cell cultures were switched from one oxygen concentration to another for eight weeks. These observations indicate that ALL cell lines established at atmospheric oxygen concentration can exhibit relatively low levels of glycolysis and these levels are semi-permanent, suggesting that physiologic oxygen concentrations may be needed from the time of cell line initiation to preserve the high level of glycolysis commonly exhibited by leukemias in vivo. - Highlights: • Establishing new ALL cell lines in 5% oxygen resulted in higher glycolytic expression and function. • Establishing new ALL cell lines in 5% oxygen resulted in higher proliferation and lower cell death. • The divergent metabolic phenotypes selected in 5% and 20% oxygen are semi-permanent.

  13. Tipifarnib in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-03-22

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); 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 Del(5q); 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); Cellular Diagnosis, Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  14. Entinostat and Clofarabine in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Poor-Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia

    ClinicalTrials.gov

    2014-07-16

    Acute Leukemias of Ambiguous Lineage; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  15. Acute lymphoid leukemia following polycythemia vera.

    PubMed

    Camós, M; Cervantes, F; Montoto, S; Hernández-Boluda, J C; Villamor, N; Montserrat, E

    1999-01-01

    The tendency to evolve into acute leukemia is a well-known characteristic of polycythemia vera (PV), which is shared with the remaining chronic myeloproliferative disorders and increases after the administration of cytotoxic agents. Acute transformation is usually of myeloid phenotype, whereas acute lymphoid leukemia (ALL) following PV is seldom observed. A 63-year-old woman is described who developed ALL at 6 years from the initial diagnosis of PV, for which she had received radioactive phosphorus and hydroxyurea. The ALL was of B-cell type, corresponding to the L-3 subtype of the FAB classification. Despite the administration of combination chemotherapy the patient died shortly after the diagnosis of acute leukemia. The present case adds to seven previously described patients with the above association, all of whom had received cytotoxic therapy for PV. Median interval from PV to ALL diagnosis was 10 years, and there was a predominance of the B-cell phenotype. The prognosis was poor since all but one of the patients had a short survival after ALL diagnosis. The possible etiological and pathogenetic link between PV and the subsequent ALL is discussed.

  16. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes.

    PubMed

    Martino, Rodrigo; Caballero, María Dolores; Pérez-Simón, José Antonio; Simón, José Antonio Pérez; Canals, Carmen; Solano, Carlos; Urbano-Ispízua, Alvaro; Bargay, Joan; Léon, Angel; Sarrá, Josep; Sanz, Guillermo F; Moraleda, José María; Brunet, Salut; San Miguel, Jesús; Sierra, Jorge

    2002-09-15

    We report the results of a prospective study of a reduced-intensity conditioning (RIC) regimen followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling in 37 patients with acute myeloid leukemia (AML; n = 17) or myelodysplastic syndrome (MDS; n = 20). The median age was 57 years, and 22 (59%) were beyond the early phase of their disease. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 19% (5% grade III-IV), and the 1-year incidence of chronic extensive GVHD was 46%. With a median follow-up of 297 days (355 days in 24 survivors), the 1-year probability of transplant-related mortality was 5%, and the 1-year progression-free survival was 66%. The 1-year incidence of disease progression in patients with and without GVHD was 13% (95% CI, 4%-34%) and 58% (95% CI, 36%-96%), respectively (P =.008). These results suggest that a graft-versus-leukemia effect plays a crucial role in reducing the risk of relapse after a RIC allograft in AML and MDS.

  17. BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors.

    PubMed

    Korfi, K; Smith, M; Swan, J; Somervaille, T C P; Dhomen, N; Marais, R

    2016-04-07

    B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential.

  18. Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia

    PubMed Central

    Davila, Marco L.; Riviere, Isabelle; Wang, Xiuyan; Bartido, Shirley; Park, Jae; Curran, Kevin; Chung, Stephen S.; Stefanski, Jolanta; Borquez-Ojeda, Oriana; Olszewska, Malgorzata; Qu, Jinrong; Wasielewska, Teresa; He, Qing; Fink, Mitsu; Shinglot, Himaly; Youssif, Maher; Satter, Mark; Wang, Yongzeng; Hosey, James; Quintanilla, Hilda; Halton, Elizabeth; Bernal, Yvette; Bouhassira, Diana C. G.; Arcila, Maria E.; Gonen, Mithat; Roboz, Gail J.; Maslak, Peter; Douer, Dan; Frattini, Mark G.; Giralt, Sergio; Sadelain, Michel; Brentjens, Renier

    2015-01-01

    We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome–positive (Ph+) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy. PMID:24553386

  19. Treosulfan, Fludarabine Phosphate, and Total Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-08-30

    Acute Myeloid Leukemia in Remission; Chronic Myelomonocytic Leukemia; Minimal Residual Disease; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

  20. Clustering of breakpoints on chromosome 10 in acute T-cell leukemias with the t(10; 14) chromosome translocation

    SciTech Connect

    Kagan, J.; Finger, L.R.; Letofsky, J.; Finan, J.; Nowell, P.C.; Croce, C.M. )

    1989-06-01

    The T-cell receptor (TCR){alpha}/{delta} chain locus on chromosome 14q11 is nonrandomly involved in translocations and inversions in human T-cell neoplasms. The authors have analyzed three acute T-lymphoblastic leukemia samples carrying a t(10;14)(q24;q11) chromosome translocation by means of somatic cell hybrids and molecular cloning. In all cases studied the translocation splits the TCR {delta} chain locus. Somatic cell hybrids containing the human 10q+ chromosome resulting from the translocation retain the human terminal deoxynucleotidyltransferase gene mapped at 10q23-q24 and the diversity and joining, D{sub {delta}}2-J{sub {delta}}1, regions of the TCR {delta} chain, but not the V{sub {alpha}} region (variable region of the TCR {alpha} chain), demonstrating that the split occurred within the V{sub {alpha}}-D{sub {delta}}2 region. Molecular cloning of the breakpoint junctions revealed that the TCR {delta} chain sequences involved are made from the D{sub {delta}}2 segment. The chromosome breakpoints are clustered within a region of {approx} 263 base pairs of chromosome 10. The results suggest that the translocation of the TCR {delta} chain locus to a locus on 10q, which the authors have designated TCL3, results in deregulation of this putative oncogene, leading to acute T-cell leukemia.

  1. MS-275 and Azacitidine in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2017-01-31

    Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  2. High frequency of clonal immunoglobulin or T cell receptor gene rearrangements in acute myelogenous leukemia expressing terminal deoxyribonucleotidyltransferase

    PubMed Central

    1987-01-01

    Ig and T cell receptor rearrangements have been used as irreversible markers of lineage and clonality in the study of B- and T-lymphoid populations. We have addressed the issue of lymphoid lineage specificity of these rearrangements by analyzing a panel of 25 TdT- acute myelogenous leukemias, 13 TdT+ AMLs, and 4 TdT+ undifferentiated leukemias. We report that while gene rearrangements represent extremely rare events in classical TdT- AML (less than 8%), rearrangements of either the Ig or T beta locus or both were detectable in the majority of the TdT+ AMLs (greater than 60%), and rearrangements of both loci were detectable in all of the TdT+ undifferentiated leukemias. These data demonstrate a significant association between TdT expression and Ig or T beta gene rearrangements even outside the lymphoid lineage, further supporting a role for TdT in Ig and T cell receptor gene assembly. These data also indicate that a coordinated program of lymphoid gene expression involving TdT-CD7-expression and Ig/T beta rearrangements can be activated before myeloid commitment. Whether the activation of this program represents a normal, albeit rare, event in early myelopoiesis or a transformation-related event present only in leukemic cells remains to be determined. PMID:3473183

  3. Mesenchymal Stem Cells Support Survival and Proliferation of Primary Human Acute Myeloid Leukemia Cells through Heterogeneous Molecular Mechanisms

    PubMed Central

    Brenner, Annette K.; Nepstad, Ina; Bruserud, Øystein

    2017-01-01

    Acute myeloid leukemia (AML) is a bone marrow malignancy, and various bone marrow stromal cells seem to support leukemogenesis, including osteoblasts and endothelial cells. We have investigated how normal bone marrow mesenchymal stem cells (MSCs) support the in vitro proliferation of primary human AML cells. Both MSCs and primary AML cells show constitutive release of several soluble mediators, and the mediator repertoires of the two cell types are partly overlapping. The two cell populations were cocultured on transwell plates, and MSC effects on AML cells mediated through the local cytokine/soluble mediator network could thus be evaluated. The presence of normal MSCs had an antiapoptotic and growth-enhancing effect on primary human AML cells when investigating a group of 51 unselected AML patients; this was associated with increased phosphorylation of mTOR and its downstream targets, and the effect was independent of cytogenetic or molecular-genetic abnormalities. The MSCs also supported the long-term proliferation of the AML cells. A subset of the patients also showed an altered cytokine network with supra-additive levels for several cytokines. The presence of cytokine-neutralizing antibodies or receptor inhibitors demonstrated that AML cells derived from different patients were heterogeneous with regard to effects of various cytokines on AML cell proliferation or regulation of apoptosis. We conclude that even though the effects of single cytokines derived from bone marrow MSCs on human AML cells differ among patients, the final cytokine-mediated effects of the MSCs during coculture is growth enhancement and inhibition of apoptosis. PMID:28232835

  4. Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2017-01-31

    Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  5. Targeting of the deubiquitinase USP9X attenuates B-cell acute lymphoblastic leukemia cell survival and overcomes glucocorticoid resistance.

    PubMed

    Zhou, Mi; Wang, Ting; Lai, Huiling; Zhao, Xuejiao; Yu, Qin; Zhou, Jianfeng; Yang, Yang

    2015-04-03

    Although previous studies attributed a pro-survival role to USP9X in human cancer, how USP9X affects B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. Here, we found that USP9X is overexpressed in B-ALL cell lines and human patients. We investigated the role of USP9X in B-ALL and found that USP9X knockdown significantly reduced leukemic cell growth and increased spontaneous apoptosis, thereby improving survival in immunodeficient mice. These effects are partially mediated by the intrinsic apoptotic pathway, as we found that USP9X-knockdown leukemic cells displayed MCL1 down-regulation, with decreased BCL-2/BCL-XL levels and increased BAX levels. In addition, we demonstrated that USP9X inhibition negatively regulates mTORC1 activity toward its substrate S6K1. Clinically, USP9X inhibition sensitized glucocorticoid-resistant ALL cells to prednisolone; this observation reveals a potential avenue for improving the treatment of drug-resistant relapses. Collectively, our findings suggest that the combination of USP9X targeting and glucocorticoids treatment has attractive utility in B-ALL. This approach represents a potential strategy for promising combination therapies for lymphoid malignancies.

  6. The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia

    PubMed Central

    Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech

    2017-01-01

    While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. PMID:28054944

  7. Vosaroxin and Infusional Cytarabine in Treating Patients With Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2017-04-05

    Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia With Multilineage Dysplasia; Myeloid Sarcoma; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Therapy-Related Myelodysplastic Syndrome

  8. Nivolumab and Dasatinib in Treating Patients With Relapsed or Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-08-25

    B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  9. Studying Biomarkers in Samples From Younger Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-17

    Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies; Childhood Acute Myelomonocytic Leukemia (M4)

  10. [Inhibition of NF-kB Activation Decreases Resistance in Acute Myeloid Leukemia Cells to TRAIL-induced Apoptosis in Multicellular Aggregates].

    PubMed

    Fadeev, R S; Solovieva, M E; Slyadovskiy, D A; Zakharov, S G; Fadeeva, I S; Senotov, A S; Golenkov, A K; Akatov, V S

    2015-01-01

    Suppression of resistance in acute myeloid leukemia cells to TRAIL-induced apoptosis in multicellular aggregates, was studied using small molecule inhibitors of the activation of the transcription factor NF-kB - NF-k9 Activation Inhibitor IV and JSH-23 at non-toxic concentrations. NF-kB Activation Inhibitor IV and JSH-23 reduced resistance in the acute myeloid leukemia cells in multicellular aggregates to cytotoxic action of recombinant protein izTRAIL. It is shown that the use of these inhibitors decreased the phosphorylation of the RelA (p65) as a main marker activation of the transcription factor NF-kB. We discuss a possible reason for increasing resistance in acute myeloid leukemia cells to TRAIL-induced apoptosis in multicellular aggregates.

  11. Acute erythroid leukemia with multilineage dysplasia in a cat.

    PubMed

    Shirani, Dariush; Nassiri, Seyed Mahdi; Aldavood, Seyed Javid; Seddigh, Hamideh Salari; Fathi, Ezzatollah

    2011-04-01

    Dysplastic features of erythroid and megakaryocytic lineages were observed in a cat with acute erythroid leukemia. We demonstrated that flow cytometry analysis of the expression of glycophorin A and CD71 by neoplastic cells can be helpful in the diagnosis of this type of feline leukemia.

  12. Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation and Donor Bone Marrow Transplant in Treating Patients With Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or High-Risk Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-12-06

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; CD45-Positive Neoplastic Cells Present; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Refractory Anemia With Excess Blasts; Refractory Anemia With Ring Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

  13. Combination Chemotherapy and Rituximab in Treating Young Patients With Recurrent or Refractory Non-Hodgkin's Lymphoma or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2013-10-07

    B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; L3 Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma

  14. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.

    PubMed

    Pusic, Iskra; Choi, Jaebok; Fiala, Mark A; Gao, Feng; Holt, Matthew; Cashen, Amanda F; Vij, Ravi; Abboud, Camille N; Stockerl-Goldstein, Keith E; Jacoby, Meghan A; Uy, Geoffrey L; Westervelt, Peter; DiPersio, John F

    2015-10-01

    Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the

  15. 3,3'-Diindolylmethane induces G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia cells.

    PubMed

    Shorey, Lyndsey E; Hagman, Amanda M; Williams, David E; Ho, Emily; Dashwood, Roderick H; Benninghoff, Abby D

    2012-01-01

    Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 µM) arrested CEM and HSB2 cells at the G(1) phase of the cell cycle and 15 µM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL.

  16. Red blood cell-encapsulated L-asparaginase: potential therapy of patients with asparagine synthetase deficient acute myeloid leukemia.

    PubMed

    Agrawal, Vaidehi; Woo, Jung Hee; Borthakur, Gautham; Kantarjian, Hagop; Frankel, Arthur E

    2013-04-01

    Red blood cell (RBC) encapsulated L-asparaginase is a novel therapeutic for the treatment of asparagine auxotrophic malignancies. The enzyme-loaded red blood cells function as bioreactors to deplete bloodstream substrate. This delivery system provides improved pharmacodynamics with protection from circulating proteolytic enzymes and avoidance of early liver or renal clearance. The "drug" is manufactured with ABO and Rh compatible donor blood when a prescription is received. Because of the industrial scale manufacturing, the "drug" is transfused the day of receipt at the clinical site. Preliminary clinical studies show utility in childhood and adult acute lymphoblastic leukemia. Based on previous studies of applications in different diseases and assessment of different biomarkers, we propose this agent offers a safe and potentially effective treatment for a subset of chemotherapy refractory acute myeloid leukemia patients. The history, chemistry, biology, pharmacology, and relevant clinical experiences with L-asparaginase as well as the properties and proposed protocols with the red cell-encapsulated enzyme are reviewed.

  17. Tim-3 is highly expressed in T cells in acute myeloid leukemia and associated with clinicopathological prognostic stratification.

    PubMed

    Li, Caixia; Chen, Xiaochen; Yu, Xiao; Zhu, Yibei; Ma, Chao; Xia, Rui; Ma, Jinfeng; Gu, Caihong; Ye, Lu; Wu, Depei

    2014-01-01

    T cells immunoglobulin mucin 3 (Tim-3) is an important inhibitory stimulatory molecule, which has been reported to play a vital role in the tumor immune escape and be correlated with clinicopathological prognostic stratification in solid tumor. However, the related research is rare of Tim-3 in non-solid tumor, such as acute myeloid leukemia (AML). In this study, we investigated the expression characteristics of Tim-3 on the peripheral blood T cells of newly diagnosed AML patients and its clinical significance. Peripheral blood was obtained from 36 patients with newly diagnosed AML before intervention, with peripheral blood from 20 cases of healthy volunteers collected as normal control. Expression levels of Tim-3 on the peripheral blood T cells were assayed with flow cytometry. We found that Tim-3 expression on the peripheral blood CD4+ T cells and CD8+ T cells in newly diagnosed AML patients were significantly increased compared with that of normal control. CD4+ T cells/CD8+ T cell ratio (CD4/CD8) of peripheral blood in AML patients was significantly correlated with NCCN high risk group. The higher expression level of Tim-3 on CD4+ T cells in the peripheral blood of AML patients had significant correlation with FLT3-ITD mutation, the higher expression level of Tim-3 on CD8+ T cells in AML patients was significantly correlated with NCCN high risk group. To conclude, our results support the concept that Tim-3 is highly expressed on the peripheral blood T cells of AML patients, and Tim-3 expression significantly correlates with clinicopathological prognostic stratification in AMLTim-3, T cell, acute myeloid leukemia, tumor immune escape, clinicopathological prognostic stratification.

  18. Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-18

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  19. Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia

    PubMed Central

    Shouval, Roni; Eldror, Shiran; Lev, Atar; Davidson, Jacqueline; Rosenthal, Esther; Volchek, Yulia; Shem-Tov, Noga; Yerushalmi, Ronit; Shimoni, Avichai; Somech, Raz; Nagler, Arnon

    2017-01-01

    Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180−270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation. PMID:27880933

  20. [Treatment of acute leukemias].

    PubMed

    Gross, R; Gerecke, D

    1982-11-12

    The effective treatment of acute (myeloblastic and lymphoblastic) leukaemias depends on the induction of remissions as well as on the maintenance of these remissions. Whereas the use of anthracyclines and of cytosine arabinoside in different combinations notably increased the rate of induction of remissions, their maintenance was less successful until now. We present a scheme using, beside MTX and 6-MP, modified COAP regimes periodically every 3 months. The follow-up of 26 patients treated in this way is encouraging since nearly one third remained in full haematological remission after 3 years of observation.

  1. A method for estimating the accuracy of measurements of optical characteristics of the nuclei of blood cells in the diagnosis of acute leukemia

    NASA Astrophysics Data System (ADS)

    Polyakov, E. V.; Nikitaev, V. G.

    2017-01-01

    The work is devoted to investigation of the random component of the measurement error of the nuclei structure characteristics, which are used in the method of structural elements to measure the differences of blood cells of different types. This method is realized in information-measuring system of the analysis of micropreparations of blood cells in the diagnosis of acute leukemia and its variants.

  2. Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis.

    PubMed

    Ysebaert, L; Chicanne, G; Demur, C; De Toni, F; Prade-Houdellier, N; Ruidavets, J-B; Mansat-De Mas, V; Rigal-Huguet, F; Laurent, G; Payrastre, B; Manenti, S; Racaud-Sultan, C

    2006-07-01

    Activation of the Wnt/beta-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether beta-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for beta-catenin expression by Western blot. beta-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, beta-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a re-plating assay. In survival analyses, beta-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with P<0.05). Furthermore, variations in beta-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/beta-catenin pathway only in leukemic cells. Indeed, beta-catenin negative leukemic cells were found to increase beta-catenin in response to Wnt3a agonist in contrast to normal counterparts. Altogether, our data pave the way to the evaluation of Wnt pathway inhibition as a new rationale for eradicating the clonogenic pool of AML cells.

  3. The poison oligonucleotide F10 is highly effective against acute lymphoblastic leukemia while sparing normal hematopoietic cells.

    PubMed

    Pardee, Timothy S; Stadelman, Kristin; Jennings-Gee, Jamie; Caudell, David L; Gmeiner, William H

    2014-06-30

    F10 is an oligonucleotide based on the thymidylate synthase (TS) inhibitory 5-fluorouracil (5-FU) metabolite, 5-fluoro-2'-deoxyuridine-5'-O-monophosphate. We sought to determine the activity of F10 against preclinical models of acute lymphoblastic leukemia (ALL). F10 treatment resulted in robust induction of apoptosis that could not be equaled by 100 fold more 5-FU. F10 was more potent than Ara-C and doxorubicin against a panel of murine and human ALL cells with an average IC50 value of 1.48 nM (range 0.07 to 5.4 nM). F10 was more than 1000 times more potent than 5-FU. In vivo, F10 treatment significantly increased survival in 2 separate syngeneic ALL mouse models and 3 separate xenograft models. F10 also protected mice from leukemia-induced weight loss. In ALL cells made resistant to Ara-C, F10 remained highly active in vitro and in vivo. Using labeled F10, uptake by the ALL cell lines DG75 and SUP-B15 was rapid and profoundly temperature-dependent. Both cell lines demonstrated increased uptake compared to normal murine lineage- depleted marrow cells. Consistent with this decreased uptake, F10 treatment did not alter the ability of human hematopoietic stem cells to engraft in immunodeficient mice.

  4. The poison oligonucleotide F10 is highly effective against acute lymphoblastic leukemia while sparing normal hematopoietic cells

    PubMed Central

    Pardee, Timothy S.; Stadelman, Kristin; Jennings-Gee, Jamie; Caudell, David L.; Gmeiner, William H.

    2014-01-01

    F10 is an oligonucleotide based on the thymidylate synthase (TS) inhibitory 5-fluorouracil (5-FU) metabolite, 5-fluoro-2'-deoxyuridine-5'-O-monophosphate. We sought to determine the activity of F10 against preclinical models of acute lymphoblastic leukemia (ALL). F10 treatment resulted in robust induction of apoptosis that could not be equaled by 100 fold more 5-FU. F10 was more potent than Ara-C and doxorubicin against a panel of murine and human ALL cells with an average IC50 value of 1.48 nM (range 0.07 to 5.4 nM). F10 was more than 1000 times more potent than 5-FU. In vivo, F10 treatment significantly increased survival in 2 separate syngeneic ALL mouse models and 3 separate xenograft models. F10 also protected mice from leukemia-induced weight loss. In ALL cells made resistant to Ara-C, F10 remained highly active in vitro and in vivo. Using labeled F10, uptake by the ALL cell lines DG75 and SUP-B15 was rapid and profoundly temperature-dependent. Both cell lines demonstrated increased uptake compared to normal murine lineage- depleted marrow cells. Consistent with this decreased uptake, F10 treatment did not alter the ability of human hematopoietic stem cells to engraft in immunodeficient mice. PMID:24961587

  5. Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia

    PubMed Central

    Wang, Qian; Qiu, Huiying; Jiang, Hui; Wu, Lili; Dong, Shasha; Pan, Jinlan; Wang, Wenjuan; Ping, Nana; Xia, Jing; Sun, Aining; Wu, Depei; Xue, Yongquan; Drexler, Hans G.; MacLeod, Roderick A. F.; Chen, Suning

    2011-01-01

    Background Mutations in the PHF6 gene were recently described in patients with T-cell acute lymphoblastic leukemia and in those with acute myeloid leukemia. The present study was designed to determine the prevalence of PHF6 gene alterations in T-cell acute lymphoblastic leukemia. Design and Methods We analyzed the incidence and prognostic value of PHF6 mutations in 96 Chinese patients with T-cell acute lymphoblastic leukemia. PHF6 deletions were screened by real-time quantitative polymerase chain reaction and array-based comparative genomic hybridization. Patients were also investigated for NOTCH1, FBXW7, WT1, and JAK1 mutations together with CALM-AF10, SET-NUP214, and SIL-TAL1 gene rearrangements. Results PHF6 mutations were identified in 11/59 (18.6%) adult and 2/37 (5.4%) pediatric cases of T-cell acute lymphoblastic leukemia, these incidences being significantly lower than those recently reported. Although PHF6 is X-linked and mutations have been reported to occur almost exclusively in male patients, we found no sex difference in the incidences of PHF6 mutations in Chinese patients with T-cell acute lymphoblastic leukemia. PHF6 deletions were detected in 2/79 (2.5%) patients analyzed. NOTCH1 mutations, FBXW7 mutations, WT1 mutations, JAK1 mutations, SIL-TAL1 fusions, SET-NUP214 fusions and CALM-AF10 fusions were present in 44/96 (45.8%), 9/96 (9.4%), 4/96 (4.1%), 3/49 (6.1%), 9/48 (18.8%), 3/48 (6.3%) and 0/48 (0%) of patients, respectively. The molecular genetic markers most frequently associated with PHF6 mutations were NOTCH1 mutations (P=0.003), SET-NUP214 rearrangements (P=0.002), and JAK1 mutations (P=0.005). No differences in disease-free survival and overall survival between T-cell acute lymphoblastic leukemia patients with and without PHF6 mutations were observed in a short-term follow-up. Conclusions Overall, these results indicate that, in T-cell acute lymphoblastic leukemia, PHF6 mutations are a recurrent genetic abnormality associated with

  6. Genetics Home Reference: acute promyelocytic leukemia

    MedlinePlus

    ... acute myeloid leukemia, a cancer of the blood-forming tissue ( bone marrow ). In normal bone marrow, hematopoietic ... 7186-203. Review. Citation on PubMed de Thé H, Chen Z. Acute promyelocytic leukaemia: novel insights into ...

  7. Chimeric antigen receptor T-cell neuropsychiatric toxicity in acute lymphoblastic leukemia.

    PubMed

    Prudent, Vasthie; Breitbart, William S

    2017-01-04

    Chimeric antigen receptor T cells are used in the treatment of B-cell leukemias. Common chimeric antigen receptor T-cell toxicities can range from mild flu-like symptoms, such as fever and myalgia, to a more striking neuropsychiatric toxicity that can present as discrete neurological symptoms and delirium. We report here two cases of chimeric antigen receptor T-cell neuropsychiatric toxicity, one who presented as a mild delirium and aphasia that resolved without intervention, and one who presented with delirium, seizures, and respiratory insufficiency requiring intensive treatment. The current literature on the treatment and proposed mechanisms of this clinically challenging chimeric antigen receptor T-cell complication is also presented.

  8. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance

    PubMed Central

    Bonapace, Laura; Bornhauser, Beat C.; Schmitz, Maike; Cario, Gunnar; Ziegler, Urs; Niggli, Felix K.; Schäfer, Beat W.; Schrappe, Martin; Stanulla, Martin; Bourquin, Jean-Pierre

    2010-01-01

    In vivo resistance to first-line chemotherapy, including to glucocorticoids, is a strong predictor of poor outcome in children with acute lymphoblastic leukemia (ALL). Modulation of cell death regulators represents an attractive strategy for subverting such drug resistance. Here we report complete resensitization of multidrug-resistant childhood ALL cells to glucocorticoids and other cytotoxic agents with subcytotoxic concentrations of obatoclax, a putative antagonist of BCL-2 family members. The reversal of glucocorticoid resistance occurred through rapid activation of autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis. This effect was associated with dissociation of the autophagy inducer beclin-1 from the antiapoptotic BCL-2 family member myeloid cell leukemia sequence 1 (MCL-1) and with a marked decrease in mammalian target of rapamycin (mTOR) activity. Consistent with a protective role for mTOR in glucocorticoid resistance in childhood ALL, combination of rapamycin with the glucocorticoid dexamethasone triggered autophagy-dependent cell death, with characteristic features of necroptosis. Execution of cell death, but not induction of autophagy, was strictly dependent on expression of receptor-interacting protein (RIP-1) kinase and cylindromatosis (turban tumor syndrome) (CYLD), two key regulators of necroptosis. Accordingly, both inhibition of RIP-1 and interference with CYLD restored glucocorticoid resistance completely. Together with evidence for a chemosensitizing activity of obatoclax in vivo, our data provide a compelling rationale for clinical translation of this pharmacological approach into treatments for patients with refractory ALL. PMID:20200450

  9. Immunophenotypic, cytogenetic, and mutational characterization of cell lines derived from myelodysplastic syndrome patients after progression to acute myeloid leukemia.

    PubMed

    Palau, Anna; Mallo, Mar; Palomo, Laura; Rodríguez-Hernández, Ines; Diesch, Jeannine; Campos, Diana; Granada, Isabel; Juncà, Jordi; Drexler, Hans G; Solé, Francesc; Buschbeck, Marcus

    2017-03-01

    Leukemia cell lines have been widely used in the hematology field to unravel mechanistic insights and to test new therapeutic strategies. Myelodysplastic syndromes (MDS) comprise a heterogeneous group of diseases that are characterized by ineffective hematopoiesis and frequent progress to acute myeloid leukemia (AML). A few cell lines have been established from MDS patients after progression to AML but their characterization is incomplete. Here we provide a detailed description of the immunophenotypic profile of the MDS-derived cell lines SKK-1, SKM-1, F-36P; and MOLM-13. Specifically, we analyzed a comprehensive panel of markers that are currently applied in the diagnostic routine for myeloid disorders. To provide high-resolution genetic data comprising copy number alterations and losses of heterozygosity we performed whole genome single nucleotide polymorphism-based arrays and included the cell line OHN-GM that harbors the frequent chromosome arm 5q deletion. Furthermore, we assessed the mutational status of 83 disease-relevant genes. Our results provide a resource to the MDS and AML field that allows researchers to choose the best-matching cell line for their functional studies. © 2016 Wiley Periodicals, Inc.

  10. Asparaginase in acute lymphoblastic leukemia.

    PubMed

    Kawedia, Jitesh D; Rytting, Michael E

    2014-09-01

    Cure rates in pediatric acute lymphoblastic leukemia have significantly improved over the past decades. Now, almost 90% of children will survive the disease. The cure rates in adolescents, young adults, and adults have not kept pace with the improvements in younger patients, even though almost an equal proportion of adult patients achieve complete remission as their pediatric counterparts. Differences in treatment regimens might be important. Intensive use of asparaginase has been a key component of successful pediatric therapy. In this review, we focus on the use of asparaginase and the potential of optimizing asparaginase use via monitoring to minimize adverse drug events and improve efficacy of the drug.

  11. Expression of CD133 in acute leukemia.

    PubMed

    Tolba, Fetnat M; Foda, Mona E; Kamal, Howyda M; Elshabrawy, Deena A

    2013-06-01

    There have been conflicting results regarding a correlation between CD133 expression and disease outcome. To assess CD133 expression in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and to evaluate its correlation with the different clinical and laboratory data as well as its relation to disease outcome, the present study included 60 newly diagnosed acute leukemic patients; 30 ALL patients with a male to female ratio of 1.5:1 and their ages ranged from 9 months to 48 years, and 30 AML patients with a male to female ratio of 1:1 and their ages ranged from 17 to 66 years. Flow cytometric assessment of CD133 expression was performed on blast cells. In ALL, no correlations were elicited between CD133 expression and some monoclonal antibodies, but in AML group, there was a significant positive correlation between CD133 and HLA-DR, CD3, CD7 and TDT, CD13 and CD34. In ALL group, patients with negative CD133 expression achieved complete remission more than patients with positive CD133 expression. In AML group, there was no statistically significant association found between positive CD133 expression and treatment outcome. The Kaplan-Meier curve illustrated a high significant negative correlation between CD133 expression and the overall survival of the AML patients. CD133 expression is an independent prognostic factor in acute leukemia, especially ALL patients and its expression could characterize a group of acute leukemic patients with higher resistance to standard chemotherapy and relapse. CD133 expression was highly associated with poor prognosis in acute leukemic patients.

  12. Heparin-binding epidermal growth factor-like growth factor/diphtheria toxin receptor expression by acute myeloid leukemia cells.

    PubMed

    Vinante, F; Rigo, A; Papini, E; Cassatella, M A; Pizzolo, G

    1999-03-01

    Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member expressed by numerous cell types that binds to EGF receptor 1 (HER-1) or 4 (HER-4) inducing mitogenic and/or chemotactic activities. Membrane-bound HB-EGF retains growth activity and adhesion capabilities and the unique property of being the receptor for diphtheria toxin (DT). The interest in studying HB-EGF in acute leukemia stems from these mitogenic, chemotactic, and receptor functions. We analyzed the expression of HB-EGF in L428, Raji, Jurkat, Karpas 299, L540, 2C8, HL-60, U937, THP-1, ML-3, and K562 cell lines and in primary blasts from 12 acute myeloid leukemia (AML) cases, by reverse-transcriptase polymerase chain reaction (RT-PCR) and Northern blot and by the evaluation of sensitivity to DT. The release of functional HB-EGF was assessed by evaluation of its proliferative effects on the HB-EGF-sensitive Balb/c 3T3 cell line. HB-EGF was expressed by all myeloid and T, but not B (L428, Raji), lymphoid cell lines tested, as well as by the majority (8 of 12) of ex vivo AML blasts. Cell lines (except for the K562 cell line) and AML blasts expressing HB-EGF mRNA underwent apoptotic death following exposure to DT, thus demonstrating the presence of the HB-EGF molecule on their membrane. Leukemic cells also released a fully functional HB-EGF molecule that was mitogenic for the Balb/c 3T3 cell line. Factors relevant to the biology of leukemic growth, such as tumor necrosis factor-alpha (TNF-alpha), 1alpha,25-(OH)2D3, and especially all-trans retinoic acid (ATRA), upregulated HB-EGF mRNA in HL-60 or ML-3 cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced HB-EGF mRNA and acquisition of sensitivity to DT in one previously HB-EGF-negative leukemia case. Moreover, the U937 and Karpas 299 cell lines expressed HER-4 mRNA. This work shows that HB-EGF is a growth factor produced by primary leukemic cells and regulated by ATRA, 1alpha, 25-(OH)2D3, and GM-CSF.

  13. Dnmt3a haploinsufficiency cooperates with oncogenic Kras to promote an early-onset T-cell acute lymphoblastic leukemia

    PubMed Central

    Chang, Yuan-I; Kong, Guangyao; Ranheim, Erik A; Tu, Po-Shu; Yu, Yi-Shan; Zhang, Jing

    2017-01-01

    Mutations in DNA methyltransferase 3A (DNMT3A) are prevalent in various myeloid and lymphoid malignancies. The most common DNMT3A R882 mutations inhibit methyltransferase activity of the remaining wild-type DNMT3A proteins at a heterozygous state due to their dominant-negative activity. Reports and COSMIC database analysis reveal significantly different frequencies of R882 mutations in myeloid versus T-cell malignancies, inspiring us to investigate whether downregulation of DNMT3A regulates malignancies of different lineages in a dose-dependent manner. In a competitive transplant setting, the survival of recipients with KrasG12D/+; Dnmt3a+/- bone marrow (BM) cells was significantly shortened than that of recipients with KrasG12D/+ cells. Moreover, all of the recipients with KrasG12D/+; Dnmt3a+/- cells developed a lethal T-cell acute lymphoblastic leukemia (T-ALL) without significant myeloproliferative neoplasm (MPN) phenotypes, while ~20% of recipients with KrasG12D/+ cells developed MPN with or without T-ALL. This is in sharp contrast to the recipients with KrasG12D/+; Dnmt3a-/- cells, in which ~60% developed a lethal myeloid malignancy (MPN or acute myeloid leukemia [AML]). Our data suggest that in the context of oncogenic Kras, loss of Dnmt3a promotes myeloid malignancies, while Dnmt3a haploinsufficiency induces T-ALL. This dose-dependent phenotype is highly consistent with the prevalence of DNMT3A R882 mutations in AML versus T-ALL in human. PMID:28386358

  14. Burkitt-Type Acute Lymphoblastic Leukemia With Precursor B-Cell Immunophenotype and Partial Tetrasomy of 1q

    PubMed Central

    Sato, Yuya; Kurosawa, Hidemitsu; Fukushima, Keitaro; Okuya, Mayuko; Arisaka, Osamu

    2016-01-01

    Abstract Burkitt-type acute lymphoblastic leukemia (B-ALL) is thought as a variant of Burkitt lymphoma/leukemia and derived from mature B-cell lymphoblast. B-ALL was developed in a 10-year-old girl. Two characteristics were apparent in this case. First, the lymphoblastic cells were positive for CD10, CD19, CD20, and CD22, but negative for terminal deoxynucleotidyl transferase and surface immunoglobulins, indicating a B-cell immunophenotype. The detection of t(8;14)(q24;q32) with a chromosomal analysis is required for a diagnosis of B-ALL. Second, der(1)(pter → q32.1::q32.1 → q21.1::q11 → qter) was detected, in which 1q21.1 to 1q32.1 was inverted and inserted. Finally, partial tetrasomy of 1q was also present. Because B-ALL with abnormal chromosome 1 has been reported poor outcome, the usual chemotherapy for stage 4 Burkitt lymphoma with added rituximab was administered for our patient. We report B-ALL with precursor B-cell immunophenotype and interesting partial tetrasomy of 1q. PMID:26962787

  15. RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis.

    PubMed

    Löder, S; Fakler, M; Schoeneberger, H; Cristofanon, S; Leibacher, J; Vanlangenakker, N; Bertrand, M J M; Vandenabeele, P; Jeremias, I; Debatin, K-M; Fulda, S

    2012-05-01

    Evasion of apoptosis may contribute to poor treatment response in pediatric acute lymphoblastic leukemia (ALL), calling for novel treatment strategies. Here, we report that inhibitors of apoptosis (IAPs) at subtoxic concentrations cooperate with various anticancer drugs (that is, AraC, Gemcitabine, Cyclophosphamide, Doxorubicin, Etoposide, Vincristine and Taxol) to induce apoptosis in ALL cells in a synergistic manner as calculated by combination index and to reduce long-term clonogenic survival. Importantly, we identify RIP1 as a critical regulator of this synergism of IAP inhibitors and AraC that mediates the formation of a RIP1/FADD/caspase-8 complex via an autocrine/paracrine loop of tumor necrosis factor-α (TNFα). Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3, mitochondrial perturbations and apoptosis. Similarly, inhibition of RIP1 kinase activity by Necrostatin-1 or blockage of TNFα by Enbrel inhibits IAP inhibitor- and AraC-triggered interaction of RIP1, FADD and caspase-8 and apoptosis. In contrast to malignant cells, IAP inhibitors and AraC at equimolar concentrations are non-toxic to normal peripheral blood lymphocytes or mesenchymal stromal cells. Thus, our findings provide first evidence that IAP inhibitors present a promising strategy to prime childhood ALL cells for chemotherapy-induced apoptosis in a RIP1-dependent manner. These data have important implications for developing apoptosis-targeted therapies in childhood leukemia.

  16. Total Body Irradiation without Chemotherapy as Conditioning for an Allogeneic Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia

    PubMed Central

    Altouri, Sultan; Allan, David; Atkins, Harry; Huebsch, Lothar; Maze, Dawn; Samant, Rajiv; Bredeson, Christopher

    2016-01-01

    Current therapies for acute myeloid leukemia (AML), failing induction, are rarely effective. We report our experience in 4 patients with AML who received 16 Gy TBI prior to allogeneic hematopoietic cell transplantation (alloHCT), between June 2010 and May 2011. Patients were 20 to 55 years of age, 2 with relapsed disease and 2 with AML failing induction. An HLA-matched graft from related or unrelated donor was infused on day 0. All but one, who received a CD34+-selected graft, received methotrexate and tacrolimus +/− antithymocyte globulin, as GVHD prophylaxis. The other patient received tacrolimus alone. Neutrophil and platelet engraftment occurred at a median of 18 and 14 days, respectively. Patients were discharged at a median of 28 days. There were no unexpected toxicities in the first 30 days. One patient had cytomegalovirus (CMV) viremia and anorexia, at two months. One patient had grade 2 acute GVHD of the skin. One patient developed chronic GVHD of the eyes, mouth, skin, joints, and lung at 4 months. Two patients died from relapse of their leukemia at days 65 and 125. Two patients remain in remission beyond day 1500. 16 Gy TBI followed by an alloHCT for AML, failing induction, is feasible and tolerable. PMID:27957357

  17. Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients.

    PubMed

    Hamaki, T; Kami, M; Kanda, Y; Yuji, K; Inamoto, Y; Kishi, Y; Nakai, K; Nakayama, I; Murashige, N; Abe, Y; Ueda, Y; Hino, M; Inoue, T; Ago, H; Hidaka, M; Hayashi, T; Yamane, T; Uoshima, N; Miyakoshi, S; Taniguchi, S

    2005-03-01

    Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.

  18. Bortezomib interferes with adhesion of B cell precursor acute lymphoblastic leukemia cells through SPARC up-regulation in human bone marrow mesenchymal stromal/stem cells.

    PubMed

    Iwasa, Masaki; Miura, Yasuo; Fujishiro, Aya; Fujii, Sumie; Sugino, Noriko; Yoshioka, Satoshi; Yokota, Asumi; Hishita, Terutoshi; Hirai, Hideyo; Andoh, Akira; Ichinohe, Tatsuo; Maekawa, Taira

    2017-01-02

    The poor prognosis of adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL) is attributed to leukemia cells that are protected by the bone marrow (BM) microenvironment. In the present study, we explored the pharmacological targeting of mesenchymal stromal/stem cells in BM (BM-MSCs) to eliminate chemoresistant BCP-ALL cells. Human BCP-ALL cells (NALM-6 cells) that adhered to human BM-MSCs (NALM-6/Ad) were highly resistant to multiple anti-cancer drugs, and exhibited pro-survival characteristics, such as an enhanced Akt/Bcl-2 pathway and increased populations in the G0 and G2/S/M cell cycle stages. Bortezomib, a proteasome inhibitor, interfered with adhesion between BM-MSCs and NALM-6 cells and up-regulated the matricellular protein SPARC (secreted protein acidic and rich in cysteine) in BM-MSCs, thereby reducing the NALM-6/Ad population. Inhibition of SPARC expression in BM-MSCs using a small interfering RNA enhanced adhesion of NALM-6 cells. Conversely, recombinant SPARC protein interfered with adhesion of NALM-6 cells. These results suggest that SPARC disrupts adhesion between BM-MSCs and NALM-6 cells. Co-treatment with bortezomib and doxorubicin prolonged the survival of BCP-ALL xenograft mice, with a significant reduction of leukemia cells in BM. Our findings demonstrate that bortezomib contributes to the elimination of BCP-ALL cells through disruption of their adhesion to BM-MSCs, and offer a novel therapeutic strategy for BCP-ALL through targeting of BM-MSCs.

  19. Evaluation of the miRNA profiling and effectiveness of the propolis on B-cell acute lymphoblastic leukemia cell line.

    PubMed

    Yilmaz, Ugur Cem; Bagca, Bakiye Goker; Karaca, Emin; Durmaz, Asude; Durmaz, Burak; Aykut, Ayca; Kayalar, Husniye; Avci, Cigir Biray; Susluer, Sunde Yilmaz; Gunduz, Cumhur; Cogulu, Ozgur

    2016-12-01

    Acute lymphoblastic leukemia (ALL) is one of the most frequent causes of death from cancer. Since the discovery of chemotherapeutic agents, ALL has become a model for improvement of survival. In parallel to this, serious side effects were observed and new natural therapeutic options has been discussed. One of these substances is called propolis which is a resinous substance gathered by honeybees. In the molecular era, miRNAs have been shown to play crucial roles in the development of many clinical conditions. The aim of this study is to evaluate the effect of Aydın propolis on 81 human miRNA activity in CCRF-SB leukemia cell line. Apoptotic effects of propolis on cell lines were also evaluated and apoptosis were found to be induced 1.5 fold in B-cell leukemia cells. The expression of 63 miRNAs (46 miRNAs were downregulated, 19 miRNAs were upregulated) in propolis treated leukemia cells have changed significantly (p<0.05). In conclusion propolis has changed expression of miRNAs which have epigenetic effects on leukemic cells. It is thought that it can be a promising agent for ALL treatment for future studies.

  20. What's New in Adult Acute Myeloid Leukemia Research and Treatment?

    MedlinePlus

    ... Leukemia (AML) About Acute Myeloid Leukemia (AML) What’s New in Acute Myeloid Leukemia Research and Treatment? Researchers ... benefit from current treatments. Researchers are studying many new chemo drugs for use in AML, including: Sapacitabine, ...

  1. Busulfan and melphalan as conditioning regimen for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission

    PubMed Central

    Bueno, Nadjanara Dorna; Dulley, Frederico Luiz; Saboya, Rosaura; Amigo Filho, José Ulysses; Coracin, Fabio Luiz; Chamone, Dalton de Alencar Fischer

    2011-01-01

    Background Allogeneic hematopoietic stem cell transplantation with HLA-identical donors has been established for the treatment of acute myeloid leukemia patients for over 30 years with a cure rate of 50% to 60%. Objectives To analyze the overall survival of patients and identify factors that influence the outcomes of this type of transplant in patients in 1st complete remission who received a busulfan and melphalan combination as conditioning regimen. Methods Twenty-five consecutive patients with acute myeloid leukemia were enrolled between 2003 and 2008. The median age was 34 years old (Range: 16 - 57 years). All patients received cyclosporine and methotrexate for prophylaxis against graft-versus-host disease. Median neutrophil engraftment time was 16 days (Range: 7 - 22 days) and 17 days (Range: 7 - 46 days) for platelets. Sinusoidal obstructive syndrome was observed in three patients, seven had grade II acute graft-versus-host disease and one extensive chronic graft-versus-host disease. Results The overall survival by the Kaplan-Meier method was 48% after 36 months with a plateau at 36 months after transplantation. Intensive consolidation with high-dose arabinoside resulted in an improved survival (p-value = 0.0001), as did grade II acute graft-versus-host disease (p-value = 0.0377) and mild chronic graft-versus-host disease (p-value < 0.0001). Thirteen patients died, five due to infection within 100 days of transplant, two due to hemorrhages, one to infection and graftversus-host disease and three relapses followed by renal failure (one) and infection (two). The cause of death could not be determined for two patients. Conclusion The busulfan and melphalan conditioning regimen is as good as other conditioning regimens providing an excellent survival rate. PMID:23049292

  2. Blood group change in acute myeloid leukemia

    PubMed Central

    Nambiar, Rakul K.; Prakash, N. P.; Vijayalakshmi, K.

    2017-01-01

    Blood group antigens are either sugars or proteins found attached to the red blood cell membrane. ABO blood group antigens are the most clinically important antigens because they are the most immunogenic. As red blood cell antigens are inherited traits, they are usually not altered throughout the life of an individual. There have been occasional case reports of ABO blood group antigen change in malignant conditions. We report two such cases of ABO antigen alteration associated with acute myeloid leukemia. These patients had suppression of their blood group antigens during their leukemic phase, and the antigens were reexpressed when the patients attained remission. PMID:28127141

  3. Serum metabonomics of acute leukemia using nuclear magnetic resonance spectroscopy

    PubMed Central

    Musharraf, Syed Ghulam; Siddiqui, Amna Jabbar; Shamsi, Tahir; Choudhary, M. Iqbal; Rahman, Atta-ur

    2016-01-01

    Acute leukemia is a critical neoplasm of white blood cells. In order to differentiate between the metabolic alterations associated with two subtypes of acute leukemia, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), we investigated the serum of ALL and AML patients and compared with two controls (healthy and aplastic anemia) using 1H NMR (nuclear magnetic resonance) spectroscopy. Thirty-seven putative metabolites were identified using Carr-Purcell-Meiboom-Gill (CPMG) sequence. The use of PLS-DA and OPLS-DA models gave results with 84.38% and 90.63% classification rate, respectively. The metabolites responsible for classification are mainly lipids, lactate and glucose. Compared with controls, ALL and AML patients showed serum metabonomic differences involving aberrant metabolism pathways including glycolysis, TCA cycle, lipoprotein changes, choline and fatty acid metabolisms. PMID:27480133

  4. Sleeping Beauty transposon screen identifies signaling modules that cooperate with STAT5 activation to induce B cell acute lymphoblastic leukemia

    PubMed Central

    Heltemes-Harris, Lynn M.; Larson, Jon D.; Starr, Timothy K.; Hubbard, Gregory K.; Sarver, Aaron L.; Largaespada, David A.; Farrar, Michael A.

    2015-01-01

    STAT5 activation occurs frequently in human progenitor B cell acute lymphoblastic leukemia (B-ALL). To identify gene alterations that cooperate with STAT5 activation to initiate leukemia we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) to mice in which a mutagenic Sleeping Beauty transposon (T2/Onc) was mobilized only in B cells. Stat5b-CA mice typically do not develop B-ALL (<2% penetrance); in contrast, 89% of Stat5b–CA mice in which the T2/Onc transposon had been mobilized died of B-ALL by 3 months of age. High-throughput sequencing approaches were used to identify genes frequently targeted by the T2/Onc transposon; these included Sos1 (74%), Kdm2a (35%), Jak1 (26%), Bmi1 (19%), Prdm14 or Ncoa2 (13%), Cdkn2a (10%), Ikzf1 (8%), Caap1 (6%) and Klf3 (6%). Collectively, these mutations target three major cellular processes: (i) the JAK/STAT5 pathway (ii) progenitor B cell differentiation and (iii) the CDKN2A tumor suppressor pathway. Transposon insertions typically resulted in altered expression of these genes, as well as downstream pathways including STAT5, ERK and p38. Importantly, expression of Sos1 and Kdm2a, and activation of p38, correlated with survival, further underscoring the role these genes and associated pathways play in B-ALL. PMID:26500062

  5. Piperlongumine inhibits the proliferation and survival of B-cell acute lymphoblastic leukemia cell lines irrespective of glucocorticoid resistance

    SciTech Connect

    Han, Seong-Su; Han, Sangwoo; Kamberos, Natalie L.

    2014-09-26

    Highlights: • PL inhibits the proliferation of B-ALL cell lines irrespective of GC-resistance. • PL selectively kills B-ALL cells by increasing ROS, but not normal counterpart. • PL does not sensitize majority of B-ALL cells to DEX. • PL represses the network of constitutively activated TFs and modulates their target genes. • PL may serve as a new therapeutic molecule for GC-resistant B-ALL. - Abstract: Piperlongumine (PL), a pepper plant alkaloid from Piper longum, has anti-inflammatory and anti-cancer properties. PL selectively kills both solid and hematologic cancer cells, but not normal counterparts. Here we evaluated the effect of PL on the proliferation and survival of B-cell acute lymphoblastic leukemia (B-ALL), including glucocorticoid (GC)-resistant B-ALL. Regardless of GC-resistance, PL inhibited the proliferation of all B-ALL cell lines, but not normal B cells, in a dose- and time-dependent manner and induced apoptosis via elevation of ROS. Interestingly, PL did not sensitize most of B-ALL cell lines to dexamethasone (DEX). Only UoC-B1 exhibited a weak synergistic effect between PL and DEX. All B-ALL cell lines tested exhibited constitutive activation of multiple transcription factors (TFs), including AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6 and YY1. Treatment of the B-ALL cells with PL significantly downregulated these TFs and modulated their target genes. While activation of AURKB, BIRC5, E2F1, and MYB mRNA levels were significantly downregulated by PL, but SOX4 and XBP levels were increased by PL. Intriguingly, PL also increased the expression of p21 in B-ALL cells through a p53-independent mechanism. Given that these TFs and their target genes play critical roles in a variety of hematological malignancies, our findings provide a strong preclinical rationale for considering PL as a new therapeutic agent for the treatment of B-cell malignancies, including B-ALL and GC-resistant B-ALL.

  6. Zoledronic acid exerts antitumor effects in NB4 acute promyelocytic leukemia cells by inducing apoptosis and S phase arrest.

    PubMed

    Liu, Shou-Sheng; Wang, Xiao-Pai; Li, Xiu-Bo; Liang, Jia-Yi; Liu, Ling-Ling; Lu, Ying; Zhong, Xue-Yun; Chen, Yun-Xian

    2014-10-01

    The aim of this study was to investigate the antitumor effect of zoledronic acid (ZOL) in the NB4 human acute promyelocytic leukemia (APL) cell line and explore the potential mechanism of action of this compound. NB4 cells were exposed to various concentrations (0-200μM) of ZOL. Cell viability was measured by MTS assay. The extent of cell apoptosis and distribution of cells in the different phases of the cell cycle were analyzed with flow cytometry. The expression of apoptosis- and cell cycle-related proteins was assayed by Western blot. The combined effect of ZOL and arsenic trioxide (ATO) on the proliferation of NB4 cells was also determined. The results of this study indicate that ZOL inhibits cell proliferation in a time- and dose-dependent fashion and also induces apoptosis and S phase arrest in a dose-dependent manner. The Western blot analysis confirmed the induction of apoptosis and S phase arrest, revealing that the pro-apoptosis proteins Bax, Puma and activated caspase-9 were upregulated and the anti-apoptosis proteins Bcl-2 and Bcl-xL were downregulated. ZOL at a concentration of 50μM synergized with 0.5μM ATO on the growth inhibition of NB4 cells. Taken together, our data indicate that ZOL exerts a potent antitumor effect on NB4 cells by inducing apoptosis and cell cycle arrest, and that ZOL can synergize with the traditional chemotherapy drug ATO.

  7. miRNA-149* promotes cell proliferation and suppresses apoptosis by mediating JunB in T-cell acute lymphoblastic leukemia.

    PubMed

    Fan, Sheng-Jin; Li, Hui-Bo; Cui, Gang; Kong, Xiao-Lin; Sun, Li-Li; Zhao, Yan-Qiu; Li, Ying-Hua; Zhou, Jin

    2016-02-01

    MicroRNA-149* (miRNA-149*) functions as an oncogenic regulator in human melanoma. However, the effect of miRNA-149* on T-cell acute lymphoblastic leukemia (T-ALL) is unclear. Here we aimed to analyze the effects of miRNA-149* on in vitro T-ALL cells and to uncover the target for miRNA-149* in these cells. The miRNA-149* level was determined in multiple cell lines and bone marrow cells derived from patients with T-ALL, B acute lymphoblastic leukemia (B-ALL), acute myelocytic leukemia (AML), and healthy donors. We found that miRNA-149* was highly expressed in T-ALL cell lines and T-ALL patients' bone marrow samples. JunB was identified as a direct target of miR-149*. miRNA-149* mimics downregulated JunB levels in Molt-4 and Jurkat cells, while miRNA-149* inhibitors dramatically upregulated JunB expression in these cells. miRNA-149* mimics promoted proliferation, decreased the proportion of cells in G1 phase, and reduced cell apoptosis in T-ALL cells, while miRNA-149* inhibitors prevented these effects. miRNA-149* mimics downregulated p21 and upregulated cyclinD1, 4EBP1, and p70s6k in Molt-4 and Jurkat cells. Again, inhibitors prevented these effects. Our findings demonstrate that miRNA-149* may serve as an oncogenic regulator in T-ALL by negatively regulating JunB.

  8. Resveratrol given intraperitoneally does not inhibit growth of high-risk t(4;11) acute lymphoblastic leukemia cells in NOD/SCID mouse model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The efficacy of the phytochemical resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL line SEM. SEM cells were injected into the tail vein and engraftment was monitored by ...

  9. The impact of molecularly targeted therapies upon the understanding of leukemogenesis and the role of hematopoietic stem cell transplantation in acute promyelocytic leukemia.

    PubMed

    Nagai, Sumimasa; Takahashi, Tsuyoshi; Kurokawa, Mineo

    2010-12-01

    Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia. An abnormal fusion gene, PML/RARA is detected in approximately 98% of patients with APL. PML/RARA confers long-term self-renewal properties to promyelocytes. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which are the major molecularly targeted therapies in APL, affect the PML/RARA fusion protein and cause differentiation and apoptosis of APL cells. Although the leukemia-initiating cells of APL may be present in a myeloid progenitor committed compartment, the precise population of those remains to be elucidated. However, recent studies have demonstrated the effect of ATRA and ATO on APL leukemia-initiating cells. Through these studies, we can understand more deeply how current clinical therapies lead to long-lasting remission of APL. ATRA and ATO have improved the prognosis of APL patients and have changed the role of hematopoietic stem cell transplantation (HSCT). At present, HSCT is not indicated for patients with APL in first complete remission, and considered for patients with relapsed APL. In this review, we discuss the three main topics as follows: the leukemia-initiating cells in APL, the current state-of-the-art treatment for newly diagnosed and relapsed APL, and the role of HSCT in APL patients.

  10. Prognostic Limitations of Donor T Cell Chimerism after Myeloablative Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    PubMed

    Wong, Eric; Mason, Kate; Collins, Jenny; Hockridge, Barbara; Boyd, Janis; Gorelik, Alexandra; Szer, Jeffrey; Ritchie, David S

    2017-02-06

    Donor T cell chimerism is associated with relapse outcomes after allogeneic stem cell transplantation (alloSCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, measures of statistical association do not adequately assess the performance of a prognostic biomarker, which is best characterized by its sensitivity and specificity for the chosen outcome. We analyzed donor T cell chimerism results at day 100 (D100chim) after myeloablative alloSCT for AML or MDS in 103 patients and determined its sensitivity and specificity for relapse-free survival at 6 months (RFS6) and 12 months (RFS12) post-alloSCT. The area under the receiver operating characteristic curve for RFS6 was .68, demonstrating only modest utility as a predictive biomarker, although this was greater than RFS12 at .62. Using a D100chim threshold of 65%, the specificity for RFS6 was 96.6%; however, sensitivity was poor at 26.7%. This equated to a negative predictive value of 88.5% and positive predictive value of 57.1%. Changing the threshold for D100chim to 75% or 85% modestly improved the sensitivity of D100chim for RFS6; however, this was at the expense of specificity. D100chim is specific but lacks sensitivity as a prognostic biomarker of early RFS after myeloablative alloSCT for AML or MDS. Caution is required when using D100chim to guide treatment decisions including immunologic manipulation, which may expose patients to unwarranted graft-versus-host disease.

  11. Veliparib and Temozolomide in Treating Patients With Acute Leukemia

    ClinicalTrials.gov

    2017-01-31

    Accelerated Phase of Disease; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Promyelocytic Leukemia With PML-RARA; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Adult T Acute Lymphoblastic Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; Chronic Myelomonocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  12. Homing of cytokine-induced killer cells during the treatment of acute promyelocytic leukemia.

    PubMed

    Wang, Hong; Cao, Fenglin; Li, Jinmei; Li, Yong; Liu, Xiuhua; Wang, Lifan; Liu, Zhiyu; Li, Yang; Zhao, Hui; Zhou, Jin

    2014-08-01

    Cytokine-induced killer (CIK) cells have been shown to be an effective immunotherapy for malignancies. However, their clinical application has been limited due to lack of knowledge on their in vivo kinesis. In this study, we explored their biodistribution by labeling CIK cells with (18)F-FDG and tracking their in vivo migration by PET/CT imaging. In the nine refractory APL patients enrolled in this study, pre-treatment PET/CT scans revealed leukemia burdens in vertebrae, and the bones of the pelvis and limbs. Post-treatment serial PET/CT tracked the localization of CIK cells over time: at 1 h, the majority of these cells accumulated diffusely in the lungs, while the first minor cell activities were observed in brain, liver and spleen; at 4 and 8 h, they not only migrated to the heart, spleen, and liver, but also showed tendencies to accumulate in bone marrow and brain. This specific cell migration route suggested that CIK cells show in vivo functional kinesis and potency as a targeted immunotherapy. The clinical outcome of this small cohort of nine patients supported the efficacy of this regimen: two patients achieved rapid complete remission after three-cycle treatment, and six patients remained stable, subsequently became sensitive to conventional therapy, and also achieved complete remission.

  13. Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation.

    PubMed

    Tao, Yan-Fang; Li, Zhi-Heng; Du, Wei-Wei; Xu, Li-Xiao; Ren, Jun-Li; Li, Xiao-Lu; Fang, Fang; Xie, Yi; Li, Mei; Qian, Guang-Hui; Li, Yan-Hong; Li, Yi-Ping; Li, Gang; Wu, Yi; Feng, Xing; Wang, Jian; He, Wei-Qi; Hu, Shao-Yan; Lu, Jun; Pan, Jian

    2017-03-01

    Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy‑inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis. Cleaved LC3 (LC3-II) and the phosphorylation of mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase, and Unc-51-like kinase 1 during autophagy was detected with western blotting. Autophagosomes were detected using transmission electron microscopy. Several inhibitors had promising autophagy inducer effects: BI2536, MLN0905, SK1-I, SBE13 HCL and RO3280. Moreover, these inhibitors all targeted PLK1. Autophagy activity was increased in the NB4 cells treated with RO3280 and BI2536. Inhibition of PLK1 expression in NB4, K562 and HL-60 leukemia cells with RNA interference increased LC3-II and autophagy activity. The phosphorylation of mTOR was reduced significantly in NB4 cells treated with RO3280 and BI2536, and was also reduced significantly when PLK1 expression was downregulated in the NB4, K562 and HL-60 cells. We demonstrate that PLK1 inhibition induces AML cell autophagy and that it results in mTOR dephosphorylation. These results may provide new insights into the molecular mechanism of PLK1 in regulating autophagy.

  14. Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

    PubMed Central

    Tao, Yan-Fang; Li, Zhi-Heng; Du, Wei-Wei; Xu, Li-Xiao; Ren, Jun-Li; Li, Xiao-Lu; Fang, Fang; Xie, Yi; Li, Mei; Qian, Guang-Hui; Li, Yan-Hong; Li, Yi-Ping; Li, Gang; Wu, Yi; Feng, Xing; Wang, Jian; He, Wei-Qi; Hu, Shao-Yan; Lu, Jun; Pan, Jian

    2017-01-01

    Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy-inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis. Cleaved LC3 (LC3-II) and the phosphorylation of mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase, and Unc-51-like kinase 1 during autophagy was detected with western blotting. Autophagosomes were detected using transmission electron microscopy. Several inhibitors had promising autophagy inducer effects: BI2536, MLN0905, SK1-I, SBE13 HCL and RO3280. Moreover, these inhibitors all targeted PLK1. Autophagy activity was increased in the NB4 cells treated with RO3280 and BI2536. Inhibition of PLK1 expression in NB4, K562 and HL-60 leukemia cells with RNA interference increased LC3-II and autophagy activity. The phosphorylation of mTOR was reduced significantly in NB4 cells treated with RO3280 and BI2536, and was also reduced significantly when PLK1 expression was downregulated in the NB4, K562 and HL-60 cells. We demonstrate that PLK1 inhibition induces AML cell autophagy and that it results in mTOR dephosphorylation. These results may provide new insights into the molecular mechanism of PLK1 in regulating autophagy. PMID:28184925

  15. Cytotoxic effects of tetracycline analogues (doxycycline, minocycline and COL-3) in acute myeloid leukemia HL-60 cells.

    PubMed

    Song, Hairong; Fares, Mona; Maguire, Kim R; Sidén, Ake; Potácová, Zuzana

    2014-01-01

    Tetracycline analogues (TCNAs) have been shown to inhibit matrix metalloproteinases and to induce apoptosis in several cancer cell types. In the present study, the cytotoxic effects of TCNAs doxycycline (DOXY), minocycline (MINO) and chemically modified tetracycline-3 (COL-3) were investigated in the human acute myeloid leukemia HL-60 cell line. Cells were incubated with TCNAs in final concentrations of 0.5-100 µg/ml for 24 h. Viability of the leukemic cells was inhibited in a concentration-dependent manner using resazurin assay. The estimated IC50s were 9.2 µg/ml for DOXY, 9.9 µg/ml for MINO and 1.3 µg/ml for COL-3. All three TCNAs induced potent cytotoxic effects and cell death. Apoptosis, which was assessed by morphological changes and annexin V positivity, was concentration- and time-dependent following incubation with any one of the drugs. TCNAs induced DNA double strand breaks soon after treatment commenced as detected by γH2AX and western blot. The loss of mitochondrial membrane potential (Δψm), caspase activation and cleavage of PARP and Bcl-2 were observed; however, the sequence of events differed among the drugs. Pancaspase inhibitor Z-VAD-FMK improved survival of TCNAs-treated cells and decreased TCNAs-induced apoptosis. In summary, we demonstrated that TCNAs had a cytotoxic effect on the HL-60 leukemic cell line. Apoptosis was induced via mitochondria-mediated and caspase-dependent pathways in HL-60 cells by all three TCNAs. COL-3 exerted the strongest anti-proliferative and pro-apoptotic effects in concentrations that have been achieved in human plasma in reported clinical trials. These results indicate that there is a therapeutic potential of TCNAs in leukemia.

  16. Development of myelodysplastic syndrome and acute myeloid leukemia 15 years after hydroxyurea use in a patient with sickle cell anemia.

    PubMed

    Baz, Walid; Najfeld, Vesna; Yotsuya, Matthew; Talwar, Jotica; Terjanian, Terenig; Forte, Frank

    2012-01-01

    We report a 41 year old male with sickle cell disease who developed a myelodysplastic syndrome and acute myeloid leukemia with complex karyotype involving chromosomes 5, 7 and 17 after 15 years of hydroxyurea treatment. He responded poorly to induction chemotherapy with cytarabine/idarubicin followed by high dose cytarabine and succumbed to neutropenic sepsis. Multiple systematic reviews, observational studies and clinical trials were conducted to identify the toxicity profile of hydroxurea. Only six cases of leukemia/myelodysplastic syndrome were identified in patients with sickle cell anemia treated with hydroxyurea. Subsequently, it was concluded that hydroxyurea is not leukemogenic. However, it was noted that most of the published studies had only up to 9 years of follow-up. Our patient was started on hydroxyurea in 1990, before the widespread use of the drug and took hydroxyurea for 15 years. His presentation may reflect an outcome otherwise not yet observed because of the short follow-up of prior studies. We believe that the leukemogenic risk of hydroxyurea should be discussed with the patients and their families. Studies evaluating the adverse effects of hydroxyurea should have longer follow-up before definitive conclusions are drawn.

  17. Chromosome abnormalities in acute lymphoblastic leukemia

    SciTech Connect

    Rowley, J.D.

    1980-01-01

    Less information is available on the cytogenetic abnormalities in marrow cells of patients with acute lymphoblastic leukemia (ALL) than on abnormalities in acute nonlymphocytic leukemia (ANLL); nonetheless, some patterns of karyotypic change in ALL are evident. Even with banding, about 50% of patients appear to have a normal karyotype. The modal chromosome number tends to be higher in ALL than in ANLL. Every patient with B-cell ALL has had an abnormality of one chromosome No. 14 that involved the translocation of material to the end of the long arm. Among seven reported cases, the translocation was from 8q in three patients and 11q in one. Cells with a haploid or near-haploid (24 to 35) chromosome number have been reported in five patients with ALL and in four patients in a lymphoid blast crisis of chronic myelogeneous leukemia. The karyotype in the four ALL patients whose cells were analyzed with banding was remarkably consistent. All patients had the haploid number, usually with both sex chromosomes, plus an additional No. 10, 18, and 21. Evolution of the karyotype, which occurs in the leukemic cells of about 50% of patients, involves cells of patients who had an initially normal or an initially abnormal karyotype. The evidence regarding a correlation between the presence of an abnormal clone prior to treatment and response to treatment is contradictory at present. Some chromosome abnormalities, such as the presence of a Philadelphia (Ph/sup 1/) chromosome, a 14q+chromosome, or a haploid clone, are associated with a relatively short survival.

  18. VSV-hIFNbeta-NIS in Treating Patients With Relapsed or Refractory Multiple Myeloma, Acute Myeloid Leukemia, or T-cell Lymphoma

    ClinicalTrials.gov

    2017-04-10

    Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Angioimmunoblastic T-cell Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides; Recurrent Plasma Cell Myeloma; Recurrent T-Cell Non-Hodgkin Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Angioimmunoblastic T-cell Lymphoma; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mycosis Fungoides; Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified; Refractory Plasma Cell Myeloma; Refractory T-Cell Non-Hodgkin Lymphoma

  19. Acute lymphoblastic leukemia in a pygmy hippopotamus (Hexaprotodon liberiensis).

    PubMed

    McCurdy, Paul; Sangster, Cheryl; Lindsay, Scott; Vogelnest, Larry

    2014-12-01

    A captive, 31-yr-old, intact male pygmy hippopotamus presented with nonspecific signs of weight loss, inappetence, diarrhea, and lethargy. After 5 wk of diagnostic investigation and symptomatic treatment, an acute leukemic process with concurrent polycystic kidney disease was suspected. The animal's condition continued to deteriorate prompting euthanasia. Necropsy, histopathologic, and immunohistochemical examination confirmed acute T-cell lymphoblastic leukemia and polycystic kidneys. Acute T-cell lymphoblastic leukemia has not previously been documented in this species; however, polycystic kidney disease has been reported. This case report adds to the increasing number of pygmy hippopotamuses diagnosed with polycystic kidney disease and describes acute T-cell lymphoblastic leukemia, a previously unreported disease of this species.

  20. CAR-pNK Cell Immunotherapy in CD7 Positive Leukemia and Lymphoma

    ClinicalTrials.gov

    2016-12-04

    Acute Myeloid Leukemia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-cell Prolymphocytic Leukemia; T-cell Large Granular Lymphocytic Leukemia; Peripheral T-cell Lymphoma, NOS; Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma, Nasal Type; Enteropathy-type Intestinal T-cell Lymphoma; Hepatosplenic T-cell Lymphoma

  1. Cutaneous presentation preceding acute monocytic leukemia

    PubMed Central

    Jin, Xianhua; Li, Fuqiu; Li, Xue; Zhu, Wenjing; Mou, Yan; Huang, Yang; Zhao, Huanyu; Gao, Wei; Xia, Jianxin

    2017-01-01

    Abstract Rationale: Cutaneous presentation preceding acute myeloid leukemia (AML) is rare, and the prognosis is poor. Patient concerns: We report 4 cases of AML cutis, where skin infiltration precedes any blood or bone marrow evidence of leukemia. We also reviewed 13 cases reported in English and Chinese literature. The 4 cases all presented typical cutaneous lesions without any systemic evidence of leukemia. Histopathological examination found that dense monomorphous cell infiltration involved the dermis. Some cells surrounded blood vessels and skin appendages in a concentric manner or showed single-row arrangement in the collagen fiber bundles. Uninvolved papillary dermis was found to separate normal epidermis from dermal infiltration. Minor cells had a large kidney-shaped or oval nucleus with nucleoli and slightly eosinophilic cytoplasm. Immunohistochemical analysis was positive for CD4, CD56, while CD123 was negative in all cases. Diagnoses: AML-M5. Interventions: 2 patients received chemotherapy ,but others rejected treatment. Outcomes: Most patients died within 1 year after the onset of skin lesions. Lessons: These findings suggest that skin infiltration of AML may precede any systemic evidence, and typical cutaneous lesions in elderly individuals may be indicative for AML. PMID:28272239

  2. Both mature KIR+ and immature KIR- NK cells control pediatric acute B-cell precursor leukemia in NOD.Cg-Prkdcscid IL2rgtmWjl/Sz mice.

    PubMed

    Kübler, Ayline; Woiterski, Jeanette; Witte, Kai-Erik; Bühring, Hans-Jörg; Hartwig, Udo F; Ebinger, Martin; Oevermann, Lena; Mezger, Markus; Herr, Wolfgang; Lang, Peter; Handgretinger, Rupert; Münz, Christian; André, Maya C

    2014-12-18

    Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B-cell precursor leukemia (BCP-ALL) appears to be resistant to NK-cell-mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. In this study, we demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity toward pediatric BCP-ALL in vivo. Notably, both adoptively transferred mature KIR(+) NK cells and immature KIR(-) NK cells arising early posttransplantation in humanized NSG mice exerted substantial antileukemic activity. Low-dose and long-term treatment of humanized NSG mice with the DNA-demethylating agent 5-aza-cytidine distinctly enhanced the antitumor response, interestingly without inducing common inhibitory KIR expression but rather by promoting the differentiation of various NK-cell precursor subsets. Collectively, these data indicate that the future design of innovative therapy protocols should consider further exploitation of NK-cell-mediated immune responses for poor prognosis pediatric BCP-ALL patients.

  3. 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)

  4. Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia.

    PubMed

    Doi, Keiko; Imai, Takahiko; Kressler, Christopher; Yagita, Hideo; Agata, Yasutoshi; Vooijs, Marc; Hamazaki, Yoko; Inoue, Joe; Minato, Nagahiro

    2015-01-23

    The Rap G protein signal regulates Notch activation in early thymic progenitor cells, and deregulated Rap activation (Rap(high)) results in the development of Notch-dependent T-cell acute lymphoblastic leukemia (T-ALL). We demonstrate that the Rap signal is required for the proliferation and leukemogenesis of established Notch-dependent T-ALL cell lines. Attenuation of the Rap signal by the expression of a dominant-negative Rap1A17 or Rap1GAP, Sipa1, in a T-ALL cell line resulted in the reduced Notch processing at site 2 due to impaired maturation of Adam10. Inhibition of the Rap1 prenylation with a geranylgeranyl transferase inhibitor abrogated its membrane-anchoring to Golgi-network and caused reduced proprotein convertase activity required for Adam10 maturation. Exogenous expression of a mature form of Adam10 overcame the Sipa1-induced inhibition of T-ALL cell proliferation. T-ALL cell lines expressed Notch ligands in a Notch-signal dependent manner, which contributed to the cell-autonomous Notch activation. Although the initial thymic blast cells barely expressed Notch ligands during the T-ALL development from Rap(high) hematopoietic progenitors in vivo, the ligands were clearly expressed in the T-ALL cells invading extrathymic vital organs. These results reveal a crucial role of the Rap signal in the Notch-dependent T-ALL development and the progression.

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

    PubMed

    Yang, Li; Weng, Wei; Sun, Zhi-Xin; Fu, Xian-Jie; Ma, Jun; Zhuang, Wen-Fang

    2015-05-15

    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, and 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.

  6. 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

  7. CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

    PubMed Central

    Negrotto, Soledad; Ng, Kwok Peng; Jankowska, Ania M.; Bodo, Juraj; Gopalan, Banu; Guinta, Kathryn; Mulloy, James C.; Hsi, Eric; Maciejewski, Jaroslaw; Saunthararajah, Yogen

    2011-01-01

    The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. The basis for these contrasting cell-fates, and for selective CpG hypomethylation by decitabine, is poorly understood. Promoter CpGs, with methylation measured by microarray, were classified by the direction of methylation change with normal myeloid maturation. In AML cells, the methylation pattern at maturation-responsive CpG suggested at least partial maturation. Consistent with partial maturation, in gene expression analyses, AML cells expressed high levels of the key lineage-specifying factor CEBPA, but relatively low levels of the key late-differentiation driver CEBPE. In methylation analysis by mass-spectrometry, CEBPE promoter CpG that are usually hypomethylated during granulocyte maturation were significantly hypermethylated in AML cells. Decitabine treatment induced cellular differentiation of AML cells, and the largest methylation decreases were at CpG that are hypomethylated with myeloid maturation, including CEBPE promoter CpG. In contrast, decitabine-treated normal HSC retained immature morphology, and methylation significantly decreased at CpG that are less methylated in immature cells. High expression of lineage-specifying factor and aberrant epigenetic repression of some key late-differentiation genes distinguishes AML cells from normal HSC and could explain the contrasting differentiation and methylation responses to decitabine. PMID:21836612

  8. T-cell receptor gamma/delta expressing acute leukemia emerging from sideroblastic anemia: morphological, immunological, and cytogenetic features.

    PubMed

    Meckenstock, G; Fonatsch, C; Heyll, A; Schneider, E M; Kögler, G; Söhngen, D; Aul, C; Schneider, W

    1992-01-01

    Striking numerical and structural chromosome abnormalities (-Y, +8, i(7q), del (10)(q24), and del (11)(q21)) were detected by cytogenetic analysis in a patient's bone marrow with morphological features of both acute lymphoblastic leukemia and myelodysplastic disorder. Surface marker analysis characterized blast cells to be CD2+ CD7+ CD3+ CD4- CD8- expressing gamma/delta-T-cell receptor antigen and coexpressing CD11b and CD16. Exhibiting an identical phenotype as the leukemic cells, a prominent gamma/delta-TCR+ lymphocyte population was found in the bone marrow as well as in the peripheral blood. Cells of the latter compartment coexpressed CD56 and HLA-DR antigens and exhibited nonspecific cytotoxic activity. In the bone marrow cells NSCA could be induced after stimulation with interleukin 2 in vitro. Morphological, immunological, and cytogenetic findings suggest that gamma/delta-T-ALL emerged from a myelodysplastic disorder after sequential steps of malignant transformation. Leukemic cells with "mixed lineage" character may provide evidence for a common progenitor cell in the bone marrow. Assuming that the leukemic cells represent the malignant counterpart of normal CD3+ gamma/delta-TCR+ cells the results may contribute to our understanding of the origin and differentiation as well as the possible steps of malignant transformation of a gamma/delta-TCR+ lymphocyte population.

  9. Acute Myeloid Leukemia: A Concise Review

    PubMed Central

    Saultz, Jennifer N.; Garzon, Ramiro

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. Cytogenetics and mutation testing remain a critical prognostic tool for post induction treatment. Despite rapid advances in the field including new drug targets and increased understanding of the biology, AML treatment remains unchanged for the past three decades with the majority of patients eventually relapsing and dying of the disease. Allogenic transplant remains the best chance for cure for patients with intermediate or high risk disease. In this review, we discuss the landmark genetic studies that have improved outcome prediction and novel therapies. PMID:26959069

  10. Acute promyelocytic leukemia, arsenic, and PML bodies

    PubMed Central

    Le Bras, Morgane; Lallemand-Breitenbach, Valérie

    2012-01-01

    Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation. PMID:22778276

  11. Inhibition of p38 MAPK Phosphorylation Is Critical for Bestatin to Enhance ATRA-Induced Cell Differentiation in Acute Promyelocytic Leukemia NB4 Cells.

    PubMed

    Qian, Xijun; He, Jingsong; Zhao, Yi; Lin, Maofang

    2016-01-01

    Bestatin has been known as an immunomodulating agent in anti-leukemia treatment. The mechanism by which Bestatin enhances all-trans retinoic acid (ATRA)-induced cell differentiation of acute promyelocytic leukemia (APL) cells is generally attributed to inhibition of cell surface CD13/aminopeptidase N activity. Bestatin also exerts its biological activities besides its ability to inhibit aminopeptidase N enzymatic activity. This article provides data to support an alternative mechanism regarding an important role of inhibition of p38 mitogen-activated protein kinase (MAPK) signal pathway in Bestatin's anti-leukemia effect. Bestatin enhanced ATRA-induced differentiation and inhibited ATRA-driven phosphorylation of p38 MAPK in ATRA-sensitive APL NB4 cells. In contrast, Bestatin could not reverse the differentiation block in ATRA-resistant APL MR2 cells, in which ATRA was unable to induce phosphorylation of p38 MAPK. Moreover, CD13 ligation with anti-CD13 antibody WM-15 resulted in phosphorylation of p38 MAPK, reduced the inhibition of Bestatin on the phosphorylation of p38 MAPK, and completely abolished the enhancement of Bestatin on ATRA-inducing differentiation in NB4 cells. This study shows that inhibition of p38 MAPK phosphorylation is critical for Bestatin to enhance ATRA-induced cell differentiation in ATRA-sensitive APL NB4 cells. Results suggested that pharmacological inhibition of the p38 MAPK pathway might enhance ATRA-dependent differentiation.

  12. PS-341 in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia in Blast Phase, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  13. Different outcome of T cell acute lymphoblastic leukemia with translocation t(11;14) treated in two consecutive children leukemia group EORTC trials.

    PubMed

    Simon, Pauline; Suciu, Stefan; Clappier, Emmanuelle; Cave, Hélène; Sirvent, Nicolas; Plat, Geneviève; Thyss, Antoine; Mechinaud, Françoise; Costa, Vitor M; Ferster, Alina; Lutz, Patrick; Mazingue, Françoise; Plantaz, Dominique; Plouvier, Emmanuel; Bertrand, Yves; Benoit, Yves; Dastugue, Nicole; Rohrlich, Pierre S

    2016-01-01

    Acute lymphoblastic leukemia of T cell lineage (T-ALL) is an aggressive malignant disease which accounts for 15 % of childhood ALL. T(11;14) is the more frequent chromosomal abnormality in childhood T-ALL, but its prognostic value remained controversial. Our aim was to analyze the outcome of childhood T-ALL with t(11;14) to know if the presence of this translocation is associated with a poor prognosis. We conducted a retrospective study from a series of 20 patients with t(11;14), treated in two consecutive trials from the European Organization for Research and Treatment of Cancer Children Leukemia Group over a 19-year period from 1989 to 2008. There were no significant differences between the 2 consecutive groups of patients with t(11;14) regarding the clinical and biological features at diagnosis. Among 19 patients who reached complete remission, 9 patients relapsed. We noticed 7 deaths all relapse- or failure-related. In the 58881 study, a presence of t(11;14) was associated with a poor outcome with an event-free survival at 5 years at 22.2 % versus 65.1 % for the non-t(11;14) T-ALL (p = 0.0004). In the more recent protocol, the outcome of T-ALL with t(11;14) reached that of non-t(11;14) T-ALL with an event-free survival at 5 years at 65.5 versus 74.9 % (p = 0.93). The presence of t(11;14) appeared as a poor prognostic feature in the 58881 trial whereas this abnormality no longer affected the outcome in the 58951 study. This difference is probably explained by the more intensive chemotherapy in the latest trial.

  14. Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells from Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo.

    PubMed

    Knorr, Katherine L B; Finn, Laura E; Smith, B Douglas; Hess, Allan D; Foran, James M; Karp, Judith E; Kaufmann, Scott H

    2017-03-01

    Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting. Stem Cells Translational Medicine 2017;6:840-850.

  15. Humanized CD7 nanobody-based immunotoxins exhibit promising anti-T-cell acute lymphoblastic leukemia potential

    PubMed Central

    Yu, Yuan; Li, Jialu; Zhu, Xuejun; Tang, Xiaowen; Bao, Yangyi; Sun, Xiang; Huang, Yuhui; Tian, Fang; Liu, Xiaomei; Yang, Lin

    2017-01-01

    Background Nanobodies, named as VHHs (variable domain of heavy chain of HCAb [heavy-chain antibodies]), are derived from heavy-chain-only antibodies that circulate in sera of camelids. Their exceptional physicochemical properties, possibility of humanization, and unique antigen recognition properties make them excellent candidates for targeted delivery of biologically active components, including immunotoxins. In our previous efforts, we have successfully generated the monovalent and bivalent CD7 nanobody-based immunotoxins, which can effectively trigger the apoptosis of CD7-positive malignant cells. To pursue the possibility of translating those immunotoxins into clinics, we humanized the nanobody sequences (designated as dhuVHH6) as well as further truncated the Pseudomonas exotoxin A (PE)-derived PE38 toxin to produce a more protease-resistant form, which is named as PE-LR, by deleting majority of PE domain II. Methods and results Three new types of immunotoxins, dhuVHH6-PE38, dVHH6-PE-LR, and dhuVHH6-PE-LR, were successfully constructed. These recombinant immunotoxins were expressed in Escherichia coli and showed that nanobody immunotoxins have the benefits of easy soluble expression in a prokaryotic expression system. Flow cytometry results revealed that all immunotoxins still maintained the ability to bind specifically to CD7-positive T lymphocyte strains without binding to CD7-negative control cells. Laser scanning confocal microscopy revealed that these proteins can be endocytosed into the cytoplasm after binding with CD7-positive cells and that this phenomenon was not observed in CD7-negative cells. WST-8 experiments showed that all immunotoxins retained the highly effective and specific growth inhibition activity in CD7-positive cell lines and primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Further in vivo animal model experiments showed that humanized dhuVHH6-PE38 immunotoxin can tolerate higher doses and extend the survival of NOD-Prkdcem26Il

  16. The effect of miR-146a on STAT1 expression and apoptosis in acute lymphoblastic leukemia Jurkat cells

    PubMed Central

    Yan, Weihong; Guo, Hua; Suo, Feng; Han, Chunling; Zheng, Hua; Chen, Tong

    2017-01-01

    The effect of miR-146a-dependent regulation of STAT1 on apoptosis in acute lymphoblastic leukemia (ALL) Jurkat cells was investigated. The miR-146a mimic and miR-146a inhibitor vectors were constructed in vitro, and experimental grouping was as follows: Control group (untreated Jurkat cells), empty vector group (Jurkat cells transfected with empty vector), agonist group (Jurkat cells transfected with miR-146a mimic) and the inhibitor group (Jurkat cells transfected with miR-146a inhibitor). Western blot analysis was used to observe the expression, respectively, of STAT1, p-STAT1 and Bcl-xL, and flow cytometry was used to test apoptosis in Jurkat cells. STAT1 and p-STAT1 expression in the agonist group was higher than that in the control and empty vector groups, but lower in the inhibitor group, and differences were statistically significant (P<0.05). The rate of apoptosis in the agonist group was significantly higher than that of the control group and blank vector group, and it was significantly lower in the inhibitor group (P<0.05). As a tumor suppressor, miR-146a can regulate expression of apoptosis-promoting factor STAT1, and anti-apoptosis factor Bcl-xL, and is able to promote apoptosis of ALL Jurkat cells. PMID:28123535

  17. Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells

    PubMed Central

    Ma, Jun; Li, Xinyu; Su, Yongwei; Zhao, Jianyun; Luedtke, Daniel A.; Epshteyn, Valeria; Edwards, Holly; Wang, Guan; Wang, Zhihong; Chu, Roland; Taub, Jeffrey W.; Lin, Hai; Wang, Yue; Ge, Yubin

    2017-01-01

    Acute myeloid leukemia (AML) continues to be a challenging disease to treat, thus new treatment strategies are needed. In this study, we investigated the antileukemic effects of ATR inhibition alone or combined with cytarabine in AML cells. Treatment with the ATR-selective inhibitor AZ20 caused proliferation inhibition in AML cell lines and primary patient samples. It partially abolished the G2 cell cycle checkpoint and caused DNA replication stress and damage, accompanied by CDK1-independent apoptosis and downregulation of RRM1 and RRM2. AZ20 synergistically enhanced cytarabine-induced proliferation inhibition and apoptosis, abolished cytarabine-induced S and G2/M cell cycle arrest, and cooperated with cytarabine in inducing DNA replication stress and damage in AML cell lines. These key findings were confirmed with another ATR-selective inhibitor AZD6738. Therefore, the cooperative induction of DNA replication stress and damage by ATR inhibition and cytarabine, and the ability of ATR inhibition to abrogate the G2 cell cycle checkpoint both contributed to the synergistic induction of apoptosis and proliferation inhibition in AML cell lines. Synergistic antileukemic interactions between AZ20 and cytarabine were confirmed in primary AML patient samples. Our findings provide insight into the mechanism of action underlying the synergistic antileukemic activity of ATR inhibition in combination with cytarabine in AML. PMID:28176818

  18. Evidence for deterministic chaos in aperiodic oscillations of acute lymphoblastic leukemia cells in long-term culture

    NASA Astrophysics Data System (ADS)

    Lambrou, George I.; Chatziioannou, Aristotelis; Vlahopoulos, Spiros; Moschovi, Maria; Chrousos, George P.

    Biological systems are dynamic and possess properties that depend on two key elements: initial conditions and the response of the system over time. Conceptualizing this on tumor models will influence conclusions drawn with regard to disease initiation and progression. Alterations in initial conditions dynamically reshape the properties of proliferating tumor cells. The present work aims to test the hypothesis of Wolfrom et al., that proliferation shows evidence for deterministic chaos in a manner such that subtle differences in the initial conditions give rise to non-linear response behavior of the system. Their hypothesis, tested on adherent Fao rat hepatoma cells, provides evidence that these cells manifest aperiodic oscillations in their proliferation rate. We have tested this hypothesis with some modifications to the proposed experimental setup. We have used the acute lymphoblastic leukemia cell line CCRF-CEM, as it provides an excellent substrate for modeling proliferation dynamics. Measurements were taken at time points varying from 24h to 48h, extending the assayed populations beyond that of previous published reports that dealt with the complex dynamic behavior of animal cell populations. We conducted flow cytometry studies to examine the apoptotic and necrotic rate of the system, as well as DNA content changes of the cells over time. The cells exhibited a proliferation rate of nonlinear nature, as this rate presented oscillatory behavior. The obtained data have been fit in known models of growth, such as logistic and Gompertzian growth.

  19. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma.

    PubMed

    Casucci, Monica; Nicolis di Robilant, Benedetta; Falcone, Laura; Camisa, Barbara; Norelli, Margherita; Genovese, Pietro; Gentner, Bernhard; Gullotta, Fabiana; Ponzoni, Maurilio; Bernardi, Massimo; Marcatti, Magda; Saudemont, Aurore; Bordignon, Claudio; Savoldo, Barbara; Ciceri, Fabio; Naldini, Luigi; Dotti, Gianpietro; Bonini, Chiara; Bondanza, Attilio

    2013-11-14

    Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.

  20. Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells From Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo.

    PubMed

    Knorr, Katherine L B; Finn, Laura E; Smith, B Douglas; Hess, Allan D; Foran, James M; Karp, Judith E; Kaufmann, Scott H

    2016-11-07

    : Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting.

  1. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts.

    PubMed

    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

    2014-11-01

    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.

  2. Treatment Option Overview (Adult Acute Lymphoblastic Leukemia)

    MedlinePlus

    ... recovery) and treatment options. Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... to radiation may increase the risk of developing ALL. Anything that increases your risk of getting a ...

  3. General Information about Adult Acute Lymphoblastic Leukemia

    MedlinePlus

    ... recovery) and treatment options. Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... to radiation may increase the risk of developing ALL. Anything that increases your risk of getting a ...

  4. Treatment Options for Adult Acute Lymphoblastic Leukemia

    MedlinePlus

    ... recovery) and treatment options. Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... to radiation may increase the risk of developing ALL. Anything that increases your risk of getting a ...

  5. Stages of Adult Acute Lymphoblastic Leukemia

    MedlinePlus

    ... recovery) and treatment options. Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... to radiation may increase the risk of developing ALL. Anything that increases your risk of getting a ...

  6. Leukemia

    MedlinePlus

    ... version of this page please turn Javascript on. Leukemia What Is Leukemia? Leukemia is a cancer of the blood cells. ... diagnosed with leukemia are over 50 years old. Leukemia Starts in Bone Marrow Click for more information ...

  7. Acute Myeloid Leukemia, Version 2.2013

    PubMed Central

    O'Donnell, Margaret R.; Tallman, Martin S.; Abboud, Camille N.; Altman, Jessica K.; Appelbaum, Frederick R.; Arber, Daniel A.; Attar, Eyal; Borate, Uma; Coutre, Steven E.; Damon, Lloyd E.; Lancet, Jeffrey; Maness, Lori J.; Marcucci, Guido; Martin, Michael G.; Millenson, Michael M.; Moore, Joseph O.; Ravandi, Farhad; Shami, Paul J.; Smith, B. Douglas; Stone, Richard M.; Strickland, Stephen A.; Wang, Eunice S.; Gregory, Kristina M.; Naganuma, Maoko

    2014-01-01

    These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL. PMID:24029121

  8. Immunomodulatory Drugs: Immune Checkpoint Agents in Acute Leukemia

    PubMed Central

    Knaus, Hanna A.; Kanakry, Christopher G.; Luznik, Leo; Gojo, Ivana

    2016-01-01

    Intrinsic immune responses to acute leukemia are inhibited by a variety of mechanisms, such as aberrant antigen expression by leukemia cells, secretion of immunosuppressive cytokines and expression of inhibitory enzymes in the tumor microenvironment, expansion of immunoregulatory cells, and activation of immune checkpoint pathways, all leading to T cell dysfunction and/or exhaustion. Leukemic cells, similar to other tumor cells, hijack these inhibitory pathways to evade immune recognition and destruction by cytotoxic T lymphocytes. Thus, blockade of immune checkpoints has emerged as a highly promising approach to augment innate anti-tumor immunity in order to treat malignancies. Most evidence for the clinical efficacy of this immunotherapeutic strategy has been seen in patients with metastatic melanoma, where anti-CTLA-4 and anti-PD-1 antibodies have recently revolutionized treatment of this lethal disease with otherwise limited treatment options. To meet the high demand for new treatment strategies in acute leukemia, clinical testing of these promising therapies is commencing. Herein, we review the biology of multiple inhibitory checkpoints (including CTLA-4, PD-1, TIM-3, LAG-3, BTLA, and CD200R) and their contribution to immune evasion by acute leukemias. In addition, we discuss the current state of preclinical and clinical studies of immune checkpoint inhibition in acute leukemia, which seek to harness the body’s own immune system to fight leukemic cells. PMID:25981611

  9. Immunomodulatory Drugs: Immune Checkpoint Agents in Acute Leukemia.

    PubMed

    Knaus, Hanna A; Kanakry, Christopher G; Luznik, Leo; Gojo, Ivana

    2017-01-01

    Intrinsic immune responses to acute leukemia are inhibited by a variety of mechanisms, such as aberrant antigen expression by leukemia cells, secretion of immunosuppressive cytokines and expression of inhibitory enzymes in the tumor microenvironment, expansion of immunoregulatory cells, and activation of immune checkpoint pathways, all leading to T cell dysfunction and/or exhaustion. Leukemic cells, similar to other tumor cells, hijack these inhibitory pathways to evade immune recognition and destruction by cytotoxic T lymphocytes. Thus, blockade of immune checkpoints has emerged as a highly promising approach to augment innate anti-tumor immunity in order to treat malignancies. Most evidence for the clinical efficacy of this immunotherapeutic strategy has been seen in patients with metastatic melanoma, where anti-CTLA-4 and anti-PD-1 antibodies have recently revolutionized treatment of this lethal disease with otherwise limited treatment options. To meet the high demand for new treatment strategies in acute leukemia, clinical testing of these promising therapies is commencing. Herein, we review the biology of multiple inhibitory checkpoints (including CTLA-4, PD-1, TIM-3, LAG-3, BTLA, and CD200R) and their contribution to immune evasion by acute leukemias. In addition, we discuss the current state of preclinical and clinical studies of immune checkpoint inhibition in acute leukemia, which seek to harness the body's own immune system to fight leukemic cells.

  10. Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Stage II-IV T-Cell Lymphoblastic Lymphoma

    ClinicalTrials.gov

    2017-04-13

    Adult T Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Stage II Childhood Lymphoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  11. Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo

    PubMed Central

    Jain, Chetan Kumar; Pradhan, Bhola Shankar; Banerjee, Sukdeb; Mondal, Nirup Bikash; Majumder, Subeer S.; Bhattacharyya, Madhumita; Chakrabarti, Saikat; Roychoudhury, Susanta; Majumder, Hemanta Kumar

    2015-01-01

    DNA topoisomerase II inhibitors e.g. doxorubicin and etoposide are currently used in the chemotherapy for acute lymphoblastic leukemia (ALL). These inhibitors have serious side effects during the chemotherapy e.g. cardiotoxicity and secondary malignancies. In this study we show that sulfonoquinovosyl diacylglyceride (SQDG) isolated from Azadirachta indica exerts potent anti-ALL activity both in vitro and in vivo in nude mice and it synergizes with doxorubicin and etoposide. SQDG selectively targets ALL MOLT-4 cells by inhibiting catalytic activity of topoisomerase I enzyme and inducing p53 dependent apoptotic pathway. SQDG treatment induces recruitment of ATR at chromatin and arrests the cells in S-phase. Down-regulation of topoisomerase I or p53 renders the cells less sensitive for SQDG, while ectopic expression of wild type p53 protein in p53 deficient K562 cells results in chemosensitization of the cells for SQDG. We also show that constant ratio combinations of SQDG and etoposide or SDQG and doxorubicin exert synergistic effects on MOLT-4 cell killing. This study suggests that doses of etoposide/doxorubicin can be substantially reduced by combining SQDG with these agents during ALL chemotherapy and side effects caused can be minimized. Thus dual targeting of topoisomerase I and II enzymes is a promising strategy for improving ALL chemotherapy. PMID:26189912

  12. Acute Myeloid Leukemia Targeting by Chimeric Antigen Receptor T Cells: Bridging the Gap from Preclinical Modeling to Human Studies.

    PubMed

    Rotiroti, Maria Caterina; Arcangeli, Silvia; Casucci, Monica; Perriello, Vincenzo; Bondanza, Attilio; Biondi, Andrea; Tettamanti, Sarah; Biagi, Ettore

    2017-03-01

    Acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric high-risk patients, thus demanding advanced and personalized therapies. In this regard, different targeted immunotherapeutic approaches are available, ranging from naked monoclonal antibodies (mAb) to conjugated and multifunctional mAbs (i.e., BiTEs and DARTs). Recently, researchers have focused their attention on novel techniques of genetic manipulation specifically to redirect cytotoxic T cells endowed with chimeric antigen receptors (CARs) toward selected tumor associated antigens. So far, CAR T cells targeting the CD19 antigen expressed by B-cell origin hematological cancers have gained impressive clinical results, leading to the possibility of translating the CAR platform to treat other hematological malignancies such as AML. However, one of the main concerns in the field of AML CAR immunotherapy is the identification of an ideal target cell surface antigen, being highly expressed on tumor cells but minimally present on healthy tissues, together with the design of an anti-AML CAR appropriately balancing efficacy and safety profiles. The current review focuses mainly on AML target antigens and the related immunotherapeutic approaches developed so far, deeply dissecting methods of CAR T cell safety improvements, when designing novel CARs approaching human studies.

  13. Ibrutinib inhibits pre-BCR(+) B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK.

    PubMed

    Kim, Ekaterina; Hurtz, Christian; Koehrer, Stefan; Wang, Zhiqiang; Balasubramanian, Sriram; Chang, Betty Y; Müschen, Markus; Davis, R Eric; Burger, Jan A

    2017-03-02

    Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR(+) B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR(+) ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR(+) ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR(+) ALL. Consequently, in mouse xenograft models of pre-BCR(+) ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR(+) ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR(+) ALL and highlight the importance of ibrutinib effects on alternative kinase targets.

  14. High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003–2007

    PubMed Central

    Kozlowski, Piotr; Åström, Maria; Ahlberg, Lucia; Bernell, Per; Hulegårdh, Erik; Hägglund, Hans; Karlsson, Karin; Markuszewska-Kuczymska, Alicja; Tomaszewska-Toporska, Beata; Smedmyr, Bengt; Hallböök, Helene

    2012-01-01

    Background A minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission. Design and Methods Between 2003–2007, 76 adults (<66 years) with relapsed acute lymphoblastic leukemia (Burkitt’s leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated. Results Reinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13–32) and 15% (95% CI: 7–24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2–8.3) after relapse, whereas all patients over 35 years old at diagnosis have died. Conclusions Allogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis. PMID:22511497

  15. Pattern of subtypes of acute lymphoblastic leukemia in India.

    PubMed

    Kamat, D M; Gopal, R; Advani, S H; Nair, C N; Kumar, A; Saikia, T; Nadkarni, J J; Nadkarni, J S

    1985-01-01

    Leukemic cells from 124 acute lymphoblastic leukemia (ALL) and 31 chronic lymphatic leukemia (CLL) were examined for sheep erythrocyte receptor (E), surface immunoglobulin (SIg) and their reactivity with a panel of monoclonal antibodies recognizing specific surface antigens including pan-T, Common ALL and Ia antigens. In acute lymphatic leukemia, 33% of patients reveal T-cell receptor associated with higher age group, mediastinal mass and high WBC count. Common ALL was predominant between 2 and 9-yr age group. Among chronic lymphatic leukemia, 2 patients were found to be T-CLL while 29 revealed presence of SIg. Ia antigen was detected in 44.4% of ALL and 64% fo CLL patients. The pattern of surface marker observed in our series may be related to our life style, socio-economic and environmental factors.

  16. An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation.

    PubMed

    Ferguson, Paul; Hills, Robert K; Grech, Angela; Betteridge, Sophie; Kjeldsen, Lars; Dennis, Michael; Vyas, Paresh; Goldstone, Anthony H; Milligan, Donald; Clark, Richard E; Russell, Nigel H; Craddock, Charles

    2016-11-01

    Up to 30% of adults with acute myeloid leukemia fail to achieve a complete remission after induction chemotherapy - termed primary refractory acute myeloid leukemia. There is no universally agreed definition of primary refractory disease, nor have the optimal treatment modalities been defined. We studied 8907 patients with newly diagnosed acute myeloid leukemia, and examined outcomes in patients with refractory disease defined using differing criteria which have previously been proposed. These included failure to achieve complete remission after one cycle of induction chemotherapy (RES), less than a 50% reduction in blast numbers with >15% residual blasts after one cycle of induction chemotherapy (REF1) and failure to achieve complete remission after two courses of induction chemotherapy (REF2). 5-year overall survival was decreased in patients fulfilling any criteria for refractory disease, compared with patients achieving a complete remission after one cycle of induction chemotherapy: 9% and 8% in patients with REF1 and REF2 versus 40% (P<0.0001). Allogeneic stem cell transplantation improved survival in the REF1 (HR 0.58 (0.46-0.74), P=0.00001) and REF2 (HR 0.55 (0.41-0.74), P=0.0001) cohorts. The utilization of REF1 criteria permits the early identification of patients whose outcome after one course of induction chemotherapy is very poor, and informs a novel definition of primary refractory acute myeloid leukemia. Furthermore, these data demonstrate that allogeneic stem cell transplantation represents an effective therapeutic modality in selected patients with primary refractory acute myeloid leukemia.

  17. Variations in mRNA and protein levels of Ikaros family members in pediatric T cell acute lymphoblastic leukemia

    PubMed Central

    Mitchell, Julie L.

    2016-01-01

    Background Pediatric T cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous disease in which the cells share phenotypic characteristics with normal human thymocytes. The Ikaros family of transcription factors includes five members that are required for normal T cell development and are implicated in leukemogenesis. The goal of this work was to correlate the pattern of expression of Ikaros family members with the phenotype of the T-ALL cells. Methods We obtained twenty-four samples from pediatric T-ALL patients and used multi-parameter flow cytometry to characterize each sample, comparing the phenotype of the leukemic cells with normal human thymocytes. Then, we defined the expression levels of each Ikaros family member to determine whether the mRNA levels or splicing or protein levels were similar to the normal patterns seen during human T cell development. Results Multi-parameter analysis of the phenotype of T-ALL cells revealed that each patient’s cells were unique and could not be readily correlated with stages of T cell development. Similarly, the pattern of Ikaros expression varied among patients. In most patients, Ikaros mRNA was the dominant family member expressed, but some patients’ cells contained mostly Helios, Aiolos, or Eos mRNA. Despite that most patients had elevated mRNA levels of Ikaros family members and unique patterns of mRNA splicing, most patients had significantly reduced protein levels of Ikaros and Aiolos. Conclusions Our analysis of the cell phenotype and Ikaros expression levels in T-ALL cells revealed the extent of heterogeneity among patients. While it is rarely possible to trace leukemic cells to their developmental origin, we found distinct patterns of Ikaros family mRNA levels in groups of patients. Further, mRNA and protein levels of Ikaros and Aiolos did not correlate, indicating that mRNA and protein levels are regulated via distinct mechanisms. PMID:27826566

  18. Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2017-02-07

    Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  19. Allogeneic Hematopoietic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Results from a Single Center, 1993-2011

    PubMed Central

    Yonal-Hindilerden, Ipek; Kalayoglu-Besisik, Sevgi; Gurses-Koc, Nuray; Hindilerden, Fehmi; Sargin, Deniz

    2017-01-01

    Background: For adult ALL patients, the indications and appropriate timing of allogeneic hematopoietic stem cell transplantation (AHSCT) continue to be debated. The primary aim of this single-institution study was to compare the results of our adult ALL patients that had been allografted with those reported in the current literature. Subjects and Methods: This study included 53 consecutive adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic stem cell transplantation (AHSCT) with myeloablative (92%) and reduced-intensity (8%) conditioning between 1993 and 2011. Results: Mean patient age was 27 years (SD:8.62) and donor age was 33.7 years (SD:9.47). Fourteen patients were in first remission; 21 in ≥2nd remission, 15 in relapse and 3 had primary refractory leukemia. Thirty-four, 15 and 4 patients received busulfan plus cyclophosphamide, cyclophosphamide/total body irradiation and fludarabine-based regimens, respectively. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine plus methotrexate were used. Forty-six donors were related and 7 were unrelated. Thirty patients received granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood and 23 received bone marrow as stem cell source. Twenty-six patients relapsed at a mean duration of 11.3 months (SD:19.1). Forty-four patients succumbed to their disease after a mean follow-up of 13.6 months (SD:19.5). The cause of mortality was relapse (n=24; 54.5%) and transplant-related etiologies (n=20; 45.5%). The estimated five year probabilities of overall survival (OS) and progression-free survival (PFS) were 37% and 12%, respectively. Conclusion: By multivariate analyses, transplantation in first remission was the most important predictor of transplant success. PMID:28286617

  20. Curcumin potentiates the effect of chemotherapy against acute lymphoblastic leukemia cells via downregulation of NF-κB

    PubMed Central

    Pimentel-Gutiérrez, Helia Judith; Bobadilla-Morales, Lucina; Barba-Barba, César Cenobio; Ortega-De-La-Torre, Citlalli; Sánchez-Zubieta, Fernando Antonio; Corona-Rivera, Jorge Román; González-Quezada, Betsy Annel; Armendáriz-Borunda, Juan S.; Silva-Cruz, Rocío; Corona-Rivera, Alfredo

    2016-01-01

    Acute lymphoblastic leukemia (ALL) accounts for 30% of all pediatric cancers. Currently available treatments exhibit toxicity and certain patients may develop resistance. Thus, less toxic and chemoresistance-reversal agents are required. In the present study, the potential effect of curcumin, a component of Curcuma longa, as a pharmacological co-adjuvant of several chemotherapeutic agents against ALL, including prednisone, 6-mercaptopurine, dexamethasone, cyclophosphamide, l-asparaginase, vincristine, daunorubicin, doxorubicin, methotrexate and cytarabine, was investigated in the REH ALL cell line cultures treated in combination with chemotherapeutic agents and curcumin. The results of cell viability, gene expression and activation of NF-κB and caspase 3 indicated that curcumin potentiates the anticancer effects of the aforementioned chemotherapeutic agents in the REH ALL cell line. Following treatment with the above chemotherapeutic agents, curcumin enhanced caspase-3 activation and downregulated nuclear factor-kappa B (NF-κB) activation. Curcumin also downregulated the oxidative stress induced by certain chemotherapies. Notably, curcumin did not affect the gene expression of cell survival proteins such as B-cell lymphoma (Bcl)-2, Bcl-extra large, survivin, c-Myc and cyclin D1, which are regulated by the NF-κB transcription factor. In conclusion, curcumin has the potential to improve the effect of chemotherapeutic agents against ALL. PMID:27895780

  1. BIBR 1532 increases arsenic trioxide-mediated apoptosis in acute promyelocytic leukemia cells: therapeutic potential for APL.

    PubMed

    Bashash, Davood; Ghaffari, Seyed H; Zaker, Farhad; Kazerani, Maryam; Hezave, Kebria; Hassani, Saeed; Rostami, Masomeh; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir

    2013-09-01

    The current treatment of acute promyelocytic leukemia with arsenic trioxide (ATO) has increased long-lasting complete remissions; however, a proportion of patients continues to die eventually as a result of disease recurrence. In an effort to enhance the effectiveness of the APL treatment, we designed experiments to evaluate the effects of ATO in combination with the lead compound of non-nucleoside inhibitor of telomerase, BIBR 1532. After combined treatments with BIBR 1532 and ATO, decreased cell viability index with a concomitant increase in apoptotic cell death was observed in NB4 leukemic cells. Apoptosis induced by the combined treatments was accompanied by elevated Bax/Bcl-2 molecular ratio and enhanced caspase 3 activation. Our study has also demonstrated that the combined treatment suppressed NB4 cell proliferative capacity and inhibited telomerase activity probably via transcriptional suppression of c-Myc and hTERT. In conclusion, this study may supply insight into the application of this new combination therapy to APL cells intrinsically less sensitive to routine therapies and suggested a novel combination therapy for patients with more aggressive disease; those who may not respond favorably to the arsenic mono-therapy.

  2. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.

    PubMed

    Weng, Andrew P; Millholland, John M; Yashiro-Ohtani, Yumi; Arcangeli, Marie Laure; Lau, Arthur; Wai, Carol; Del Bianco, Cristina; Rodriguez, Carlos G; Sai, Hong; Tobias, John; Li, Yueming; Wolfe, Michael S; Shachaf, Cathy; Felsher, Dean; Blacklow, Stephen C; Pear, Warren S; Aster, Jon C

    2006-08-01

    Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.

  3. Delphinidin induces cytotoxicity and potentiates cytocidal effect in combination with arsenite in an acute promyelocytic leukemia NB4 cell line.

    PubMed

    Yuan, Bo; Okusumi, Saki; Yoshino, Yuta; Moriyama, Chihiro; Tanaka, Sachiko; Hirano, Toshihiko; Takagi, Norio; Toyoda, Hiroo

    2015-07-01

    The effects of delphinidin were investigated by focusing on growth inhibition, cell cycle arrest and apoptosis induction in the human acute promyelocytic leukemia (APL) NB4 cell line. Delphinidin exhibited a dose- and time-dependent cytotoxic effect against NB4 cells. Almost no cell cycle arrest, but an apparent increase in the percentage of sub-G1 cells was observed in delphinidin-treated cells. The activation of caspase-8 and -9 was observed as early as 1-h post-exposure to delphinidin, followed by the activation of caspase-3 from 3-h post-exposure. A substantial decrease in the expression level of Bid was also observed as early as 1-h post-exposure. A modest decrease in the mitochondrial membrane potential (ΔΨm) was observed at 3-h post-exposure, followed by a substantial time-dependent decrease in ΔΨm in treated cells. Delphinidin exerted more potent cytotoxicity against NB4 cells than normal peripheral blood mononuclear cells (PBMNCs). In addition, delphinidin in combination with an arsenic derivative arsenite (As(III)), which has demonstrated marked efficacy in patients with APL, achieved an enhanced cytocidal effect against NB4 cells, but lesser on PBMNCs. Treatment of NB4 cells with As(III) plus delphinidin did not increase, but decreased slightly, intracellular arsenic accumulation (As[i]) as compared to that treated with As(III) alone. These results suggested that delphinidin selectively sensitized NB4 cells to As(III), resulting in the enhancement of As(III) cytotoxicity by strengthening intrinsic/extrinsic pathway-mediated apoptosis induction, rather than affecting the As[i] levels. These observations may offer a rationale for the use of delphinidin to improve the clinical efficacy of As(III).

  4. Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

    SciTech Connect

    Wong, Jeffrey Y.C.; Forman, Stephen; Somlo, George; Liu An; Schultheiss, Timothy; Radany, Eric; Palmer, Joycelynne; Stein, Anthony

    2013-01-01

    Purpose: We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens. Methods and Materials: Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 {mu}M min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily. Results: Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials. Conclusions: TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to

  5. The CCL2/CCR2 Axis Affects Transmigration and Proliferation but Not Resistance to Chemotherapy of Acute Myeloid Leukemia Cells

    PubMed Central

    Macanas-Pirard, Patricia; Quezada, Thomas; Navarrete, Leonardo; Broekhuizen, Richard; Leisewitz, Andrea; Nervi, Bruno; Ramírez, Pablo A.

    2017-01-01

    Acute myeloid leukemia (AML) has a high mortality rate despite chemotherapy and transplantation. Both CXCR4/SDF-1 and VLA-4/VCAM1 axes are involved in leukemia protection but little is known about the role of CCL2/CCR2 in AML biology and protection against chemotherapy. We measured CCR2 expression in AML cell lines and primary AML cells by flow cytometry (FCM), real time PCR (RT-PCR) and western blot (WB). CCL2 production was quantified by solid phase ELISA in peripheral blood (PB) and bone marrow (BM) serum. We measured chemotaxis in a transwell system with different concentrations of CCL2/CCR2 blockers; cell cycle with BrDU and propidium iodide and proliferation with yellow tetrazolium MTT. We determined synergy in in vitro cell apoptosis combining chemotherapy and CCL2/CCR2 blockade. Finally, we performed chemoprotection studies in an in vivo mouse model. Of 35 patients, 23 (65%) expressed CCR2 by FCM in PB. Two cell lines expressed high levels of CCR2 (THP-1 and murine AML). RT-PCR and WB confirmed CCR2 production. CCL2 solid phase ELISA showed significantly lower levels of CCL2 in PB and BM compared to normal controls. Chemotaxis experiments confirmed a dose-dependent migration in AML primary cells expressing CCR2 and THP-1 cells. A significant inhibition of transmigration was seen after CCL2/CCR2 blockade. Proliferation of CCR2+ AML cell lines was slightly increased (1.4-fold) after axis stimulation. We observed a non-significant increase in phase S THP-1 cells exposed to CCL2 and a concomitant decrease of cells in G1. The chemotherapy studies did not show a protective effect of CCL2 on cytarabine-induced apoptosis or synergy with chemotherapy after CCL2/CCR2 blockade both in vitro and in vivo. In conclusion, CCL2/CCR2 axis is expressed in the majority of monocytoid AML blasts. The axis is involved in cell trafficking and proliferation but no in vitro and in vivo chemotherapy protective effect was seen. PMID:28045930

  6. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.

    PubMed

    Davila, Marco L; Kloss, Christopher C; Gunset, Gertrude; Sadelain, Michel

    2013-01-01

    Although many adults with B cell acute lymphoblastic leukemia (B-ALL) are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs) and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ζ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL.

  7. Understanding Leukemia

    MedlinePlus

    ... the leukemia cells crowd out or suppress the development of normal cells. The rate at which leukemia progresses and how the cells replace the normal blood and marrow cells are different with each type of leukemia. Acute myeloid leukemia (AML) and acute ...

  8. Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia

    PubMed Central

    Kariminia, Amina; Ivison, Sabine M.; Leung, Vivian M.; Sung, Susanna; Couto, Nicole; Rozmus, Jacob; Rolf, Nina; Narendran, Aru; Dunn, Sandra E.; Reid, Gregor S.D.; Schultz, Kirk R.

    2017-01-01

    Y-box-binding protein 1 (YB-1) is a regulatory protein that is associated with drug resistance and relapse in solid tumors. As YB-1 mediates some of its activity through growth factor receptor signaling dysregulation, the present study compared the expression of YB-1 and interleukin 7 (IL-7) receptor α (IL-7Rα) in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) and normal BCP cells. The expression levels of IL-7Rα and YB-1 were higher in relapsed vs. diagnostic samples of primary BCP ALL; however, co-expression was also observed in a minor BCP cell population in samples from healthy donors. Functional crosstalk between YB-1 and IL-7R was detected: Overexpression of YB-1 increased surface levels of IL-7R in B cells, and the stimulation of BCP ALL cell lines and primary samples by IL-7 activated YB-1 by phosphorylation at S102 in a phosphatidylinositol 3-kinase-independent and MEK1/2-dependent manner. Targeted knockdown of YB-1 reduced IL-7-mediated protection against rapamycin, and an inhibitor of MEK1/2 potentiated rapamycin-mediated killing in the presence of IL-7. These data establish a novel link between two well-characterized pro-survival factors in acute leukemia, and suggest that YB-1 inhibition may represent a novel therapeutic strategy for increasing sensitivity to chemotherapy in patients with refractory acute B-cell leukemia. PMID:28123588

  9. 5-Fluoro-2'-Deoxycytidine and Tetrahydrouridine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2015-06-03

    Adult Acute Myeloid Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  10. Selumetinib in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-07-06

    Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Promyelocytic Leukemia (M3); Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  11. Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.

    PubMed

    Rahman, Sunniyat; Magnussen, Michael; León, Theresa E; Farah, Nadine; Li, Zhaodong; Abraham, Brian J; Alapi, Krisztina Z; Mitchell, Rachel J; Naughton, Tom; Fielding, Adele K; Pizzey, Arnold; Bustraan, Sophia; Allen, Christopher; Popa, Teodora; Pike-Overzet, Karin; Garcia-Perez, Laura; Gale, Rosemary E; Linch, David C; Staal, Frank J T; Young, Richard A; Look, A Thomas; Mansour, Marc R

    2017-03-07

    Somatic mutations within non-coding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines, in addition to 3.7% (6/160) of pediatric and 5.5% (9/163) of adult T-ALL patient samples. The majority of indels harbour putative de novo MYB, ETS1 or RUNX1 consensus binding sites. Analysis of 5'-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provide important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy induced T-ALL, suggesting that such events occur at preferential sites in the non-coding genome.

  12. PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia

    PubMed Central

    Silveira, André Bortolini; Laranjeira, Angelo Brunelli Albertoni; Rodrigues, Gisele Olinto Libanio; Leal, Paulo César; Cardoso, Bruno António; Barata, João Taborda; Yunes, Rosendo Augusto; Zanchin, Nilson Ivo Tonin; Brandalise, Sílvia Regina; Yunes, José Andrés

    2015-01-01

    The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy. PMID:25869207

  13. Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines

    PubMed Central

    Mohan, Chakrabhavi D.; Madan, Vikas; Kanojia, Deepika; Shobith, Rangappa; Nanjundaswamy, Shivananju; Mason, Daniel J.; Bender, Andreas; Basappa; Rangappa, Kanchugarakoppal S.; Koeffler, H. Phillip

    2014-01-01

    The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular π-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent. PMID:25268519

  14. Histiocytic differentiation in acute monocytic leukemia.

    PubMed

    Ru, Yong-xin; Dong, Shu-xu; Zhao, Shi-xuan; Liang, Hao-yue; Wang, Hui-jun; Hu, Xiao; Mi, Ying-chang; Wang, Jian-xiang

    2016-01-01

    Myeloid histocytes of dendritic cells (DCs), Langerhans cells (LCs), and macrophages in varied tissues, as leukemic blasts in acute monoblastic and monocytic leukemia (AML-M5a and M5b), are derived from monocyte progenitors in bone marrow. Based on DC induction from hematopoietic stem cells, myeloid progenitors, and monocytes, and occasional expressions of histocyte-related antigens (HRAs) in M5, we presume some M5 cases share histiocytic phenotypes originally. To clarify the conception, 93 M5 cases were tested with antibodies for HRAs, CD1a, CD163, S100, fascin, and langerin by immunostaining, and their morphologic characteristics were studied by light and transmission electron microscopy. The study revealed that 23 M5 cases were positive for two or more kinds of HRAs and shared a serial of histocytic immunophenotype and morphologic features, which were closely associated with M5b subtype and expression of CD14 in M5.

  15. Acute lymphoblastic leukemia and developmental biology

    PubMed Central

    Campos-Sanchez, Elena; Toboso-Navasa, Amparo; Romero-Camarero, Isabel; Barajas-Diego, Marcos

    2011-01-01

    The latest scientific findings in the field of cancer research are redefining our understanding of the molecular and cellular basis of the disease, moving the emphasis toward the study of the mechanisms underlying the alteration of the normal processes of cellular differentiation. The concepts best exemplifying this new vision are those of cancer stem cells and tumoral reprogramming. The study of the biology of acute lymphoblastic leukemias (ALLs) has provided seminal experimental evidence supporting these new points of view. Furthermore, in the case of B cells, it has been shown that all the stages of their normal development show a tremendous degree of plasticity, allowing them to be reprogrammed to other cellular types, either normal or leukemic. Here we revise the most recent discoveries in the fields of B-cell developmental plasticity and B-ALL research and discuss their interrelationships and their implications for our understanding of the biology of the disease. PMID:22031225

  16. Anti-CD19 chimeric antigen receptor T-cell therapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia

    PubMed Central

    Zhu, Yang-min; Wu, Zhao; Tan, You-ping; Du, Yuan-yuan; Liu, Zhi; Ou, Rui-ming; Liu, Shuang; Pu, Cheng-fei; Jiang, Jing; Wang, Jin-ping; Xiao, Lei; Zhang, Qing

    2016-01-01

    Abstract Rationale: The presence of the Philadelphia chromosome (Ph) in acute lymphoblastic leukemia (ALL) has been associated with a high risk of disease relapse and a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for adults with Ph-positive ALL, but relapse remains the primary cause of treatment failure, and is associated with an extremely poor prognosis. The emergence of resistance to tyrosine kinase inhibitors (TKIs) poses a challenge for patients with disease relapses after initial treatment with TKI-containing regimens. Patient concerns: Two patients with TKI-resistant recurrent Ph-positive ALL. Diagnoses: Ph-positive ALL. Interventions: Anti-CD19 CAR T-cell infusion. Outcomes: One patient's bone marrow blasts decreased significantly, and the other reached negative minimal residual disease (MRD). However, we first recorded the development of new-onset acute graft-versus-host disease (aGVHD) after anti-CD19 CAR T-cell infusion in a patient who received allogeneic HSCT. Our 2 case reports also demonstrate the efficacy of anti-CD19 CAR T-cell therapy in the treatment of TKI-resistant Ph-positive ALL. Lessons: Our report suggests that anti-CD19 CAR T-cell therapy may be a promising option for the treatment of relapsed Ph-positive ALL after conventional chemotherapy or allogeneic HSCT. However, caution is due given the possibility of the adverse effects of cytokine release syndrome (CRS)-induced aGVHD for patients receiving allogeneic HSCT. PMID:28002337

  17. Combined treatment with fenretinide and indomethacin induces AIF-mediated, non-classical cell death in human acute T-cell leukemia Jurkat cells

    SciTech Connect

    Hojka-Osinska, Anna; Ziolo, Ewa; Rapak, Andrzej

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer The combination of fenretinide and indomethacin induces a high level of cell death. Black-Right-Pointing-Pointer Apoptotic pathway is caspase-independent. Black-Right-Pointing-Pointer Jurkat cells undergo AIF-mediated cell death. -- Abstract: Currently used cytotoxic drugs in cancer therapy have a similar mechanism of action and low specificity. Applied simultaneously, they show an additive effect with strong side effects. Clinical trials with the use of different agents in cancer therapy show that the use of these compounds alone is not very effective in fighting cancer. An alternative solution could be to apply a combination of these agents, because their combination has a synergistic effect on some cancer cells. Therefore, in our investigations we examined the effects of a synthetic retinoid-fenretinide when combined with a non-steroidal anti-inflammatory drug-indomethacin on the process of apoptosis in the acute human T-cell leukemia cell line Jurkat. We demonstrate that treatment with the combination of the tested compounds induces the death of cells, that is peculiar and combines features of apoptosis as well as non-apoptotic cell death. In detail we observed, cell membrane permeabilization, phosphatydylserine exposure, no oligonucleosomal DNA fragmentation, no caspase-3 activation, but apoptosis inducing factor (AIF) nuclear translocation. Taken together these results indicate, that Jurkat cells after treatment with a combination of fenretinide and indomethacin undergo AIF-mediated programmed cell death.

  18. WP1066 disrupts Janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells.

    PubMed

    Ferrajoli, Alessandra; Faderl, Stefan; Van, Quin; Koch, Patricia; Harris, David; Liu, Zhiming; Hazan-Halevy, Inbal; Wang, Yongtao; Kantarjian, Hagop M; Priebe, Waldemar; Estrov, Zeev

    2007-12-01

    Several cytokines and growth factors that stimulate the proliferation of acute myelogenous leukemia (AML) cells transduce their signals by activating the transcription factor Janus-activated kinase 2 (JAK2). Accordingly, the inhibition of JAK2 or of its downstream signaling pathways suppresses the proliferation of AML cells. Because (E)-3(6-bromopyridin-2-yl)-2-cyano-N-((S0-1-phenylethyl)acrylamide) (WP1066) is a novel analogue of the JAK2 inhibitor AG490, we tested its activity in AML cells and investigated its mechanism of action. Using clonogenic assays, we found that although WP1066 had a marginal effect on normal marrow progenitors, it inhibited the proliferation of AML colony-forming cells obtained from patients with newly diagnosed AML and that of the AML cell lines OCIM2 and K562. WP1066 inhibited OCIM2 cell multiplication by inducing accumulation of cells at the G(0)-G(1) phase of the cell cycle. Similar to its parent compound AG490, WP1066 inhibited the phosphorylation of JAK2, but unlike AG490, WP1066 also degraded JAK2 protein, thereby blocking its downstream signal transducer and activator of transcription (STAT) and phosphoinositide-3-kinase pathways. These effects resulted in the activation of the caspase pathway. Incubation of both OCIM2 and K562 cells with WP1066 activated caspase-3, induced cleavage of poly(ADP-ribose) polymerase, and caused caspase-dependent apoptotic cell death. Thus, WP1066 is a potent JAK2 inhibitor whose effects in AML and other hematologic malignancies merit further investigation.

  19. Intracerebral metastasis in pediatric acute lymphoblastic leukemia: A rare presentation

    PubMed Central

    Gokce, Müge; Aytac, Selin; Altan, Ilhan; Unal, Sule; Tuncer, Murat; Gumruk, Fatma; Cetin, Mualla

    2012-01-01

    Central nervous system leukemia may present in different ways. However, intraparenchymal mass is extremely rare in childhood leukemia. Herein, we report a boy who presented with right hemiparesis and anisocoria 1 year after the cessation of the chemotherapy protocol for acute lymphoblastic leukemia. Cranial imaging demonstrated an extensive mass located in the anterior white matter of left frontal lobe, and cerebrospinal fluid examination revealed concomitant lymphoblasts. Immunohistochemical staining of the biopsy material showed neoplastic cells with positive CD10 and TdT. Complete remission was achieved with chemotherapy alone for a duration of 2 years. PMID:23560011

  20. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.

    PubMed

    Pegram, H J; Purdon, T J; van Leeuwen, D G; Curran, K J; Giralt, S A; Barker, J N; Brentjens, R J

    2015-02-01

    Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19(+) tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.

  1. A reliable Raman-spectroscopy-based approach for diagnosis, classification and follow-up of B-cell acute lymphoblastic leukemia

    PubMed Central

    Managò, Stefano; Valente, Carmen; Mirabelli, Peppino; Circolo, Diego; Basile, Filomena; Corda, Daniela; De Luca, Anna Chiara

    2016-01-01

    Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder that shows high mortality rates due to immature lymphocyte B-cell proliferation. B-ALL diagnosis requires identification and classification of the leukemia cells. Here, we demonstrate the use of Raman spectroscopy to discriminate normal lymphocytic B-cells from three different B-leukemia transformed cell lines (i.e., RS4;11, REH, MN60 cells) based on their biochemical features. In combination with immunofluorescence and Western blotting, we show that these Raman markers reflect the relative changes in the potential biological markers from cell surface antigens, cytoplasmic proteins, and DNA content and correlate with the lymphoblastic B-cell maturation/differentiation stages. Our study demonstrates the potential of this technique for classification of B-leukemia cells into the different differentiation/maturation stages, as well as for the identification of key biochemical changes under chemotherapeutic treatments. Finally, preliminary results from clinical samples indicate high consistency of, and potential applications for, this Raman spectroscopy approach. PMID:27089853

  2. A reliable Raman-spectroscopy-based approach for diagnosis, classification and follow-up of B-cell acute lymphoblastic leukemia

    NASA Astrophysics Data System (ADS)

    Managò, Stefano; Valente, Carmen; Mirabelli, Peppino; Circolo, Diego; Basile, Filomena; Corda, Daniela; de Luca, Anna Chiara

    2016-04-01

    Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder that shows high mortality rates due to immature lymphocyte B-cell proliferation. B-ALL diagnosis requires identification and classification of the leukemia cells. Here, we demonstrate the use of Raman spectroscopy to discriminate normal lymphocytic B-cells from three different B-leukemia transformed cell lines (i.e., RS4;11, REH, MN60 cells) based on their biochemical features. In combination with immunofluorescence and Western blotting, we show that these Raman markers reflect the relative changes in the potential biological markers from cell surface antigens, cytoplasmic proteins, and DNA content and correlate with the lymphoblastic B-cell maturation/differentiation stages. Our study demonstrates the potential of this technique for classification of B-leukemia cells into the different differentiation/maturation stages, as well as for the identification of key biochemical changes under chemotherapeutic treatments. Finally, preliminary results from clinical samples indicate high consistency of, and potential applications for, this Raman spectroscopy approach.

  3. Inhibitory effects of physalin B and physalin F on various human leukemia cells in vitro.

    PubMed

    Chiang, H C; Jaw, S M; Chen, P M

    1992-01-01

    Physalins B and F were isolated and characterized from the ethanolic extract of the whole plant of Physalis angulata L. (Solanaceae). Both physalin B and physalin F inhibited the growth of several human leukemia cells: K562 (erythroleukemia), APM1840 (acute T lymphoid leukemia), HL-60 (acute promyelocytic leukemia), KG-1 (acute myeloid leukemia), CTV1 (acute monocytic leukemia) and B cell (acute B lymphoid leukemia). Physalin F showed a stronger activity against these leukemia cells than physalin B, especially against acute myeloid leukemia (KG-1) and acute B lymphoid leukemia (B cell). From the structural features, the active site seems to be the functional epoxy group for physalin F and the double bond for physalin B located at carbon 5 and 6; the former is much more active than the latter as regards anti-leukemic effects.

  4. Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-05-05

    Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  5. Romidepsin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-12-03

    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); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  6. Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2017-03-09

    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); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  7. Azacitidine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With High-Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-10-24

    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 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(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); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  8. Tipifarnib and Etoposide in Treating Older Patients With Newly Diagnosed, Previously Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-10-01

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Del(5q); 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  9. Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-06-03

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Del(5q); 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  10. Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-07-14

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  11. Omacetaxine Mepesuccinate, Cytarabine, and Decitabine in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-05

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Del(5q); 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  12. Choline Magnesium Trisalicylate and Combination Chemotherapy in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2017-02-01

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 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(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); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  13. Eltrombopag Olamine in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-04

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Del(5q); 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); Recurrent Adult Acute Myeloid Leukemia

  14. S0432 Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-01-14

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 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(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); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  15. A murine model of acute myeloid leukemia with Evi1 overexpression and autocrine stimulation by an intracellular form of GM-CSF in DA-3 cells.

    PubMed

    Cardona, Maria E; Simonson, Oscar E; Oprea, Iulian I; Moreno, Pedro M D; Silva-Lara, Maria F; Mohamed, Abdalla J; Christensson, Birger; Gahrton, Gösta; Dilber, M Sirac; Smith, C I Edvard; Arteaga, H Jose

    2016-01-01

    The poor treatment response of acute myeloid leukemia (AML) overexpressing high-risk oncogenes such as EVI1, demands specific animal models for new treatment evaluations. Evi1 is a common site of activating integrations in murine leukemia virus (MLV)-induced AML and in retroviral and lentiviral gene-modified HCS. Still, a model of overt AML induced by Evi1 has not been generated. Cell lines from MLV-induced AML are growth factor-dependent and non-transplantable. Hence, for the leukemia maintenance in the infected animals, a growth factor source such as chronic immune response has been suggested. We have investigated whether these leukemias are transplantable if provided with growth factors. We show that the Evi1(+)DA-3 cells modified to express an i