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1

Involvement of primary mesenchymal precursors and hematopoietic bone marrow cells from chronic myeloid leukemia patients by BCR-ABL1 fusion gene.  

PubMed

For decades now, it is well established that chronic myeloid leukemia (CML) is a hematopoietic stem cell(HPC) disorder. However, it remains to be determined whether BCR-ABL1 gene rearrangement occurs in a HPC or at an earlier stem cell and whether the degree of involvement of hematopoiesis by the BCR-ABL1 fusion gene relates to the response to therapy. Here, we have investigated by interphase fluorescence in situ hybridization (iFISH) the distribution of BCR-ABL1 fusion gene in FACS-sorted bone marrow (BM) populations of mesenchymal precursor cells (MPC) and other hematopoietic cell populations from 18 newly diagnosed CML patients. Overall, our results showed systematic involvement at relatively high percentages of BM maturing neutrophils (97%615%), basophils (95%612%), eosinophils (90%68%), CD341 precursors cells (90%67%),monocytes (84%630%), nucleated red blood cells (87%624%), and mast cells (77%633%). By contrast, MPC(30%634%), B-cells (15%627%), T-lymphocytes (50%626%), and NK-cells (35%634%) were involved at lower percentages. In 8/18 CML patients, 2 tumor BCR-ABL11 subclones were detected by iFISH. Of note, all tumor cell subclones were systematically detected in CD341 cells, whereas MPC were only involved by the ancestral tumor cell subclone. In summary, here we confirm the presence at diagnosis of the BCR-ABL1 fusion gene inMPC, CD341 precursors, and other different BM hematopoietic myeloid cell lineages from CML patients,including also in a significant fraction of cases, a smaller percentage of T, B, and NK lymphocytes.Interestingly, involvement of MPC was restricted to the ancestral BCR-ABL11 subclone. PMID:24779036

Chandia, Mauricio; Sayagués, José-María; Gutiérrez, María-Laura; Chillón, María-Laura; Aristizábal, José-Alejandro; Corrales, Alejandro; Castellanos, Marta; Melón, Alberto; Sánchez, María-Luz; Bárcena, Paloma; Matarraz, Sergio; González-González, María; Barrena, Susana; López, Antonio; Cañizo, María-Consuelo; Sánchez-Guijo, Fermín; Orfao, Alberto

2014-03-01

2

Flk2/Flt3 promotes both myeloid and lymphoid development by expanding non-self-renewing multipotent hematopoietic progenitor cells.  

PubMed

Defining differentiation pathways is central to understanding the pathogenesis of hematopoietic disorders, including leukemia. The function of the receptor tyrosine kinase Flk2 (Flt3) in promoting myeloid development remains poorly defined, despite being commonly mutated in acute myeloid leukemia. We investigated the effect of Flk2 deficiency on myelopoiesis, focusing on specification of progenitors between HSC and mature cells. We provide evidence that Flk2 is critical for proliferative expansion of multipotent progenitors that are common precursors for all lymphoid and myeloid lineages, including megakaryocyte/erythroid (MegE) cells. Flk2 deficiency impaired the generation of both lymphoid and myeloid progenitors by abrogating propagation of their common upstream precursor. At steady state, downstream compensatory mechanisms masked the effect of Flk2 deficiency on mature myeloid output, whereas transplantation of purified progenitors revealed impaired generation of all mature lineages. Flk2 deficiency did not affect lineage choice, thus dissociating the role of Flk2 in promoting cell expansion and regulating cell fate. Surprisingly, despite impairing myeloid development, Flk2 deficiency afforded protection against myeloablative insult. This survival advantage was attributed to reduced cell cycling and proliferation of progenitors in Flk2-deficient mice. Our data support the existence of a common Flk2(+) intermediate for all hematopoietic lineages and provide insight into how activating Flk2 mutations promote hematopoietic malignancy by non-Flk2-expressing myeloid cells. PMID:24333663

Beaudin, Anna E; Boyer, Scott W; Forsberg, E Camilla

2014-03-01

3

Myeloid skewing in murine autoimmune arthritis occurs in hematopoietic stem and primitive progenitor cells  

PubMed Central

Skewing toward myeloid cell production is often observed in chronic inflammation and autoimmune diseases. Herein, we determined whether persistent myeloid activation and proinflammatory output occurring in pathologic conditions is at the level of hematopoietic stem and primitive progenitor cells (HSPPCs). By using a mouse arthritis model, we found that even though HSPPCs in arthritis still retained the capacity to differentiate into different lineages, they acquired enhanced in vitro and in vivo propensity in a disease-dependent manner to generate myeloid cells, the key perpetrators of tissue damage in arthritis. This myeloid skewing was cell intrinsic, as arthritic HSPPCs up-regulate myeloid-specific transcripts including S100a8. Exogenous S100a8 promoted myeloid cell output from wild-type HSPPCs, suggesting mechanistic involvement of this gene in the myeloid priming that occurs in arthritic HSPPCs. Therefore, our results indicate that in arthritic mice, HSPPCs adopt a pathologic state that favors disease persistence. PMID:22855602

Oduro, Kwadwo A.; Liu, Fang; Tan, Qing; Kim, Chan-Kyu; Lubman, Olga; Fremont, Daved; Mills, Jason C.

2012-01-01

4

FLT3 internal tandem duplication in CD34\\/CD33 precursors predicts poor outcome in acute myeloid leukemia  

Microsoft Academic Search

Acute myeloid leukemia (AML) is a clonal disease characterized by heterogeneous involvement of hematopoietic stem cell\\/ progenitor cell populations. Using FLT3 internal tandem duplication (FLT3\\/ITD) as a molecular marker, we tested the hypoth- esis that clinical outcome in AML corre- lates with disease involvement of CD34\\/ CD33precursors. Diagnostic specimens from 24 children with FLT3\\/ITD-positive AML were sorted by fluorescence- activated

Jessica A. Pollard; Todd A. Alonzo; Robert B. Gerbing; William G. Woods; Beverly J. Lange; David A. Sweetser; Jerald P. Radich; Irwin D. Bernstein; Soheil Meshinchi

2006-01-01

5

Transcriptome-wide Profiling and Posttranscriptional Analysis of Hematopoietic Stem/Progenitor Cell Differentiation toward Myeloid Commitment  

PubMed Central

Summary Hematopoietic stem cells possess lifelong self-renewal activity and generate multipotent progenitors that differentiate into lineage-committed and subsequently mature cells. We present a comparative transcriptome analysis of ex vivo isolated mouse multipotent hematopoietic stem/progenitor cells (LinnegSCA-1+c-KIT+) and myeloid committed precursors (LinnegSCA-1negc-KIT+). Our data display dynamic transcriptional networks and identify a stem/progenitor gene expression pattern that is characterized by cell adhesion and immune response components including kallikrein-related proteases. We identify 498 expressed lncRNAs, which are potential regulators of multipotency or lineage commitment. By integrating these transcriptome with our recently reported proteome data, we found evidence for posttranscriptional regulation of processes including metabolism and response to oxidative stress. Finally, our study identifies a high number of genes with transcript isoform regulation upon lineage commitment. This in-depth molecular analysis outlines the enormous complexity of expressed coding and noncoding RNAs and posttranscriptional regulation during the early differentiation steps of hematopoietic stem cells toward the myeloid lineage.

Klimmeck, Daniel; Cabezas-Wallscheid, Nina; Reyes, Alejandro; von Paleske, Lisa; Renders, Simon; Hansson, Jenny; Krijgsveld, Jeroen; Huber, Wolfgang; Trumpp, Andreas

2014-01-01

6

Transcriptome-wide Profiling and Posttranscriptional Analysis of Hematopoietic Stem/Progenitor Cell Differentiation toward Myeloid Commitment.  

PubMed

Hematopoietic stem cells possess lifelong self-renewal activity and generate multipotent progenitors that differentiate into lineage-committed and subsequently mature cells. We present a comparative transcriptome analysis of ex vivo isolated mouse multipotent hematopoietic stem/progenitor cells (Lin(neg)SCA-1(+)c-KIT(+)) and myeloid committed precursors (Lin(neg)SCA-1(neg)c-KIT(+)). Our data display dynamic transcriptional networks and identify a stem/progenitor gene expression pattern that is characterized by cell adhesion and immune response components including kallikrein-related proteases. We identify 498 expressed lncRNAs, which are potential regulators of multipotency or lineage commitment. By integrating these transcriptome with our recently reported proteome data, we found evidence for posttranscriptional regulation of processes including metabolism and response to oxidative stress. Finally, our study identifies a high number of genes with transcript isoform regulation upon lineage commitment. This in-depth molecular analysis outlines the enormous complexity of expressed coding and noncoding RNAs and posttranscriptional regulation during the early differentiation steps of hematopoietic stem cells toward the myeloid lineage. PMID:25418729

Klimmeck, Daniel; Cabezas-Wallscheid, Nina; Reyes, Alejandro; von Paleske, Lisa; Renders, Simon; Hansson, Jenny; Krijgsveld, Jeroen; Huber, Wolfgang; Trumpp, Andreas

2014-11-11

7

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function  

PubMed Central

Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b–/loLy6Chi BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell–suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint. PMID:23114597

Charles, Julia F.; Hsu, Lih-Yun; Niemi, Erene C.; Weiss, Arthur; Aliprantis, Antonios O.; Nakamura, Mary C.

2012-01-01

8

Vav promotes differentiation of human tumoral myeloid precursors  

SciTech Connect

Vav is one of the genetic markers that correlate with the differentiation of hematopoietic cells. In T and B cells, it appears crucial for both development and functions, while, in non-lymphoid hematopoietic cells, Vav seems not involved in cell maturation, but rather in the response of mature cells to agonist-dependent proliferation and phagocytosis. We have previously demonstrated that the amount and the tyrosine phosphorylation of Vav are up-regulated in both whole cells and nuclei of tumoral promyelocytes induced to granulocytic maturation by ATRA and that tyrosine-phosphorylated Vav does not display any ATRA-induced GEF activity but contributes to the regulation of PI 3-K activity. In this study, we report that Vav accumulates in nuclei of ATRA-treated APL-derived cells and that the down-modulation of Vav prevents differentiation of tumoral promyelocytes, indicating that it is a key molecule in ATRA-dependent myeloid maturation. On the other hand, the overexpression of Vav induces an increased expression of surface markers of granulocytic differentiation without affecting the maturation-related changes of the nuclear morphology. Consistent with an effect of Vav on the transcriptional machinery, array profiling shows that the inhibition of the Syk-dependent tyrosine phosphorylation of Vav reduces the number of ATRA-induced genes. Our data support the unprecedented notion that Vav plays crucial functions in the maturation process of myeloid cells, and suggest that Vav can be regarded as a potential target for the therapeutic treatment of myeloproliferative disorders.

Bertagnolo, Valeria [Signal Transduction Unit-Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara, 66, 44100 Ferrara (Italy); Brugnoli, Federica [Signal Transduction Unit-Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara, 66, 44100 Ferrara (Italy); Mischiati, Carlo [Department of Biochemistry and Molecular Biology, University of Ferrara (Italy); Sereni, Alessia [Department of Biochemistry and Molecular Biology, University of Ferrara (Italy); Bavelloni, Alberto [Laboratory of Cell Biology and Electron Microscopy, IOR, Bologna (Italy); Carini, Cinzia [Signal Transduction Unit-Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara, 66, 44100 Ferrara (Italy); Capitani, Silvano [Signal Transduction Unit-Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara, 66, 44100 Ferrara (Italy) and MIUR ICSI, Interdisciplinary Center for the Study of Inflammation, University of Ferrara (Italy)]. E-mail: cps@unife.it

2005-05-15

9

Differentiation of hematopoietic stem cell and myeloid populations by ATP is modulated by cytokines  

PubMed Central

Extracellular nucleotides are emerging as important regulators of inflammation, cell proliferation and differentiation in a variety of tissues, including the hematopoietic system. In this study, the role of ATP was investigated during murine hematopoiesis. ATP was able to reduce the percentage of hematopoietic stem cells (HSCs), common myeloid progenitors and granulocyte–macrophage progenitors (GMPs), whereas differentiation into megakaryocyte–erythroid progenitors was not affected. In addition, in vivo administration of ATP to mice reduced the number of GMPs, but increased the number of Gr-1+Mac-1+ myeloid cells. ATP also induced an increased proliferation rate and reduced Notch expression in HSCs and impaired HSC-mediated bone marrow reconstitution in sublethally irradiated mice. Moreover, the effects elicited by ATP were inhibited by suramin, a P2 receptor antagonist, and BAPTA, an intracellular Ca2+ chelator. We further investigated whether the presence of cytokines might modulate the observed ATP-induced differentiation. Treatment of cells with cytokines (stem cell factor, interleukin-3 and granulocyte–monocyte colony stimulator factor) before ATP stimulation led to reduced ATP-dependent differentiation in long-term bone marrow cultures, thereby restoring the ability of HSCs to reconstitute hematopoiesis. Thus, our data suggest that ATP induces the differentiation of murine HSCs into the myeloid lineage and that this effect can be modulated by cytokines. PMID:21633388

Barbosa, C M V; Leon, C M M P; Nogueira-Pedro, A; Wasinsk, F; Araujo, R C; Miranda, A; Ferreira, A T; Paredes-Gamero, E J

2011-01-01

10

B-myb is an essential regulator of hematopoietic stem cell and myeloid progenitor cell development  

PubMed Central

The B-myb (MYBL2) gene is a member of the MYB family of transcription factors and is involved in cell cycle regulation, DNA replication, and maintenance of genomic integrity. However, its function during adult development and hematopoiesis is unknown. We show here that conditional inactivation of B-myb in vivo results in depletion of the hematopoietic stem cell (HSC) pool, leading to profound reductions in mature lymphoid, erythroid, and myeloid cells. This defect is autonomous to the bone marrow and is first evident in stem cells, which accumulate in the S and G2/M phases. B-myb inactivation also causes defects in the myeloid progenitor compartment, consisting of depletion of common myeloid progenitors but relative sparing of granulocyte–macrophage progenitors. Microarray studies indicate that B-myb–null LSK+ cells differentially express genes that direct myeloid lineage development and commitment, suggesting that B-myb is a key player in controlling cell fate. Collectively, these studies demonstrate that B-myb is essential for HSC and progenitor maintenance and survival during hematopoiesis. PMID:24516162

Baker, Stacey J.; Ma'ayan, Avi; Lieu, Yen K.; John, Premila; Reddy, M. V. Ramana; Chen, Edward Y.; Duan, Qiaonan; Snoeck, Hans-Willem; Reddy, E. Premkumar

2014-01-01

11

Current status of hematopoietic stem cell transplant in chronic myeloid leukemia  

PubMed Central

Indications for hematopoietic stem cell transplant (HSCT) in chronic myeloid leukemia (CML) have changed over time. This change has largely been influenced by the advent of tyrosine kinase inhibitors, increased understanding of the mechanisms underlying disease phase progression as well as drug resistance, refinement of transplant techniques and exploitation of graft versus leukemia effect in this disease. Here, we have discussed the status of HSCT in CML in the present era with regards to the current indications, factors determining outcome and management strategies for posttransplant relapse.

Gupta, Alok; Khattry, Navin

2014-01-01

12

Treatment of relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.  

PubMed

Disease relapse remains a major cause of mortality for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Historically, patients who experience disease relapse after HSCT have a dismal prognosis with very few long-term survivors. There is no standard treatment for patients in this situation given the variability in patient characteristics, disease biology, complications such as graft-vs.-host disease (GVHD) and infections, donor availability, and patient choice. Here, we discuss the current options for treatment of relapsed AML after HSCT including conventional chemotherapy, novel agents, donor leukocyte infusion, second allogeneic HSCT, and emerging therapies. PMID:24643311

Fathi, Amir T; Chen, Yi-Bin

2014-06-01

13

The AML1/ETO target gene LAT2 interferes with differentiation of normal hematopoietic precursor cells  

PubMed Central

The adaptor protein linker activator of T-cells 2 (LAT2) is a known AML1/ETO target gene whose function during normal hematopoiesis is unknown. We addressed the role of LAT2 during erythroid and myeloid differentiation of normal human CD34+ hematopoietic cells. LAT2 is expressed at low levels in CD34+ cells and upregulated during cytokine-induced myeloid and erythroid differentiation. Forced LAT2 expression leads to a delay of erythroid and myeloid differentiation keeping CD34+ cells in a more immature state, whereas LAT2 knockdown accelerates differentiation. It is tempting to speculate that by affecting the differentiation capacity of normal hematopoietic progenitors, LAT2 may contribute to the pathogenesis of AML. PMID:24456692

Essig, Aitomi; Duque-Afonso, Jesus; Schwemmers, Sven; Pahl, Heike L.; Lubbert, Michael

2014-01-01

14

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

PubMed

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. PMID:25074248

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

2014-06-01

15

Hematopoietic cell crisis: An early stage of evolving myeloid leukemia following radiation exposure  

SciTech Connect

Under select radiological conditions, chronic radiation exposure elicits a high incidence of myeloproliferative disease, principally myeloid leukemia (ML), in beagles. Previously we demonstrated that for full ML expression, a four-stage preclinical sequence is required, namely (1) suppression, (2) recovery, (3) accommodation, and (4) preleukemic transition. Within this pathological sequence, a critical early event has been identified as the acquisition of radioresistance by hematopoietic progenitors that serves to mediate a newfound regenerative hematopoietic capacity. As such, this event sets the stage'' for preleukemic progression by initiating progression from preclinical phase 1 to 2. Due to the nature of target cell suppression, the induction of crisis, and the outgrowth of progenitors with altered phenotypes, this preleukemic event resembles the immortalization'' step of the in vitro transformation sequence following induction with either physical and chemical carcinogens. The radiological, temporal, and biological dictates governing this event have been extensively evaluated and will be discussed in light of their role in the induction and progression of chronic radiation leukemia. 35 refs., 2 tabs.

Seed, T.M.

1990-01-01

16

Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT.  

PubMed

Patients with hematopoietic malignancies relapsing after allogeneic hematopoietic SCT (allo-HSCT) have a poor prognosis. We retrospectively analyzed the patients who received azacitidine in our center in the course of treatment of their post-transplant relapse. We identified 31 patients. Relapse occurred at a median of 3.7 (1.7-37.6) months following allo-HSCT. Patients received a median number of three cycles (1-12) of azacitidine (7 days, 75 mg/m(2) daily). Thirty-nine percent of patients had either a monosomal karyotype or a complex karyotype. Eleven patients (35%) received at least one DLI. Eleven patients responded to azacitidine, with four patients achieving a CR (13%). Median time to best response was 92 (35-247) days, with a median duration of 209 (64-751) days. One-year estimated survival rate was 14%. In conclusion, azacitidine may reinduce durable remissions in very few patients with AML or myelodysplastic syndrome. The toxicity related to azacitidine was high, although it may be difficult to distinguish between treatment-related side effects, namely due to cytopenia and toxicity due to the relapse or disease progression itself. Early administration of azacitidine after transplant followed by DLI should be considered as a pre-emptive therapy for potential relapse in patients with minimal residual disease or high-risk myeloid malignancies. PMID:24488048

Tessoulin, B; Delaunay, J; Chevallier, P; Loirat, M; Ayari, S; Peterlin, P; Le Gouill, S; Gastinne, T; Moreau, P; Mohty, M; Guillaume, T

2014-04-01

17

Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells  

PubMed Central

Acute myeloid leukemia (AML) often relapses following chemotherapy-induced remission and is generally chemo-resistant. Given the potential role for cancer stem cells in relapse, targeting of the leukemia-initiating cell (LIC) in AML may provide improved outcome following remission induction. However, due to overlap in their self-renewal program with normal hematopoietic stem cells (HSCs), therapeutic targeting of the LIC may have an adverse effect on long-term hematopoietic recovery. Here we used a mouse model of relapsed AML to explore whether the hypoxia-inducible factor (HIF)1? inhibitor echinomycin can be used to treat relapsed AML without affecting host HSCs. We show that echinomycin cured 40% to 60% of mice transplanted with relapsed AML. Bone marrow cells from the cured mice displayed normal composition of HSCs and their progenitors and were as competent as those isolated from nonleukemic mice in competitive repopulation assays. Importantly, in mice with complete remission, echinomycin appeared to completely eliminate LICs because no leukemia could be propagated in vivo following serial transplantation. Taken together, our data demonstrate that in a mouse model of relapsed AML, low-dose echinomycin selectively targets LICs and spares normal hematopoiesis. PMID:24994068

Wang, Yin; Liu, Yan; Tang, Fei; Bernot, Kelsie M.; Schore, Reuven; Marcucci, Guido

2014-01-01

18

Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque  

PubMed Central

We report, for the first time, a replication-defective retroviral vector–associated neoplasia in a nonhuman primate. Five years after transplantation with CD34+ cells transduced with a retroviral vector expressing enhanced green fluorescent protein (eGFP) and a drug-resistant variant of the dihydrofolate reductase gene (L22Y), a rhesus macaque developed a fatal myeloid sarcoma, a type of acute myeloid leukemia. Tumor cells contained 2 clonal vector insertions. One insertion was found in BCL2-A1, an antiapoptotic gene. This event suggests that currently available retroviral vectors may have long-term side effects, particularly in hematopoietic stem and progenitor cells. PMID:16439674

Seggewiss, Ruth; Pittaluga, Stefania; Adler, Rima L.; Guenaga, F. Javier; Ferguson, Cole; Pilz, Ingo H.; Ryu, Byoung; Sorrentino, Brian P.; Young, W. Scott; Donahue, Robert E.; von Kalle, Christof; Nienhuis, Arthur W.; Dunbar, Cynthia E.

2006-01-01

19

HoxB4 Confers Definitive Lymphoid-Myeloid Engraftment Potential on Embryonic Stem Cell and Yolk Sac Hematopoietic Progenitors  

Microsoft Academic Search

The extent to which primitive embryonic blood progenitors contribute to definitive lymphoid-myeloid hematopoiesis in the adult remains uncertain. In an effort to characterize factors that distinguish the definitive adult hematopoietic stem cell (HSC) and primitive progenitors derived from yolk sac or embryonic stem (ES) cells, we examined the effect of ectopic expression of HoxB4, a homeotic selector gene implicated in

Michael Kyba; Rita C. R. Perlingeiro; George Q. Daley

2002-01-01

20

Temozolomide-mediated DNA methylation in human myeloid precursor cells:differential involvement of intrinsic and extrinsic apoptotic pathways  

PubMed Central

Purpose An understanding of how hematopoietic cells respond to therapy that causes myelosuppression will help develop approaches to prevent this potentially life-threatening toxicity. The goal of this study was to determine how human myeloid precursor cells (MP) respond to temozolomide (TMZ)-induced DNA damage. Experimental Design We developed an ex vivo primary human MP cells model system to investigate the involvement of cell-death pathways using a known myelosuppressive regimen of O6-benzylguanine (6BG) and TMZ. Results Exposure to 6BG/TMZ led to increases in p53, p21, ?-H2AX, and mitochondrial DNA damage. Increases in mitochondrial membrane depolarization correlated with increased caspase-9 and caspase-3 activities following 6BG/TMZ treatment. These events correlated with decreases in activated AKT, downregulation of the DNA repair protein O6methylguanine-DNA methyltransferase (MGMT), and increased cell death. During MP cell expansion, FAS/CD95/APO1(FAS) expression increased over time and was present on ~100% of the cells following exposure to 6BG/TMZ. While c-flipshort, an endogenous inhibitor of FAS-mediated signaling, was decreased in 6BG/TMZ-treated versus control, 6BG-, or TMZ alone-treated cells, there were no changes in caspase-8 activity. Additionally, there were no changes in the extent of cell death in MP cells exposed to 6BG/TMZ in the presence of neutralizing or agonistic anti-FAS antibodies, indicating that FAS-mediated signaling was not operative. Conclusions In human MP cells, 6BG/TMZ-initiated apoptosis occurred by intrinsic, mitochondrial-mediated and not extrinsic, FAS-mediated apoptosis. Human MP cells represent a clinically relevant model system for gaining insight into how hematopoietic cells respond to chemotherapeutics and offer an approach for selecting effective chemotherapeutic regimens with limited hematopoietic toxicity. PMID:23536437

Wang, Haiyan; Cai, Shanbao; Ernstberger, Aaron; Bailey, Barbara J.; Wang, Michael Z.; Cai, Wenjing; Goebel, W. Scott; Czader, Magdalena B.; Crean, Colin; Suvannasankhah, Attaya; Shokolenkoc, Inna; Wilson, Glenn L.; Baluyut, Arthur R.; Mayo, Lindsey D.; Pollok, Karen E.

2013-01-01

21

Allogeneic hematopoietic cell transplant for acute myeloid leukemia: Current state in 2013 and future directions  

PubMed Central

Acute myeloid leukemia (AML) represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes. Though remission-induction is an important first step in the management of AML, additional treatment strategies are essential to ensure long-term disease-free survival. Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse-risk. Allogeneic hematopoietic cell transplantation (allo-HCT) represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions, with a demonstrable survival advantage in younger patients with intermediate- or poor-risk cytogenetics. Herein we review the published data regarding the role of allo-HCT in adults with AML. We searched MEDLINE/PubMed and EMBASE/Ovid. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. We discuss the role of allo-HCT in AML patients stratified by cytogenetic- and molecular-risk in first complete remission, as well as allo-HCT as an option in relapsed/refractory AML. Besides the conventional sibling and unrelated donor allografts, we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood. We also discuss conditioning regimens, including reduced intensity conditioning which has broadened the applicability of allo-HCT. Finally we explore recent advances and future possibilities and directions of allo-HCT in AML. Practical therapeutic recommendations have been made where possible based on available data and expert opinion. PMID:24772235

Kanate, Abraham S; Pasquini, Marcelo C; Hari, Parameswaran N; Hamadani, Mehdi

2014-01-01

22

Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.  

PubMed

Patients with acute myeloid leukemia (AML) and abnormalities of chromosome 17p (abnl(17p)) are at high-risk of treatment failure. Poor outcomes have been reported with conventional chemotherapy. To accurately define the outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with abnl(17p) AML, we analyzed the results of patients with this abnormality who received an allogeneic HSCT between January 2000 and December 2010 in 1 of 4 well-defined cohorts (Fred Hutchinson Cancer Research Center, Haemato Oncology Foundation for Adults in the Netherlands, Study Alliance Leukemia, German Cooperative Transplant Study Group). Data of 201 patients with a median age of 54 years were evaluable. At the time of analysis, 30 patients were alive with a median follow-up of 30 months. The 3-year probability of overall survival (OS) was 15% (95% confidence interval [CI], 10-20). The cumulative incidence of relapse at 3 years was 49% (95% CI, 42-56). Notably, almost 70% of all relapses occurred within the first 6 months after HSCT. Patients who were transplanted in first complete remission (CR1) had superior OS compared with those with advanced disease (22% vs 9%, P < .001). Our findings confirm the high-risk of treatment failure in abnl(17p) AML even after allogeneic HSCT in CR1. Although allogeneic HSCT remains a valid option in CR1, alternative treatment strategies are needed for the remaining patients. PMID:24652988

Middeke, Jan M; Fang, Min; Cornelissen, Jan J; Mohr, Brigitte; Appelbaum, Frederick R; Stadler, Michael; Sanz, Jaime; Baurmann, Herrad; Bug, Gesine; Schäfer-Eckart, Kerstin; Hegenbart, Ute; Bochtler, Tilmann; Röllig, Christoph; Stölzel, Friedrich; Walter, Roland B; Ehninger, Gerhard; Bornhäuser, Martin; Löwenberg, Bob; Schetelig, Johannes

2014-05-01

23

Growth after Hematopoietic Stem Cell Transplantation in Children with Acute Myeloid Leukemia  

PubMed Central

Previous studies have shown that hematopoietic stem cell transplantation (HSCT) may result in growth impairment. The purpose of this study was to evaluate the growth during 5 yr after HSCT and to determine factors that influence final adult height (FAH). We retrospectively reviewed the medical records of acute myeloid leukemia (AML) patients who received HSCT. Among a total of 37 eligible patients, we selected 24 patients who began puberty at 5 yr after HSCT (Group 1) and 19 patients who reached FAH without relapse (Group 2). In Group 1, with younger age at HSCT, sex, steroid treatment, hypogonadism and hypothyroidism were not significantly associated with growth impairment 5 yr after HSCT. History of radiotherapy (RT) significantly impaired the 5 yr growth after HSCT. Chronic graft-versus-host disease (cGVHD) only temporarily impaired growth after HSCT. In Group 2, with younger age at HSCT, steroid treatment and hypogonadism did not significantly reduce FAH. History of RT significantly reduced FAH. Growth impairment after HSCT may occur in AML patients, but in patients without a history of RT, growth impairment seemed to be temporary and was mitigated by catch-up growth. PMID:23341720

Chung, Seung Joon; Park, Seung Wan; Kim, Min Kyoung; Kang, Min Jae; Lee, Young Ah; Lee, Seong Yong; Yang, Sei Won; Kang, Hyoung Jin; Park, Kyung Duk; Shin, Hee Young; Ahn, Hyo Seop

2013-01-01

24

Erythroid/myeloid progenitors and hematopoietic stem cells originate from distinct populations of endothelial cells  

PubMed Central

Summary Hematopoietic stem cells (HSC) and an earlier wave of definitive erythroid/myeloid progenitors (EMPs) differentiate from hemogenic endothelial cells in the conceptus. EMPs can be generated in vitro from embryonic or induced pluripotent stem cells, but efforts to produce HSCs have largely failed. The formation of both EMPs and HSCs requires the transcription factor Runx1 and its non-DNA binding partner core binding factor ?(CBF?). Here we show that the requirements for CBF? in EMP and HSC formation in the conceptus are temporally and spatially distinct. Pan-endothelial expression of CBF? in Tek-expressing cells was sufficient for EMP formation, but was not adequate for HSC formation. Expression of CBF? in Ly6a-expressing cells, on the other hand, was sufficient for HSC but not EMP formation. The data indicate that EMPs and HSCs differentiate from distinct populations of hemogenic endothelial cells, with Ly6a expression specifically marking the HSC-generating hemogenic endothelium. PMID:22136929

Chen, Michael J.; Li, Yan; De Obaldia, Maria Elena; Yang, Qi; Yzaguirre, Amanda D.; Yamada-Inagawa, Tomoko; Vink, Chris S.; Bhandoola, Avinash; Dzierzak, Elaine; Speck, Nancy A.

2011-01-01

25

Donor lymphocyte infusion for the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the adult acute myeloid leukemia working group of the Japan society for hematopoietic cell transplantation.  

PubMed

Because the efficacy of donor lymphocyte infusion (DLI) for acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) remains uncertain, especially in the Asian population, a nationwide registry study was retrospectively performed by the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation to identify the factors affecting the patient survival after DLI. Among 143 adult AML patients who received DLI for the treatment of first hematological relapse after HSCT, the overall survival rates at 1 year, 2 years, and 5 years were 32% ± 4%, 17% ± 3%, and 7% ± 3%, respectively. Complete remission (CR) at the time of DLI, which was obtained in 8% of the patients, was the strongest predictive factor for survival after DLI. Therefore, long-term survival after DLI was achieved almost exclusively in patients who successfully achieved a CR before DLI, indicating the limited efficacy of DLI in a minority of patients. PMID:25034960

Takami, Akiyoshi; Yano, Shingo; Yokoyama, Hiroki; Kuwatsuka, Yachiyo; Yamaguchi, Takuhiro; Kanda, Yoshinobu; Morishima, Yasuo; Fukuda, Takahiro; Miyazaki, Yasushi; Nakamae, Hirohisa; Tanaka, Junji; Atsuta, Yoshiko; Kanamori, Heiwa

2014-11-01

26

Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome.  

PubMed

Hematopoietic stem cells sequentially pass through a series of decision points affecting self-renewal or lineage-specific differentiation. Notch1 receptor is a known modulator of lineage-specific events in hematopoiesis that we assessed in the context of in vivo stem cell kinetics. Using RAG-1(-/-) mouse stems cells, we documented increased stem cell numbers due to decreased differentiation and enhanced stem cell self-renewal induced by Notch1. Unexpectedly, preferential lymphoid over myeloid lineage commitment was noted when differentiation occurred. Therefore, Notch1 affects 2 decision points in stem cell regulation, favoring self-renewal over differentiation and lymphoid over myeloid lineage outcome. Notch1 offers an attractive target for stem cell manipulation strategies, particularly in the context of immunodeficiency and acquired immunodeficiency syndrome. PMID:11895769

Stier, Sebastian; Cheng, Tao; Dombkowski, David; Carlesso, Nadia; Scadden, David T

2002-04-01

27

FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia  

PubMed Central

Acute myeloid leukemia (AML) is a clonal disease characterized by heterogeneous involvement of hematopoietic stem cell/progenitor cell populations. Using FLT3 internal tandem duplication (FLT3/ITD) as a molecular marker, we tested the hypothesis that clinical outcome in AML correlates with disease involvement of CD34+/CD33- precursors. Diagnostic specimens from 24 children with FLT3/ITD-positive AML were sorted by fluorescence-activated cell sorting (FACS), and resultant CD34+/CD33- and CD34+/CD33+ progenitors were analyzed directly and after colony-forming cell (CFC) assay for the presence of FLT3/ITD. FLT3/ITD was present in all CD34+/CD33+ patient samples. In contrast, FLT3/ITD was detected in CD34+/CD33- progenitors in only 19 of 24 samples. A bipotent progenitor was affected in a subset of patients, as evidenced by the presence of FLT3/ITD in both granulocyte-macrophage colony-forming unit (CFU-GM) and erythroid burst-forming unit (BFU-E) colonies. Those patients in whom CD34+/CD33- precursors harbored the FLT3/ITD had worse clinical outcome; actuarial event-free survival (EFS) at 4 years from study entry for those patients with and without FLT3/ITD detection in CD34+/CD33- progenitors was 11% ± 14% versus 100% ± 0%, respectively (P = .002). This study suggests that FLT3/ITD involvement in CD34+/CD33- precursors is heterogeneous and that detection of the mutation in the less-mature progenitor population may be associated with disease resistance. PMID:16809615

Pollard, Jessica A.; Alonzo, Todd A.; Gerbing, Robert B.; Woods, William G.; Lange, Beverly J.; Sweetser, David A.; Radich, Jerald P.; Bernstein, Irwin D.; Meshinchi, Soheil

2006-01-01

28

Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes  

PubMed Central

Extramedullary relapse after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia is a contributor to post-transplant mortality but risk factors for, and outcomes of, this condition are not well characterized. We analyzed 257 consecutive patients undergoing allogeneic stem cell transplantation for acute myeloid leukemia at our institution to characterize extramedullary relapse, identify predictive variables and assess outcomes. The 5-year cumulative incidence of isolated extramedullary or bone marrow relapse was 9% and 29%, respectively. Extramedullary relapse occurred later than marrow relapse and most frequently involved skin and soft tissue. Factors predictive of extramedullary relapse after transplantation included previous extramedullary disease, French-American-British classification M4/M5 leukemia, high risk cytogenetics, and advanced disease status at the time of transplantation. Children were more likely than adults to develop extramedullary relapse, a finding probably explained by an overrepresentation of extramedullary disease prior to transplantation and M4/M5 leukemia in children. Acute graft-versus-host disease was not protective against relapse. Unlike medullary relapse, chronic graft-versus-host disease was not protective against extramedullary relapse. The survival rate after extramedullary relapse was 30% at 1 year and 12% at 2 years. Extramedullary relapse is a significant contributor to mortality after allogeneic transplantation for acute myeloid leukemia and appears to be resistant to the immunotherapeutic effect of allogeneic grafting. Effective strategies for patients with extramedullary relapse are needed to improve outcomes after transplantation. PMID:23065502

Harris, Andrew C.; Kitko, Carrie L.; Couriel, Daniel R.; Braun, Thomas M.; Choi, Sung W.; Magenau, John; Mineishi, Shin; Pawarode, Attaphol; Yanik, Gregory; Levine, John E.

2013-01-01

29

Transcriptional dysregulation during myeloid transformation in AML  

Microsoft Academic Search

The current paradigm on leukemogenesis indicates that leukemias are propagated by leukemic stem cells. The genomic events and pathways involved in the transformation of hematopoietic precursors into leukemic stem cells are increasingly understood. This concept is based on genomic mutations or functional dysregulation of transcription factors in malignant cells of patients with acute myeloid leukemia (AML). Loss of the CCAAT\\/enhancer

T Pabst; B U Mueller

2007-01-01

30

Stem cell biology is population biology: differentiation of hematopoietic multipotent progenitors to common lymphoid and myeloid progenitors  

PubMed Central

The hematopoietic stem cell (HSC) system is a demand control system, with the demand coming from the organism, since the products of the common myeloid and lymphoid progenitor (CMP, CLP respectively) cells are essential for activity and defense against disease. We show how ideas from population biology (combining population dynamics and evolutionary considerations) can illuminate the feedback control of the HSC system by the fully differentiated products, which has recently been verified experimentally. We develop models for the penultimate differentiation of HSC Multipotent Progenitors (MPPs) into CLP and CMP and introduce two concepts from population biology into stem cell biology. The first concept is the Multipotent Progenitor Commitment Response (MPCR) which is the probability that a multipotent progenitor cell follows a CLP route rather than a CMP route. The second concept is the link between the MPCR and a measure of Darwinian fitness associated with organismal performance and the levels of differentiated lymphoid and myeloid cells. We show that many MPCRs are consistent with homeostasis, but that they will lead to different dynamics of cells and signals following a wound or injury and thus have different consequences for Darwinian fitness. We show how coupling considerations of life history to dynamics of the HSC system and its products allows one to compute the selective pressures on cellular processes. We discuss ways that this framework can be used and extended. PMID:23327512

2013-01-01

31

Lentinan: Hematopoietic, Immunological, and Efficacy Studies in a Syngeneic Model of Acute Myeloid Leukemia  

Microsoft Academic Search

Lentinan, a ?-glucan nutritional supplement isolated from the shitake mushroom (Lentula edodes), is a biological response modifier with immunostimulatory properties. Concomitantly, the role of ?-glucans as chemoimmunotherapeutic in a number of solid cancers has been widely documented. We investigated the effects of nutritional grade lentinan upon BN rats and in a preclinical syngeneic model of acute myeloid leukemia. BN rats

Emmet McCormack; Jørn Skavland; Maja Muji?; Øystein Bruserud; Bjørn Tore Gjertsen

2010-01-01

32

Molecular analysis of hematopoietic colonies derived from chronic myeloid leukemia patients: interphase fluorescence in situ hybridization compared with RT-PCR  

Microsoft Academic Search

In this study we compared interphase fluorescence in situ hybridization (I-FISH) with reverse transcription polymerase chain reaction (RT-PCR) for the molecular analysis of hematopoietic colonies derived from patients with chronic myeloid leukemia (CML). Molecular analysis of individual colonies is often performed to monitor purging efficacy in CML. We harvested individual colony-forming unit granulocyte–macrophage (CFU-GM) colonies. One half was analyzed with

SFT Thijsen; GJ Schuurhuis; JW van Oostveen; AP Theijsmeijer; MMAC Langenhuijsen; GJ Ossenkoppele

1997-01-01

33

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor  

Microsoft Academic Search

We analyzed predictive factors for the outcome of 113 acute myeloid leukemia patients receiving reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT). Patients were ineligible for conventional-intensity HSCT. Conditioning consisted of fludarabine and 50% of the conventional dose of busulfan (n=93) or total body irradiation (n=20). The source of stem cells was blood in 102 patients, marrow in

H G Sayer; M Kröger; J Beyer; M Kiehl; S A Klein; K Schaefer-Eckart; R Schwerdtfeger; W Siegert; V Runde; C Theuser; H Martin; J Schetelig; D W Beelen; A Fauser; J Kienast; K Höffken; G Ehninger; M Bornhäuser

2003-01-01

34

Busulfan and melphalan as conditioning regimen for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission  

PubMed Central

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

Bueno, Nadjanara Dorna; Dulley, Frederico Luiz; Saboya, Rosaura; Amigo Filho, Jose Ulysses; Coracin, Fabio Luiz; Chamone, Dalton de Alencar Fischer

2011-01-01

35

The value of allogeneic and autologous hematopoietic stem cell transplantation in prognostically favorable acute myeloid leukemia with double mutant CEBPA.  

PubMed

The clinical value of allogeneic hematopoietic stem cell transplantation (alloHSCT) and autologous hematopoietic stem cell transplantation (autoHSCT) in the subtype of acute myeloid leukemia (AML) with double mutant CEBPA (CEBPAdm) has remained unsettled. Among 2983 patients analyzed for CEBPA mutational status (age 18-60 years) treated on 4 published Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group (HOVON/SAKK) and 3 German-Austrian AML Study Group (AMLSG) protocols (2 published, 1 registered, clinicaltrials.gov NCT00151255), 124 had AML with CEBPAdm and achieved first complete remission (CR1). Evaluation of the clinical impact of alloHSCT and autoHSCT vs chemotherapy was performed by addressing time dependency in the statistical analyses. Thirty-two patients proceeded to alloHSCT from a matched related (MRD, n = 29) or a matched unrelated donor (MUD, n = 3), 20 to autoHSCT in CR1 and 72 received chemotherapy. Relapse-free survival was significantly superior in patients receiving an alloHSCT or autoHSCT in CR1 as compared with chemotherapy (P < .001), whereas overall survival was not different (P < .12). Forty-five patients relapsed. Of 42 patients treated with reinduction therapy, 35 achieved a second CR (83%) and most patients (n = 33) received an alloHSCT MRD, n = 11; MUD, n = 19; haplo-identical donor, n = 3). Survival of relapsed patients measured from date of relapse was 46% after 3 years. Adult AML patients with CEBPAdm benefit from alloHSCT and autoHSCT; relapsed patients still have a favorable outcome after reinduction followed by alloHSCT. PMID:23863898

Schlenk, Richard F; Taskesen, Erdogan; van Norden, Yvette; Krauter, Jürgen; Ganser, Arnold; Bullinger, Lars; Gaidzik, Verena I; Paschka, Peter; Corbacioglu, Andrea; Göhring, Gudrun; Kündgen, Andrea; Held, Gerhard; Götze, Katharina; Vellenga, Edo; Kuball, Juergen; Schanz, Urs; Passweg, Jakob; Pabst, Thomas; Maertens, Johan; Ossenkoppele, Gert J; Delwel, Ruud; Döhner, Hartmut; Cornelissen, Jan J; Döhner, Konstanze; Löwenberg, Bob

2013-08-29

36

PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts.  

PubMed

Missense mutations that reduce or abrogate myeloid cell expression of the F-BAR domain protein, proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), lead to autoinflammatory disease involving extramedullary hematopoiesis, skin and bone lesions. However, little is known about how PSTPIP2 regulates osteoclast development. Here we examined how PSTPIP2 deficiency causes osteopenia and bone lesions, using the mouse PSTPIP2 mutations, cmo, which fails to express PSTPIP2 and Lupo, in which PSTPIP2 is dysfunctional. In both models, serum levels of the pro-osteoclastogenic factor, MIP-1?, were elevated and CSF-1 receptor (CSF-1R)-dependent production of MIP-1? by macrophages was increased. Treatment of cmo mice with a dual specificity CSF-1R and c-Kit inhibitor, PLX3397, decreased circulating MIP-1? and ameliorated the extramedullary hematopoiesis, inflammation, and osteopenia, demonstrating that aberrant myelopoiesis drives disease. Purified osteoclast precursors from PSTPIP2-deficient mice exhibit increased osteoclastogenesis in vitro and were used to probe the structural requirements for PSTPIP2 suppression of osteoclast development. PSTPIP2 tyrosine phosphorylation and a functional F-BAR domain were essential for PSTPIP2 inhibition of TRAP expression and osteoclast precursor fusion, whereas interaction with PEST-type phosphatases was only required for suppression of TRAP expression. Thus, PSTPIP2 acts as a negative feedback regulator of CSF-1R signaling to suppress inflammation and osteoclastogenesis. PMID:22923495

Chitu, Violeta; Nacu, Viorel; Charles, Julia F; Henne, William M; McMahon, Harvey T; Nandi, Sayan; Ketchum, Halley; Harris, Renee; Nakamura, Mary C; Stanley, E Richard

2012-10-11

37

The hematopoietic transcription factor PU.1 regulates RANK gene expression in myeloid progenitors  

SciTech Connect

Osteoclasts are bone resorbing cells of hematopoietic origin. The hematopoietic transcription factor PU.1 is critical for osteoclastogenesis; however, the molecular mechanisms of PU.1-regulated osteoclastogenesis have not been explored. Here, we present evidence that the receptor activator of nuclear factor {kappa}B (RANK) gene that has been shown to be crucial for osteoclastogenesis is a transcriptional target of PU.1. The PU.1 {sup -/-} progenitor cells failed to express the RANK gene and reconstitution of PU.1 in these cells induced RANK expression. Treatment of the PU.1 reconstituted cells with M-CSF and RANKL further augmented the RANK gene expression. To explore the regulatory mechanism of the RANK gene expression by PU.1, we have cloned the human RANK promoter. Transient transfection assays have revealed that the 2.2-kb RANK promoter was functional in a monocyte line RAW264.7, whereas co-transfection of PU.1 transactivated the RANK promoter in HeLa cells. Taken together, these results suggest that PU.1 regulates the RANK gene transcription and this may represent one of the key roles of PU.1 in osteoclast differentiation.

Kwon, Oh Hyung [Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Daejeon 305-333 (Korea, Republic of); Lee, Chong-Kil [College of Pharmacy, Chungbuk National University (Korea, Republic of); Lee, Young Ik [Liver Cell Signal Transduction Laboratory, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Daejeon 305-333 (Korea, Republic of); Paik, Sang-Gi [Department of Biology, School of Bioscience and Biotechnology, Chungnam National University (Korea, Republic of); Lee, Hyun-Jun [Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Daejeon 305-333 (Korea, Republic of)]. E-mail: hjlee7@kribb.re.kr

2005-09-23

38

Toll-Like Receptor 4/Stem Cell Antigen 1 Signaling Promotes Hematopoietic Precursor Cell Commitment to Granulocyte Development during the Granulopoietic Response to Escherichia coli Bacteremia  

PubMed Central

In response to severe bacterial infection, bone marrow hematopoietic activity shifts toward promoting granulopoiesis. The underlying cell signaling mechanisms remain obscure. To study the role of Toll-like receptor 4 (TLR4)/stem cell antigen-1 (Sca-1) signaling in this process, bacteremia was induced in mice by intravenous injection of Escherichia coli. A subgroup of animals also received intravenous 5-bromo-2-deoxyuridine (BrdU). In a separate set of experiments, bone marrow lineage-negative (lin?) stem cell growth factor receptor-positive (c-kit+) Sca-1? cells containing primarily common myeloid progenitors were cultured in vitro without or with E. coli lipopolysaccharide (LPS). In genotypic background control mice, bacteremia significantly upregulated Sca-1 expression by lin? c-kit+ cells, as reflected by a marked increase in BrdU-negative lin? c-kit+ Sca-1+ cells in the bone marrow. In mice with the TLR4 gene deletion, this bacteremia-evoked Sca-1 response was blocked. In vitro, LPS induced a dose-dependent increase in Sca-1 expression by cultured marrow lin? c-kit+ Sca-1? cells. LPS-induced upregulation of Sca-1 expression was regulated at the transcriptional level. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity with the specific inhibitor SP600125 suppressed LPS-induced upregulation of Sca-1 expression by marrow lin? c-kit+ Sca-1? cells. Engagement of Sca-1 with anti-Sca-1 antibodies enhanced the expression of Sfpi1 spleen focus-forming virus (SFFV) proviral integration 1 (PU.1) in marrow lin? c-kit+ Sca-1? cells cultured with LPS. Sca-1 null mice failed to maintain the marrow pool of granulopoietic cells following bacteremia. These results demonstrate that TLR4/Sca-1 signaling plays an important role in the regulation of hematopoietic precursor cell programming and their enhancement of granulocyte lineage commitment in response to E. coli bacteremia. PMID:23545304

Shi, Xin; Siggins, Robert W.; Stanford, William L.; Melvan, John N.; Basson, Marc D.

2013-01-01

39

A Human Myeloid Cell Line Producing Stem Cell Growth Factor, KPB-M15, Secretes Another Growth Factor Active on Murine Hematopoietic Progenitor Cells  

Microsoft Academic Search

Human stem cell growth factor (SCGF) produced by a myeloid cell line, KPB-M15, exhibits species-specific hematopoietic activities. However, KPB-M15-conditioned medium induced colony formation of mouse bone marrow cells. KPB-M15-derived colony-stimulating activity (CSA) was purified through Butyl-Toyopearl 650c and Cu2+ chelating-Sepharose 6B chromatography. TSK-G3000SW gel filtration of the purified preparation presented 3 distinct peaks around Vo, 150 kD and 85 kD.

Atsunobu Hiraoka; Tetsuji Nagasawa; Naomi Ohta; Atsushi Sugimura; Norihide Shimizu; Kiyomoto Ooi; Shin Shimizu

1998-01-01

40

Epigenetic changes during hematopoietic cell granulocytic differentiation - comparative analysis of primary CD34+ cells, KG1 myeloid cells and mature neutrophils  

PubMed Central

Background Epigenetic regulation is known to affect gene expression, and recent research shows that aberrant DNA methylation patterning and histone modifications may play a role in leukemogenesis. In order to highlight the co-operation of epigenetic mechanisms acting during the latter process it is important to clarify their potential as biomarkers of granulocytic differentiation. Results In this study we investigated epigenetic alterations in human hematopoietic cells at a distinct differentiation stages: primary hematopoietic CD34+ cells, KG1 myeloid leukemic cells, whose development is stopped at early stage of differentiation, and mature neutrophils. We focused on the epigenetic status of cell cycle regulating (p15, p16) and differentiation related (E-cadherin and RAR?) genes. We found that the methylation level in promoter regions of some of these genes was considerably higher in KG1 cells and lower in CD34+ cells and human neutrophils. As examined and evaluated by computer-assisted methods, histone H3 and H4 modifications, i.e. H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc, were similar in CD34+ cells and human mature neutrophils. By contrast, in the KG1 cells, histone H3 and H4 modifications were quite high and increased after induction of granulocytic differentiation with the HDAC inhibitor phenyl butyrate. Conclusions We found the methylation status of the examined gene promoters and histone modifications to be characteristically associated with the hematopoietic cell progenitor state, induced to differentiate myeloid KG1 cells and normal blood neutrophils. This could be achieved through epigenetic regulation of E-cadherin, p15, p16 and RAR? genes expression caused by DNA methylation/demethylation, core and linker histones distribution in stem hematopoietic cells, induced to differentiation KG1 cells and mature human neutrophils, as well as the histone modifications H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc in relation to hematopoietic cell differentiation to granulocyte. These findings also suggest them as potentially important biomarkers of hematopoietic cell granulocytic differentiation and could be valuable for leukemia induced differentiation therapy. PMID:24443786

2014-01-01

41

Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines  

PubMed Central

Transforming growth factor beta 1 (TGF-beta 1) has been shown to be associated with active centers of hematopoiesis and lymphopoiesis in the developing fetus. Therefore, the effects of TGF-beta 1 on mouse hematopoiesis were studied. TGF-beta 1 is a potent inhibitor of IL-3- induced bone marrow proliferation, but it does not inhibit the proliferation induced by granulocyte/macrophage, colony-stimulating factor (CSF), granulocyte CSF, and erythropoietin (Epo). TGF-beta 1 also inhibits IL-3-induced multipotential colony formation of bone marrow cells in soft agar, which includes early erythroid differentiation, while Epo-induced terminal differentiation is unaffected. In addition, IL-3-induced granulocyte/macrophage colonies were inhibited; however, small clusters of differentiated myeloid cells were consistently seen in cultures containing IL-3 and TGF-beta 1. Thus, TGF-beta 1 selectively inhibits early hematopoietic progenitor growth and differentiation but not more mature progenitors. TGF-beta 1 is also a potent inhibitor of IL-3-dependent and -independent myelomonocytic leukemic cell growth, while the more mature erythroid and macrophage leukemias are insensitive. Therefore, TGF-beta 1 functions as a selective regulator of differentiating normal hematopoietic cells, and suppresses myeloid leukemic cell growth. PMID:3261777

1988-01-01

42

Identification of Key Factors Regulating Self-renewal and Differentiation in EML Hematopoietic Precursor Cells by RNA-sequencing Analysis.  

PubMed

Hematopoietic stem cells (HSCs) are used clinically for transplantation treatment to rebuild a patient's hematopoietic system in many diseases such as leukemia and lymphoma. Elucidating the mechanisms controlling HSCs self-renewal and differentiation is important for application of HSCs for research and clinical uses. However, it is not possible to obtain large quantity of HSCs due to their inability to proliferate in vitro. To overcome this hurdle, we used a mouse bone marrow derived cell line, the EML (Erythroid, Myeloid, and Lymphocytic) cell line, as a model system for this study. RNA-sequencing (RNA-Seq) has been increasingly used to replace microarray for gene expression studies. We report here a detailed method of using RNA-Seq technology to investigate the potential key factors in regulation of EML cell self-renewal and differentiation. The protocol provided in this paper is divided into three parts. The first part explains how to culture EML cells and separate Lin-CD34+ and Lin-CD34- cells. The second part of the protocol offers detailed procedures for total RNA preparation and the subsequent library construction for high-throughput sequencing. The last part describes the method for RNA-Seq data analysis and explains how to use the data to identify differentially expressed transcription factors between Lin-CD34+ and Lin-CD34- cells. The most significantly differentially expressed transcription factors were identified to be the potential key regulators controlling EML cell self-renewal and differentiation. In the discussion section of this paper, we highlight the key steps for successful performance of this experiment. In summary, this paper offers a method of using RNA-Seq technology to identify potential regulators of self-renewal and differentiation in EML cells. The key factors identified are subjected to downstream functional analysis in vitro and in vivo. PMID:25407807

Zong, Shan; Deng, Shuyun; Chen, Kenian; Wu, Jia Qian

2014-01-01

43

The Cebpa +37-kb enhancer directs transgene expression to myeloid progenitors and to long-term hematopoietic stem cells.  

PubMed

C/EBP? is expressed preferentially in myeloid compared with lymphoid or erythroid cells and directs myeloid lineage specification. C/EBP? is also expressed at lower levels in HSCs and in several nonhematopoietic tissues. The Cebpa gene has a conserved, 450-bp segment at +37 kb that harbors enhancer-specific epigenetic marks and is activate in a myeloid cell line. Herein, we characterize transgenic C57BL/6 mice, in which the Cebpa enhancer and 845-bp promoter regulate a hCD4 reporter. FACS analysis, in vitro colony assays, and in vivo competitive and secondary transplantation revealed that myeloid but not MEPs or lymphoid progenitors and also functional LT-HSCs are found almost exclusively in the Cebpa-hCD4(+) compared with hCD4(-) marrow population. hCD4(+) CMP yielded predominantly myeloid, whereas hCD4(-) CMP generated mainly Meg/E colonies. Providing insight into control of CMP maturation, Cebpa and Pu.1 RNAs were preferentially expressed in hCD4(+) CMP, Scl, Gata2, Gata1, Klf1, Ets1, and Fli1 predominated in hCD4(-) CMP, and Runx1, Myb, HoxA9, and Erg levels were similar in both. Cebpa-hCD4 transgene expression was lacking in multiple nonhematopoietic tissues. In summary, the +37-kb Cebpa enhancer and promoter are sufficient for marrow myeloid progenitor and LT-HSC-specific expression. PMID:24868087

Guo, Hong; Ma, Ou; Friedman, Alan D

2014-09-01

44

Characteristics of Myeloid Differentiation and Maturation Pathway Derived from Human Hematopoietic Stem Cells Exposed to Different Linear Energy Transfer Radiation Types  

PubMed Central

Exposure of hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation causes a marked suppression of mature functional blood cell production in a linear energy transfer (LET)- and/or dose-dependent manner. However, little information about LET effects on the proliferation and differentiation of HSPCs has been reported. With the aim of characterizing the effects of different types of LET radiations on human myeloid hematopoiesis, in vitro hematopoiesis in Human CD34+ cells exposed to carbon-ion beams or X-rays was compared. Highly purified CD34+ cells exposed to each form of radiation were plated onto semi-solid culture for a myeloid progenitor assay. The surviving fractions of total myeloid progenitors, colony-forming cells (CFC), exposed to carbon-ion beams were significantly lower than of those exposed to X-rays, indicating that CFCs are more sensitive to carbon-ion beams (D0?=?0.65) than to X-rays (D0?=?1.07). Similar sensitivities were observed in granulocyte-macrophage and erythroid progenitors, respectively. However, the sensitivities of mixed-type progenitors to both radiation types were similar. In liquid culture for 14 days, no significant difference in total numbers of mononuclear cells was observed between non-irradiated control culture and cells exposed to 0.5 Gy X-rays, whereas 0.5 Gy carbon-ion beams suppressed cell proliferation to 4.9% of the control, a level similar to that for cells exposed to 1.5 Gy X-rays. Cell surface antigens associated with terminal maturation, such as CD13, CD14, and CD15, on harvest from the culture of X-ray-exposed cells were almost the same as those from the non-irradiated control culture. X-rays increased the CD235a+ erythroid-related fraction, whereas carbon-ion beams increased the CD34+CD38? primitive cell fraction and the CD13+CD14+/?CD15? fraction. These results suggest that carbon-ion beams inflict severe damage on the clonal growth of myeloid HSPCs, although the intensity of cell surface antigen expression by mature myeloid cells derived from HSPCs exposed to each type of radiation was similar to that by controls. PMID:23555027

Monzen, Satoru; Yoshino, Hironori; Kasai-Eguchi, Kiyomi; Kashiwakura, Ikuo

2013-01-01

45

Distinct regulation of c-myb gene expression by HoxA9, Meis1 and Pbx proteins in normal hematopoietic progenitors and transformed myeloid cells  

PubMed Central

The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells. PMID:22829978

Dasse, E; Volpe, G; Walton, D S; Wilson, N; Del Pozzo, W; O'Neill, L P; Slany, R K; Frampton, J; Dumon, S

2012-01-01

46

STAT5 requires the N-domain to maintain hematopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output  

PubMed Central

Objective STAT5 is a critical regulator of hematopoietic development and its impaired activation is associated with hematopoietic and immune cell defects. However, much of this information has been learned from knockout mice that still retain the potential for expression of STAT5 proteins that are N-terminally truncated due to alternative internal translation initiation codons. The goal of these studies was to use transplantation based assays to analyze the degree of STAT5?N activity in HSC and throughout lymphomyeloid development. Methods We have directly compared E14.5 fetal liver cells from mice with potential to express STAT5ab?N (STAT5ab?N/?N) with mice completely lacking STAT5a and STAT5b (STAT5abnull/null). We have also utilized retroviral complementation of STAT5abnull/null fetal liver hematopoietic stem cells (HSC) to enforce expression of full-length STAT5a or STAT5a lacking the first 136 amino acids (STAT5a? N). Results We report that STAT5 is required for HSC, lymphocyte, and erythrocyte development. We demonstrate that restored expression of STAT5a in STAT5abnull/null HSC provides a strong selective advantage, correcting T/B lymphocyte and erythrocyte development. Interestingly, Gr-1+ blood cells were inversely correlated with B-lymphocytes and both were normalized by STAT5a expression. In contrast, transduction of STAT5a?N only provided partial B-lymphocyte development. Conclusions These studies define the role of STAT5 in maintaining normal lymphoid vs. myeloid balance during hematopoiesis and highlight a major role for the N/domain in HSC function. The platform of retroviral complementation described here will be particularly useful for future studies to sub-define the N-domain regions that are critical for hematopoiesis. PMID:17976521

Li, Geqiang; Wang, Zhengqi; Zhang, Yi; Kang, Zizhen; Haviernikova, Eleonora; Cui, Yongzhi; Hennighausen, Lothar; Moriggl, Richard; Wang, Demin; Tse, William; Bunting, Kevin D.

2007-01-01

47

Differential expression of transforming growth factor-beta, basic fibroblast growth factor, and their receptors in CD34+ hematopoietic progenitor cells from patients with myelofibrosis and myeloid metaplasia.  

PubMed

Myelofibrosis with myeloid metaplasia (MMM) is a myeloproliferative disorder characterized by clonal expansion of hematopoiesis and marrow fibrosis. Previous results from our group have shown an increased production of two potent fibrogenic factors also involved in the regulation of primitive hematopoietic cells, namely transforming growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF), in patients with MMM. It is likely to assume that the myeloproliferation characteristic of this disease may result from an abnormal proliferation of CD34+ hematopoietic progenitors. Thus, we were particularly concerned in studying the gene and protein expression of these cytokines and their receptors in CD34+ progenitors purified from the peripheral blood of MMM patients by using semiquantitative reverse transcriptase-polymerase chain reaction and immunolabeling methods. Our data showed that the expression of TGF-beta1 is not altered in patients CD34+ cells; in contrast, the expression of TGF-beta type II receptor is significantly decreased in such cells, as compared with CD34+ cells from healthy subjects. Regarding bFGF, the very low expression of the cytokine and its type I and II receptors detected in normal CD34+ cells contrasts with that observed in patients' CD34+ cells, which is significantly higher. Our results might be a clue for a better understanding of the mechanism(s) involved in the dysregulation of hematopoiesis in MMM. Actually, the increased expression of bFGF and its receptors associated with the reduction of the TGF-beta binding receptor in CD34+ progenitors from MMM patients might facilitate the expansion of hematopoietic progenitors, not only by stimulating their growth and/or survival, but also by overcoming negative regulatory signals. PMID:8977245

Le Bousse-Kerdilès, M C; Chevillard, S; Charpentier, A; Romquin, N; Clay, D; Smadja-Joffe, F; Praloran, V; Dupriez, B; Demory, J L; Jasmin, C; Martyré, M C

1996-12-15

48

C/EBPalpha is required for proteolytic cleavage of cyclin A by calpain 3 in myeloid precursor cells.  

PubMed

In this report, we present novel findings that implicate CCAAT/enhancer-binding protein (C/EBPalpha) in regulating the expression and activity of calpain 3 in vivo and data showing a new physiological substrate for calpain 3, cyclin A. Our results demonstrate that cleavage of cyclin A by calpain 3 occurs in mouse and human myeloid precursor cells. Calpain 3 cleaves cyclin A in vitro and in vivo, resulting in the production of a truncated product that lacks the N-terminal destruction box required for its degradation at the end of mitosis. The cleaved form of cyclin A retains the cyclin-dependent kinase (cdk) binding domain and forms active complexes with cdk2. Calpain 3-mediated cleavage of cyclin A is lacking in C/EBPalpha-/- mice, which are not able to produce mature granulocytes. Our data support a model in which calpain 3-mediated cleavage of cyclin A in dividing myeloid progenitor cells is important for the onset of differentiation. Deficits in this pathway in C/EBPalpha-/- mice might contribute to the failure of these mice to produce mature granulocytes. These data reveal a new pathway involving tightly controlled post-translational processing of cyclin A during differentiation of granulocytes. PMID:12105198

Welm, Alana L; Timchenko, Nikolai A; Ono, Yasuko; Sorimachi, Hiroyuki; Radomska, Hannah S; Tenen, Daniel G; Lekstrom-Himes, Julie; Darlington, Gretchen J

2002-09-13

49

Errata 2 - Hematopoietic Diseases Coding Guide  

Cancer.gov

Page Diagnosis Change ICD-9-CM code to 23 Acute panmyelosis with myelofibrosis 238.79 Other lymphatic and hematopoietic tissues 30 Chronic myeloproliferative disease 238.79 Other lymphatic and hematopoietic tissues 31 Myelosclerosis with myeloid metaplasia

50

Intraembryonic, but Not Yolk Sac Hematopoietic Precursors, Isolated before Circulation, Provide Long-Term Multilineage Reconstitution  

Microsoft Academic Search

The relative contribution of yolk sac and intraembryonic precursors to hematopoiesis has been a matter of long-standing controversy. As reconstitution activity has so far only been found in embryonic tissues after the onset of circulation, the origin of reconstituting cells could not be formally established. Here, we separated yolk sac and intraembryonic splanchnopleura prior to circulation and maintained the explants

Ana Cumano; José Candido Ferraz; Michèle Klaine; James P Di Santo; Isabelle Godin

2001-01-01

51

Acute myeloid leukemia arising from a donor derived premalignant hematopoietic clone: A possible mechanism for the origin of leukemia in donor cells  

PubMed Central

During recent years, it has become increasingly evident that donor leukemia following allogeneic transplant may be more common then realized in the past. We identified five cases of potential donor leukemia cases during past five years. The precise mechanism of the origin of such leukemias, however, remains poorly defined. In this short communication, we report a well documented case of donor-derived de novo acute myeloid leukemia (AML) that developed fourteen years after allogeneic stem cell transplantation for treatment induced AML for his primary malignancy Immunoblastic lymphoma. This case allows us to postulate a possible mechanism of the origin of donor leukemia. The de novo AML clone contained a distinct cytogenetic abnormality, trisomy 11, which was simultaneously detected in preserved peripheral blood obtained at the time of transplantation as well as in the current bone marrow from an otherwise clinically and phenotypically normal donor. The findings from this unique case, provides insight into the process of leukemogenesis, and suggests that the sequence of events leading to leukemogenesis in this patient involved the senescence/apoptosis of normal donor hematopoietic cells due to telomere shortening resulting in the selective proliferation and transformation of this clone with MLL (mixed-lineage leukemia) gene amplification. PMID:24918066

Dickson, Mark A.; Papadopoulos, Esperanza B.; Hedvat, Cyrus V.; Jhanwar, Suresh C.; Brentjens, Renier J.

2014-01-01

52

Treosulfan, fludarabine, and 2-Gy total body irradiation followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and acute myeloid leukemia.  

PubMed

Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial, we assessed the efficacy and toxicity of treosulfan, fludarabine, and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n = 36: 15 refractory cytopenia with multilineage dysplasia, 10 refractory anemia with excess blasts type 1, 10 refractory anemia with excess blasts type 2, 1 chronic myelomonocytic leukemia type 1) or AML (n = 60: 35 first complete remission [CR], 18 second CR, 3 advanced CR, 4 refractory relapse) were enrolled; median age was 51 (range, 1 to 60) years. Twelve patients had undergone a prior HCT with high-intensity conditioning. Patients received 14 g/m(2)/day treosulfan i.v. on days -6 to -4, 30 mg/m(2)/day fludarabine i.v. on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n = 27) or unrelated (n = 69) donors. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence, and nonrelapse mortality were 73%, 27%, and 8%, respectively. The incidences of grades II to IV (III to IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor-risk and good/intermediate-risk cytogenetics (69% and 85%, respectively) or between AML patients with unfavorable and favorable/intermediate-risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n = 10) at the time of HCT predicted higher relapse incidence (70% versus 18%) and lower OS (41% versus 79%) at 2 years, when compared with patients without MRD. In conclusion, treosulfan, fludarabine, and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse. PMID:24440648

Gyurkocza, Boglarka; Gutman, Jonathan; Nemecek, Eneida R; Bar, Merav; Milano, Filippo; Ramakrishnan, Aravind; Scott, Bart; Fang, Min; Wood, Brent; Pagel, John M; Baumgart, Joachim; Delaney, Colleen; Maziarz, Richard T; Sandmaier, Brenda M; Estey, Elihu H; Appelbaum, Frederick R; Storer, Barry E; Deeg, Hans Joachim

2014-04-01

53

Wilms' tumor gene 1 transcript levels in leukapheresis of peripheral blood hematopoietic cells predict relapse risk in patients autografted for acute myeloid leukemia.  

PubMed

Autologous hematopoietic stem cell transplantation (ASCT) is a curative option alternative to allogeneic transplantation for patients with acute myeloid leukemia (AML). Relapse after ASCT can be due to contamination with leukemic blasts of autologous peripheral blood stem cells (PBSCs) collected by leukapheresis (LK). Identification and quantification of a minimal residual disease (MRD) marker in PBSCs could be relevant in determining the relapse risk after ASCT. High levels of the WT1 gene transcript in bone marrow of AML patients after treatment completion predict disease relapse. We evaluated WT1 transcript levels in autologous PBSC from LK used for ASCT in 30 consecutive AML patients in complete remission (CR) and established a correlation with clinical outcome. At diagnosis, all patients had WT1 overexpression. All patients were in morphological and genetic CR at the time of PBSC collection and before ASCT. Real-time quantitative PCR of WT1 was performed in samples of each LK, using TaqMan technology on RNA from mononucleated cells. The median WT1 transcript level in the PBSC graft (WT1-LK) of patients who relapsed was significantly higher than of those who did not relapse after transplantation (P <.0001). We defined a cut-off level of 80 WT1-LK copies/ABL 10e4 copies to discriminate between positive and negative PBSC grafts. The cut-off level was strongly associated with disease recurrence, DFS and OS. Our study represents the largest series of patients evaluating WT1 as a marker of MRD in PBSC LK products using a completely standardized real-time WT1-reverse transcriptase-PCR based assay. These data, if confirmed by prospective study, will help to determine an individual patient's adapted postremission allocation strategy. PMID:24954546

Messina, Carlo; Candoni, Anna; Carrabba, Matteo G; Tresoldi, Cristina; Sala, Elisa; Tassara, Michela; Crippa, Alessandra; Peccatori, Jacopo; Assanelli, Andrea; Gattillo, Salvatore; Bellio, Laura; Fanin, Renato; Ciceri, Fabio; Bernardi, Massimo

2014-10-01

54

Outcomes of allogeneic hematopoietic cell transplantation for adolescent and young adults compared to children and older adults with acute myeloid leukemia  

PubMed Central

Purpose Adolescents and young adults (AYAs) with cancer have not experienced improvements in survival to the same extent as children and older adults. We compared outcomes among children (<15 years), AYAs (15-40 years) and older adults (>40 years) receiving allogeneic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML). Patients and Methods Our cohort consisted of 900 children, 2708 AYA and 2728 older adult recipients of HLA-identical sibling or unrelated donor (URD) transplant using myeloablative or reduced-intensity/non-myeloablative conditioning. Outcomes were assessed over three time periods (1980-1988, 1989-1997, 1998-2005) for sibling and two time periods (1989-1997, 1998-2005) for URD HCT. Analyses were stratified by donor type. Results Overall survival for AYAs using either siblings or URD improved over time. Although children had better and older adults had worse survival compared to AYAs, improvements in survival for AYAs did not lag behind those for children and older adults. After sibling donor HCT, five-year adjusted survival for the three time periods was 40%, 48% and 53% for children, 35%, 41% and 42% for AYAs and 22%, 30% and 34% for older adults. Among URD HCT recipients, five-year adjusted survival for the two time periods was 38% and 37% for children, 24% and 28% for AYAs and 19% and 23% for older adults. Improvements in survival occurred due to a reduction in risk of treatment-related mortality. The risk of relapse did not change over time. Conclusion Improvements in survival among AYAs undergoing allogeneic HCT for AML have paralleled those among children and older adults. PMID:22040843

Majhail, Navneet S.; Brazauskas, Ruta; Hassebroek, Anna; Bredeson, Christopher N.; Hahn, Theresa; Hale, Gregory A.; Horowitz, Mary M.; Lazarus, Hillard M.; Maziarz, Richard T.; Wood, William A.; Parsons, Susan K.; Joffe, Steven; Rizzo, J. Douglas; Lee, Stephanie J.; Hayes-Lattin, Brandon M.

2011-01-01

55

Overexpression of Snai3 suppresses lymphoid- and enhances myeloid-cell differentiation  

PubMed Central

The altered expression of transcription factors in hematopoietic stem cells and their subsequent lineages can alter the development of lymphoid and myeloid lineages. The role of the transcriptional repressor Snai3 protein in the derivation of cells of the hematopoietic system was investigated. Snai3 is expressed in terminal T-cell and myeloid lineages, therefore, we chose to determine if expressing Snai3 in the early stages of hematopoietic development would influence cell-lineage determination. Expression of Snai3 by retroviral transduction of hematopoietic stem cells using bone marrow chimera studies demonstrated a block in lymphoid-cell development and enhanced expansion of myeloid-lineage cells. Analysis of Snai3-expressing hematopoietic precursor cells showed normal numbers of immature cells, but a block in the development of cells committed to lymphoid lineages. These data indicate that the overexpression of Snai3 does alter bone marrow cell development and that the identification of genes whose expression is altered by the presence of Snai3 would aid in our understanding of these developmental pathways. PMID:22531927

Dahlem, Timothy; Cho, Scott; Spangrude, Gerald J.; Weis, Janis J.; Weis, John H.

2012-01-01

56

Benzene-Induced Hematopoietic Neoplasms Including Myeloid Leukemia in Trp53-Deficient C57BL/6 and C3H/He Mice  

PubMed Central

This research focused on three major questions regarding benzene-induced hematopoietic neoplasms (HPNs). First, why are HPNs induced equivocally and at only threshold level with low-dose benzene exposure despite the significant genotoxicity of benzene even at low doses both in experiments and in epidemiology? Second, why is there no linear increase in incidence at high-dose exposure despite a lower acute toxicity (LD50 > 1000 mg/kg body weight; WHO, 2003, Benzene in drinking-water. Background document for development of WHO Guidelines for Drinking-Water Quality)? Third, why are particular acute myeloid leukemias (AMLs) not commonly observed in mice, although AMLs are frequently observed in human cases of occupational exposure to benzene? In this study, we hypothesized that the threshold-like equivocal induction of HPNs at low-dose benzene exposure is based on DNA repair potential in wild-type mice and that the limited increase in HPNs at a high-dose exposure is due to excessive apoptosis in wild-type mice. To determine whether Trp53 deficiency satisfies the above hypotheses by eliminating or reducing DNA repair and by allowing cells to escape apoptosis, we evaluated the incidence of benzene-induced HPNs in Trp53-deficient C57BL/6 mice with specific regard to AMLs. We also used C3H/He mice, AML prone, with Trp53 deficiency to explore whether a higher incidence of AMLs on benzene exposure might explain the above human-murine differences. As a result, heterozygous Trp53-deficient mice of both strains showed a nonthreshold response of the incidence of HPNs at the lower dose, whereas both strains showed an increasing HPN incidence up to 100% with increasing benzene exposure dose, including AMLs, that developed 38% of heterozygous Trp53-deficient C3H/He mice compared to only 9% of wild-type mice exposed to the high dose. The detection of AMLs in heterozygous Trp53-deficient mice, even in the C57BL/6 strain, implies that benzene may be a potent inducer of AMLs also in mice with some strain differences. PMID:19478238

Kawasaki, Yasushi; Hirabayashi, Yoko; Kaneko, Toyozo; Kanno, Jun; Kodama, Yukio; Matsushima, Yuuko; Ogawa, Yukio; Saitoh, Minoru; Sekita, Kiyoshi; Uchida, Osayuki; Umemura, Takashi; Yoon, Byung-Il; Inoue, Tohru

2009-01-01

57

Pineal region myeloid sarcoma.  

PubMed

The overwhelming majority of pineal region tumors are malignant germ cell tumors, pineal cell tumors, or glial tumors. To our knowledge we report the first patient with myeloid sarcoma in the pineal region. Myeloid sarcomas are composed of immature granulocytic precursor cells and are associated with acute myelogenous leukemia. Thus, myeloid sarcoma should be considered in the differential diagnosis of pineal region masses in patients with a known history of acute myelogenous leukemia. PMID:22560847

Wilson, Thomas J; Than, Khoi D; Parmar, Hemant A; Lieberman, Andrew P; Valdivia, Juan M; Sullivan, Stephen E

2012-07-01

58

Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera  

PubMed Central

In the current model of the pathogenesis of polycythemia vera (PV), the JAK2V617F mutation arises in hematopoietic stem cells (HSCs) that maintain the disease, while erythroid precursor populations expand, resulting in excessive red blood cell production. We examined the role of these specific cell populations using a conditional Jak2V617F knockin murine model. We demonstrate that the most immature long-term (LT) HSCs are solely responsible for initiating and maintaining the disease in vivo and that Jak2V617F mutant LT-HSCs dominate hematopoiesis over time. When we induced Jak2V617F expression in erythropoietin receptor expressing precursor cells, the mice developed elevated hematocrit, expanded erythroid precursors, and suppressed erythropoietin levels. However, the disease phenotype was significantly attenuated compared with mice expressing Jak2V617F in LT-HSCs. In addition to developing a PV phenotype, all mice transplanted with Jak2V617F LT-HSCs underwent myelofibrotic transformation over time. These findings recapitulate the development of post-PV myelofibrosis in human myeloproliferative neoplasms. In aggregate, these results demonstrate the distinct roles of LT-HSCs and erythroid precursors in the pathogenesis of PV. PMID:22627765

Mullally, Ann; Poveromo, Luke; Schneider, Rebekka K.; Al-Shahrour, Fatima; Lane, Steven W.

2012-01-01

59

NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights.  

PubMed

Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodomain proteins, and at least 5 NUP98 fusions involve known histone-modifying genes. Several of the NUP98 fusions, including NUP98-homeobox (HOX)A9, NUP98-HOXD13, and NUP98-JARID1A, have been used to generate animal models of both lymphoid and myeloid malignancy; these models typically up-regulate HOXA cluster genes, including HOXA5, HOXA7, HOXA9, and HOXA10. In addition, several of the NUP98 fusion proteins have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of hematopoietic stem or progenitor cells, providing a potential mechanism for malignant transformation. PMID:21948299

Gough, Sheryl M; Slape, Christopher I; Aplan, Peter D

2011-12-01

60

Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block  

Microsoft Academic Search

Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression of a stable form of ?-catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the

Peggy Kirstetter; Kristina Anderson; Bo T Porse; Sten Eirik W Jacobsen; Claus Nerlov

2006-01-01

61

Homeostatic action of adenosine A3 and A1 receptor agonists on proliferation of hematopoietic precursor cells.  

PubMed

Two adenosine receptor agonists, N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and N6-cyclopentyladenosine (CPA), which selectively activate adenosine A3 and A1 receptors, respectively, were tested for their ability to influence proliferation of granulocytic and erythroid cells in femoral bone marrow of mice using morphological criteria. Agonists were given intraperitoneally to mice in repeated isomolar doses of 200 nmol/kg. Three variants of experiments were performed to investigate the action of the agonists under normal resting state of mice and in phases of cell depletion and subsequent regeneration after treatment with the cytotoxic drug 5-fluorouracil. In the case of granulopoiesis, IB-MECA 1) increased by a moderate but significant level proliferation of cells under normal resting state; 2) strongly increased proliferation of cells in the cell depletion phase; but 3) did not influence cell proliferation in the regeneration phase. CPA did not influence cell proliferation under normal resting state and in the cell depletion phase, but strongly suppressed the overshooting cell proliferation in the regeneration phase. The stimulatory effect of IB-MECA on cell proliferation of erythroid cells was observed only when this agonist was administered during the cell depletion phase. CPA did not modulate erythroid proliferation in any of the functional states investigated, probably due to the lower demand for cell production as compared with granulopoiesis. The results indicate opposite effects of the two adenosine receptor agonists on proliferation of hematopoietic cells and suggest the plasticity and homeostatic role of the adenosine receptor expression. PMID:18445770

Hofer, Michal; Pospísil, Milan; Znojil, Vladimír; Holá, Jirina; Streitová, Denisa; Vacek, Antonín

2008-07-01

62

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

SciTech Connect

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

Pagel, John M.; Gooley, T. A.; Rajendran, Joseph G.; Fisher, Darrell R.; Wilson, Wendy A.; Sandmaier, B. M.; Matthews, D. C.; Deeg, H. Joachim; Gopal, Ajay K.; Martin, P. J.; Storb, R.; Press, Oliver W.; Appelbaum, Frederick R.

2009-12-24

63

Alcohol Impairs the Myeloid Proliferative Response to Bacteremia in Mice via Inhibiting the Stem Cell Antigen-1 - Extracellular-Regulated Kinase Pathway1  

PubMed Central

Enhancement of stem cell antigen-1 (Sca-1) expression by myeloid precursors promotes the granulopoietic response to bacterial infection. However, the underlying mechanisms remain unclear. Extracellular-regulated kinase (ERK) pathway activation strongly enhances proliferation of hematopoietic progenitor cells. Here, we investigated the role of Sca-1 in promoting ERK-dependent myeloid lineage proliferation and the effects of alcohol on this process. Thirty minutes after intraperitoneal injection of alcohol, mice received intravenous challenge with 5 × 107 E.coli for 8 or 24 h. A subset of mice received intravenous BrdU injection 20 h post challenge. Bacteremia increased Sca-1 expression, ERK activation, and proliferation of myeloid and granulopoietic precursors. Alcohol administration suppressed this response and impaired granulocyte production. Sca-1 expression positively correlated with ERK activation and cell cycling, but negatively correlated with myeloperoxidase content in granulopoietic precursors. Alcohol intoxication suppressed ERK activation in granulopoietic precursors and proliferation of these cells during bacteremia. Granulopoietic precursors in Sca-1?/? mice failed to activate ERK signaling and could not increase CFU-GM activity following bacteremia. These data indicate that Sca-1 expression promotes ERK-dependent myeloid cell proliferation during bacteremia. Suppression of this response could represent an underlying mechanism for developing myelosuppression in alcohol abusing hosts with severe bacterial infection. PMID:22238460

Melvan, John Nicholas; Siggins, Robert W.; Stanford, William L.; Porretta, Connie; Nelson, Steve; Bagby, Gregory J.; Zhang, Ping

2011-01-01

64

A Case of Systemic Mastocytosis Associated with Acute Myeloid Leukemia Terminating as Aleukemic Mast Cell Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation  

PubMed Central

In up to 40% of systemic mastocytosis (SM) cases, an associated clonal hematological non-mast cell lineage disease such as AML is diagnosed before, simultaneously with, or after the diagnosis of SM. A 40-yr-old man was diagnosed with AML with t(8;21)(q22;q22). Mast cells were not noted at diagnosis, but appeared as immature forms at relapse. After allogeneic hematopoietic stem cell transplantation (HSCT), leukemic myeloblasts were not observed; however, neoplastic metachromatic blasts strikingly proliferated during the state of bone marrow aplasia, and finally, aleukemic mast cell leukemia developed. As the disease progressed, we observed serial morphologic changes from immature mast cells with myeloblasts to only metachromatic blasts and atypical mast cells as mast cell leukemia; FISH analysis showed that the neoplastic mast cells originated from the same clone as the leukemic myeloblasts of AML. PMID:23483057

Bae, Mi Hyun; Kim, Hyun-Ki; Seo, Eul-Ju; Park, Sang Hyuk; Cho, Young-Uk; Jang, Seongsoo; Chi, Hyun-Sook; Lee, Kyu-Hyung

2013-01-01

65

Intra-hematopoietic cell fusion as a source of somatic variation in the hematopoietic system  

PubMed Central

Summary Cell fusion plays a well-recognized, physiological role during development. Bone-marrow-derived hematopoietic cells have been shown to fuse with non-hematopoietic cells in a wide variety of tissues. Some organs appear to resolve the changes in ploidy status, generating functional and mitotically-competent events. However, cell fusion exclusively involving hematopoietic cells has not been reported. Indeed, genomic copy number variation in highly replicative hematopoietic cells is widely considered a hallmark of malignant transformation. Here we show that cell fusion occurs between cells of the hematopoietic system under injury as well as non-injury conditions. Experiments reveal the acquisition of genetic markers in fusion products, their tractable maintenance during hematopoietic differentiation and long-term persistence after serial transplantation. Fusion events were identified in clonogenic progenitors as well as differentiated myeloid and lymphoid cells. These observations provide a new experimental model for the study of non-pathogenic somatic diversity in the hematopoietic system. PMID:22393240

Skinner, Amy M.; Grompe, Markus; Kurre, Peter

2012-01-01

66

Myeloid-derived Suppressor Cells Adhere to Physiologic STAT3- vs STAT5-dependent Hematopoietic Programming, Establishing Diverse Tumor-Mediated Mechanisms of Immunologic Escape  

PubMed Central

The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib’s profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF’s capacity to preempt STAT3-dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m-MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-? or to TLR agonists with nitric oxide and peroxynitrate production. PMID:23017141

Cohen, Peter A.; Ko, Jennifer S.; Storkus, Walter J.; Spencer, Christopher D.; Bradley, Judy M.; Gorman, Jessica E.; McCurry, Dustin B.; Zorro-Manrique, Soroya; Dominguez, Anna Lucia; Pathangey, Latha B.; Rayman, Patricia A.; Rini, Brian I.; Gendler, Sandra J.; Finke, James H.

2013-01-01

67

Hematopoietic cell transplantation for chronic myeloid leukemia in developing countries: perspectives from Latin America in the post-tyrosine kinase inhibitor era.  

PubMed

Tyrosine kinase inhibitors (TKIs) are currently the first line treatment for chronic myelogenous leukemia (CML) in countries with high and intermediate-high gross national income. Hematopoietic cell transplantation (HCT) in these countries is considered salvage therapy for eligible patients who failed TKI or progress to advanced disease stages. In Latin America, treatment for CML also changed with availability of TKI in the region. However, many challenges remain, as the cost of this class of medication and recommended monitoring is high. CML treatment practices in Latin America demonstrate that the majority of patients are treated with TKI at some point after diagnosis, most commonly imatinib mesylate, but still TKI can only be used after interferon failure in some countries. Other treatment practices are different from established international guidelines, outlying the importance of continuing medical education. Allogeneic HCT is a treatment option for CML in this region and could be considered a cost-effective approach in a small subset of young patients with available donors, as the overall cost of long-term non-transplant treatment may surpass the cost of transplantation. However, there are many challenges with HCT in Latin America such as access to experienced transplant centers, donor availability, and cost of essential drugs used after transplant, which further impacts expansion of this treatment approach in patients in need. In conclusion, Latin American patients with CML have access to state of the art CML treatment. Yet, drug costs have a tremendous impact on developing health systems. Optimization of CML treatment in the region with appropriate monitoring, recognizing patients who would be transplant candidates, and expanding access to transplantation for eligible patients may curtail these costs and further improve patient care. PMID:22507787

Pasquini, Marcelo C

2012-04-01

68

Lymphoid reconstitution of the human fetal thymus in SCID mice with CD34+ precursor cells  

PubMed Central

The search for human hematopoietic stem cells has been hampered by the lack of appropriate assay systems. Demonstration of the ability of precursor cell candidates to give rise to T cells is of significant difficulty since dissociated in vitro cultured thymus stroma cells lose their ability to sustain thymocyte maturation. To define further the differentiative capacities of the rare human fetal liver and bone marrow cells that express the CD34 surface antigen and exhibit in vitro myeloid and pre-B cell activities, we have microinjected them into HLA- mismatched fetal thymus fragments, partially depleted of hematopoietic cells by low temperature culture. In vitro colonized thymuses have then been allowed to develop upon engraftment into immunodeficient SCID mice. Using this modification of the SCID-hu system, we show that low numbers of fetal CD34+ progenitor cells can repopulate the lymphoid compartment in the human thymus. PMID:1719121

1991-01-01

69

Ontogeny of Myeloid Cells  

PubMed Central

Granulocytes, monocytes, macrophages, and dendritic cells (DCs) represent a subgroup of leukocytes, collectively called myeloid cells. During the embryonic development of mammalians, myelopoiesis occurs in a stepwise fashion that begins in the yolk sac and ends up in the bone marrow (BM). During this process, these early monocyte progenitors colonize various organs such as the brain, liver, skin, and lungs and differentiate into resident macrophages that will self-maintain throughout life. DCs are constantly replenished from BM precursors but can also arise from monocytes in inflammatory conditions. In this review, we summarize the different types of myeloid cells and discuss new insights into their early origin and development in mice and humans from fetal to adult life. We specifically focus on the function of monocytes, macrophages, and DCs at these different developmental stages and on the intrinsic and environmental influences that may drive these adaptations.

De Kleer, Isme; Willems, Fabienne; Lambrecht, Bart; Goriely, Stanislas

2014-01-01

70

Type I Interferon Limits the Capacity of Bluetongue Virus To Infect Hematopoietic Precursors and Dendritic Cells In Vitro and In Vivo  

PubMed Central

Hematopoietic stem cells (HSCs) give rise to progenitors with potential to produce multiple cell types, including dendritic cells (DCs). DCs are the principal antigen-presenting cells and represent the crucial link between innate and adaptive immune responses. Bluetongue virus (BTV), an economically important Orbivirus of the Reoviridae family, causes a hemorrhagic disease mainly in sheep and occasionally in other species of ruminants. BTV is transmitted between its mammalian hosts by certain species of biting midges (Culicoides spp.) and is a potent alpha interferon (IFN-?) inducer. In the present report, we show that BTV infects cells of hematopoietic origin but not HSCs in immunocompetent sheep. However, BTV infects HSCs in the absence of type I IFN (IFN-I) signaling in vitro and in vivo. Infection of HSCs in vitro results in cellular death by apoptosis. Furthermore, BTV infects bone marrow-derived DCs (BM-DCs), interfering with their development to mature DCs in the absence of type I IFN signaling. Costimulatory molecules CD80 and CD86 and costimulatory molecules CD40 and major histocompatibility complex class II (MHC-II) are affected by BTV infection, suggesting that BTV interferes with DC antigen-presenting capacity. In vivo, different DC populations are also affected during the course of infection, probably as a result of a direct effect of BTV replication in DCs and the production of infectious virus. These new findings suggest that BTV infection of HSCs and DCs can impair the immune response, leading to persistence or animal death, and that this relies on IFN-I. PMID:24173228

Rodriguez-Calvo, Teresa; Rojas, Jose-Manuel; Martin, Veronica

2014-01-01

71

Mobilisation of Hematopoietic CD34+ Precursor Cells in Patients with Acute Stroke Is Safe - Results of an Open-Labeled Non Randomized Phase I/II Trial  

PubMed Central

Background Regenerative strategies in the treatment of acute stroke may have great potential. Hematopoietic growth factors mobilize hematopoietic stem cells and may convey neuroprotective effects. We examined the safety, potential functional and structural changes, and CD34+ cell–mobilization characteristics of G-CSF treatment in patients with acute ischemic stroke. Methods and Results Three cohorts of patients (8, 6, and 6 patients per cohort) were treated subcutaneously with 2.5, 5, or 10 µg/kg body weight rhG-CSF for 5 consecutive days within 12 hrs of onset of acute stroke. Standard treatment included IV thrombolysis. Safety monitoring consisted of obtaining standardized clinical assessment scores, monitoring of CD34+ stem cells, blood chemistry, serial neuroradiology, and neuropsychology. Voxel-guided morphometry (VGM) enabled an assessment of changes in the patients' structural parenchyma. 20 patients (mean age 55 yrs) were enrolled in this study, 5 of whom received routine thrombolytic therapy with r-tPA. G-CSF treatment was discontinued in 4 patients because of unrelated adverse events. Mobilization of CD34+ cells was observed with no concomitant changes in blood chemistry, except for an increase in the leukocyte count up to 75,500/µl. Neuroradiological and neuropsychological follow-up studies did not disclose any specific G-CSF toxicity. VGM findings indicated substantial atrophy of related hemispheres, a substantial increase in the CSF space, and a localized increase in parenchyma within the ischemic area in 2 patients. Conclusions We demonstrate a good safety profile for daily administration of G-CSF when begun within 12 hours after onset of ischemic stroke and, in part in combination with routine IV thrombolysis. Additional analyses using VGM and a battery of neuropsychological tests indicated a positive functional and potentially structural effect of G-CSF treatment in some of our patients. Trial Registration German Clinical Trial Register DRKS 00000723 PMID:21887230

Kraemer, Mathias; Schormann, Thorsten; Schlachetzki, Felix; Schuierer, Gerhard; Luerding, Ralph; Hennemann, Burkhard; Orso, Evelyn; Dabringhaus, Andreas; Winkler, Jurgen; Bogdahn, Ulrich

2011-01-01

72

Expression and Function of PML-RARA in the Hematopoietic Progenitor Cells of Ctsg-PML-RARA Mice  

PubMed Central

Because PML-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many groups have speculated about whether its leukemic cell of origin is a committed myeloid precursor (e.g. a promyelocyte) versus an hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg, and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice), are expressed in the purified KLS cells of these mice (KLS?=?Kit+Lin?Sca+, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Further, we demonstrate the transcriptional consequences of PML-RARA expression in Ctsg-PML-RARA mice in early myeloid development in other myeloid progenitor compartments [common myeloid progenitors (CMPs) and granulocyte/monocyte progenitors (GMPs)], which have a distinct gene expression signature compared to wild-type (WT) mice. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice and alters the transcriptional signature of these cells, it does not induce their self-renewal. In sum, these results demonstrate that in the Ctsg-PML-RARA mouse model of APL, PML-RARA is expressed in and affects the function of multipotent progenitor cells. Finally, since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in this mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients. PMID:23056333

Uy, Geoffrey L.; Klco, Jeffery M.; Lamprecht, Tamara; Varghese, Nobish; Nagarajan, Rakesh; Ley, Timothy J.

2012-01-01

73

Acute Fibrinous and Organizing Pneumonia Following Hematopoietic Stem Cell Transplantation  

PubMed Central

A 60-year-old man presented with cough, sputum, and dyspnea. He had a history of acute myeloid leukemia and hematopoietic stem cell transplantation with chronic renal failure. Chest CT scans showed miliary nodules and patchy consolidations. Histological examination revealed numerous fibrin balls within the alveoli and thickening of the alveolar septum, both of which are typical pathological features of acute fibrinous and organizing pneumonia (AFOP). We report the first case of AFOP following allogeneic hematopoietic stem cell transplantation. PMID:19543497

Lee, Sang Min; Park, Jae-Jung; Sung, Sun Hee; Kim, Yookyung; Lee, Kyoung Eun; Lee, Soon Nam; Seong, Chu Myong

2009-01-01

74

Alcohol Exposure Impairs Myeloid Dendritic Cell Function in Rhesus Macaques  

PubMed Central

Background Alcohol intoxication suppresses both the innate and adaptive immunities. Dendritic cells (DCs) are the major cell type bridging the innate and acquired immune responses. At the present time, the effects of alcohol on DC development in hematopoietic tissues and the functional activities of DCs are incompletely elucidated. This study investigated the impact of chronic alcohol exposure on the alteration of hematopoietic precursor cell and DC populations in the bone marrow and peripheral blood of rhesus macaques. Methods Rhesus macaques were administered EtOH or isocaloric sucrose daily for a period of three months through surgically-implanted gastric catheters. Peripheral blood mononuclear cells (PBMCs) and bone marrow cells (BMCs) were isolated for flow cytometric analysis after three months. Monocytes were cultured with human IL-4 (10 ng/ml) and GM-CSF (50 ng/ml) in the absence and presence of alcohol (50 mM). On day 6 of the culture, a cocktail of stimulants including IL-1? (18 ng), IL-6 (1800 U), TNF-? (18 ng), PGE2 (1.8 µg) were added to the designated wells for transformation of immature dendritic cells (iDCs) to mature myeloid DCs. The cells were analyzed on day 8 by flow cytometry for expression of DC costimulatory molecule expression. Results EtOH-treated animals had significantly lower numbers of myeloid DCs (lineage?HLA?DR+CD11c+CD123?) in both the PBMCs and BMCs compared to controls (5,654±1,273/106 vs. 2,353±660/106 PBMCs and 503±34 vs. 195±44/106 BMCs). Under culture conditions, the number of lineage?HLA?DR+CD83+ cells was low in control wells (0.38±0.08%). Alcohol inhibited the increase in the number of lineage?HLA?DR+CD83+ cells in iDC wells (2.30±0.79% vs. 5.73±1.40%). Alcohol also inhibited the increase in the number of lineage?HLA?DR+CD83+ cells in mature DC wells (1.23±0.15% vs. 4.13±0.62%). Conclusions Chronic EtOH decreases the bone marrow and circulating pools of myeloid DCs. Additionally, EtOH suppresses costimulatory molecule CD83 expression during DC transformation, which may attenuate the ability of DCs to initiate T cell expansion. PMID:19485975

Siggins, Robert W.; Bagby, Gregory J.; Molina, Patricia; Dufour, Jason; Nelson, Steve; Zhang, Ping

2010-01-01

75

Rosiglitazone promotes the differentiation of Langerhans cells and inhibits that of other dendritic cell types from CD133 positive hematopoietic precursors.  

PubMed

Dendritic cells and their precursors express PPAR-gamma, whose stimulation has inhibitory effects on the maturation and function of dendritic cells in vivo. Dendritic cells can differentiate in vitro from CD133+ progenitors; the influence of PPAR-gamma stimulation on this process is unknown. We have addressed the effect of PPAR-gamma agonist rosiglitazone, at a concentration as used in clinics, on the differentiation of dendritic cells from human CD133+ progenitors. Cells were harvested from cord blood by density gradient and immunomagnetic separation, and cultured for 18 days with fetal calf serum, cytokines and 1 ?mol/L rosiglitazone. Analyses included flow cytometry, electron microscopy and mixed lymphocyte reaction. As expected, control cells generated without rosiglitazone were dendritic, expressed MHC-II, CD80, CD83 and CD86 and stimulated mixed reaction potently. A minority of cells expressed the Langerhans cell marker CD207/langerin, but none contained Birbeck granules. With rosiglitazone much fewer cells were generated; they were all dendritic, expressed differentiation and maturation-related antigens in higher percentage and were better stimulators of lymphocytes than those generated without the drug. The vast majority of cells expressed CD207/langerin and many contained Birbeck granules, i.e. were full-fledged Langerhans cells. We conclude that stimulation of PPAR-gamma, while negatively affecting the number of generated cells, promotes the maturation of human cord blood CD133 positive precursors into efficient, immunostimulating dendritic cells with a Langerhans cell phenotype. PMID:23881602

Bonetti, Maria Ida; Bacci, Stefano; Santosuosso, Michela; Mazzanti, Benedetta; Aldinucci, Alessandra; Ballerini, Clara; Guasti, Daniele; Calosi, Laura; Bosi, Alberto; Romagnoli, Paolo

2014-03-01

76

Adenosine A(1), A(2a), A(2b), and A(3) receptors in hematopoiesis. 1. Expression of receptor mRNA in four mouse hematopoietic precursor cells.  

PubMed

Four mouse bone marrow or thymus cell populations, namely granulopoietic/monocytopoietic, erythropoietic, B-lymphopoietic, and T-lymphopoietic precursor cells have been assayed by RT-PCR technique for the presence and relative amounts of adenosine A(1), A(2a), A(2b), and A(3) receptor mRNA. It has been found that (i) all four populations studied express all four adenosine receptor subtypes, (ii) the A(1), receptor is the least expressed in all populations studied, (iii) the A(3) receptor is markedly expressed in the populations of granulopoietic/monocytopoietic and erythropoietic cells, (iv) the A(2a) receptor is markedly expressed in the populations of B-lymphopoietic and T-lymphopoietic cells, and v) the A(2b) receptor does not predominate in any of the precursor cells studied. Our data offer a new possibility for the assessment of the readiness of these cells to respond, by receptor-mediated mechanisms, to adenosine or its analogs present in the tissues as a result of endogenous processes and/or following their administration. PMID:19249907

Streitová, D; Sefc, L; Savvulidi, F; Pospísil, M; Holá, J; Hofer, M

2010-01-01

77

Expression of myeloid-specific genes in childhood acute lymphoblastic leukemia - a cDNA array study.  

PubMed

Several specific cytogenetic changes are known to be associated with childhood acute lymphoblastic leukemia (ALL), and many of them are important prognostic factors for the disease. Little is known, however, about the changes in gene expression in ALL. Recently, the development of cDNA array technology has enabled the study of expression of hundreds to thousands of genes in a single experiment. We used the cDNA array method to study the gene expression profiles of 17 children with precursor-B ALL. Normal B cells from adenoids were used as reference material. We discuss the 25 genes that were most over-expressed compared to the reference. These included four genes that are normally expressed only in the myeloid lineages of the hematopoietic cells: RNASE2, GCSFR, PRTN3 and CLC. We also detected over-expression of S100A12, expressed in nerve cells but also in myeloid cells. In addition to the myeloid-specific genes, other over-expressed genes included AML1, LCP2 and FGF6. In conclusion, our study revealed novel information about gene expression in childhood ALL. The data obtained may contribute to further studies of the pathogenesis and prognosis of childhood ALL. PMID:12399964

Niini, T; Vettenranta, K; Hollmén, J; Larramendy, M L; Aalto, Y; Wikman, H; Nagy, B; Seppänen, J K; Ferrer Salvador, A; Mannila, H; Saarinen-Pihkala, U M; Knuutila, S

2002-11-01

78

ERK1 Regulates the Hematopoietic Stem Cell Niches  

PubMed Central

The mitogen-activated protein kinases (MAPK) ERK1 and ERK2 are among the major signal transduction molecules but little is known about their specific functions in vivo. ERK activity is provided by two isoforms, ERK1 and ERK2, which are ubiquitously expressed and share activators and substrates. However, there are not in vivo studies which have reported a role for ERK1 or ERK2 in HSCs and the bone marrow microenvironment. The present study shows that the ERK1-deficient mice present a mild osteopetrosis phenotype. The lodging and the homing abilities of the ERK1?/? HSC are impaired, suggesting that the ERK1?/?-defective environment may affect the engrafment of HSCs. Serial transplantations demonstrate that ERK1 is involved in the maintenance of an appropriate medullar microenvironment, but that the intrinsic properties of HSCs are not altered by the ERK1?/? defective microenvironment. Deletion of ERK1 impaired in vitro and in vivo osteoclastogenesis while osteoblasts were unaffected. As osteoclasts derive from precursors of the monocyte/macrophage lineage, investigation of the monocytic compartment was performed. In vivo analysis of the myeloid lineage progenitors revealed that the frequency of CMPs increased by approximately 1.3-fold, while the frequency of GMPs significantly decreased by almost 2-fold, compared with the respective WT compartments. The overall mononuclear-phagocyte lineage development was compromised in these mice due to a reduced expression of the M-CSF receptor on myeloid progenitors. These results show that the cellular targets of ERK1 are M-CSFR-responsive cells, upstream to osteoclasts. While ERK1 is well known to be activated by M-CSF, the present results are the first to point out an ERK1-dependent M-CSFR regulation on hematopoietic progenitors. This study reinforces the hypothesis of an active cross-talk between HSCs, their progeny and bone cells in the maintenance of the homeostasis of these compartments. PMID:22303456

Saulnier, Nathalie; Guihard, Soizic; Holy, Xavier; Decembre, Elodie; Jurdic, Pierre; Clay, Denis; Feuillet, Vincent; Pages, Gilles; Pouyssegur, Jacques; Porteu, Francoise; Gaudry, Murielle

2012-01-01

79

Granulocyte Colony-Stimulating Factor Receptor Mutations in Myeloid Malignancy  

PubMed Central

Granulocyte colony-stimulating factor is a cytokine able to stimulate both myelopoiesis and hematopoietic stem cell mobilization, which has seen it used extensively in the clinic to aid hematopoietic recovery. It acts specifically via the homodimeric granulocyte colony-stimulating factor receptor (G-CSFR), which is principally expressed on the surface of myeloid and hematopoietic progenitor cells. A number of pathogenic mutations have now been identified in CSF3R, the gene encoding G-CSFR. These fall into distinct classes, each of which is associated with a particular spectrum of myeloid disorders, including malignancy. This review details the various CSF3R mutations, their mechanisms of action, and contribution to disease, as well as discussing the clinical implications of such mutations. PMID:24822171

Liongue, Clifford; Ward, Alister Curtis

2014-01-01

80

Cell Stem Cell Induction of Multipotential Hematopoietic  

E-print Network

patients with hematologic diseases, including Fanconi anemia (Mu¨ ller et al., 2012), sickle cell anemiaCell Stem Cell Article Induction of Multipotential Hematopoietic Progenitors from Human Pluripotent Stem Cells via Respecification of Lineage-Restricted Precursors Sergei Doulatov,1,2 Linda T. Vo,1

Collins, James J.

81

What Is Acute Myeloid Leukemia?  

MedlinePLUS

... get acute myeloid leukemia? What is acute myeloid leukemia? Leukemia is a type of cancer that starts ... person to bleed or bruise easily. Acute myeloid leukemia Acute myeloid leukemia (AML) goes by many names, ...

82

A comprehensive methylome map of lineage commitment from hematopoietic progenitors  

PubMed Central

Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Hematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. While DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs1, a comprehensive DNA methylation map of hematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Dramatic epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, suggesting a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome appears to be important in hematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions. PMID:20720541

Ji, Hong; Ehrlich, Lauren I. R.; Seita, Jun; Murakami, Peter; Doi, Akiko; Lindau, Paul; Lee, Hwajin; Aryee, Martin J.; Irizarry, Rafael A.; Kim, Kitai; Rossi, Derrick J; Inlay, Matthew A.; Serwold, Thomas; Karsunky, Holger; Ho, Lena; Daley, George Q.; Weissman, Irving L.; Feinberg, Andrew P.

2010-01-01

83

The vent-like homeobox gene VENTX promotes human myeloid differentiation and is highly expressed in acute myeloid leukemia  

PubMed Central

Recent data indicate that a variety of regulatory molecules active in embryonic development may also play a role in the regulation of early hematopoiesis. Here we report that the human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus xvent2 gene, is a unique regulatory hematopoietic gene that is aberrantly expressed in CD34+ leukemic stem-cell candidates in human acute myeloid leukemia (AML). Quantitative RT–PCR documented expression of the gene in lineage positive hematopoietic subpopulations, with the highest expression in CD33+ myeloid cells. Notably, expression levels of VENTX were negligible in normal CD34+/CD38? or CD34+ human progenitor cells. In contrast to this, leukemic CD34+/CD38? cells from AML patients with translocation t(8,21) and normal karyotype displayed aberrantly high expression of VENTX. Gene expression and pathway analysis demonstrated that in normal CD34+ cells enforced expression of VENTX initiates genes associated with myeloid development and down-regulates genes involved in early lymphoid development. Functional analyses confirmed that aberrant expression of VENTX in normal CD34+ human progenitor cells perturbs normal hematopoietic development, promoting generation of myeloid cells and impairing generation of lymphoid cells in vitro and in vivo. Stable knockdown of VENTX expression inhibited the proliferation of human AML cell lines. Taken together, these data extend our insights into the function of embryonic mesodermal factors in human postnatal hematopoiesis and indicate a role for VENTX in normal and malignant myelopoiesis. PMID:20833819

Rawat, Vijay P. S.; Arseni, Natalia; Ahmed, Farid; Mulaw, Medhanie A.; Thoene, Silvia; Heilmeier, Bernhard; Sadlon, Tim; D'Andrea, Richard J.; Hiddemann, Wolfgang; Bohlander, Stefan K.; Buske, Christian; Feuring-Buske, Michaela

2010-01-01

84

Ectopic expression of HOXC6 blocks myeloid differentiation and predisposes to malignant transformation.  

PubMed

Insertional mutagenesis resulting from the integration of retroviral vectors has led to the discovery of many oncogenes associated with leukemia. We investigated the role of HOXC6, identified by proximal provirus integration in a large animal hematopoietic stem cell gene therapy study, for a potential involvement in hematopoietic stem cell activity and hematopoietic cell fate decision. HOXC6 was overexpressed in the murine bone marrow transplantation model and tested in a competitive repopulation assay in comparison to the known hematopoietic stem cell expansion factor, HOXB4. We have identified HOXC6 as a factor that enhances competitive repopulation capacity in vivo and colony formation in vitro. Ectopic HOXC6 expression also induced strong myeloid differentiation and expansion of granulocyte-macrophage progenitors/common myeloid progenitors (GMPs/CMPs) in vivo, resulting in myeloid malignancies with low penetrance (3 of 17 mice), likely in collaboration with Meis1 because of a provirus integration mapped to the 3' region in the malignant clone. We characterized the molecular basis of HOXC6-induced myeloid differentiation and malignant cell transformation with complementary DNA microarray analysis. Overexpression of HOXC6 induced a gene expression signature similar to several acute myeloid leukemia subtypes when compared with normal GMPs/CMPs. These results demonstrate that HOXC6 acts as a regulator in hematopoiesis and is involved in malignant transformation. PMID:24513167

Wurm, Melanie; Kowalski, John; Heckl, Dirk; Zhang, Xiao-Bing; Nelson, Veronica; Beard, Brian C; Kiem, Hans-Peter

2014-02-01

85

Translocation (8;21) acute myeloid leukemia presenting as severe aplastic anemia  

PubMed Central

We report a case of t(8;21) acute myeloid leukemia presenting as severe aplastic anemia. While initial bone marrow biopsy lacked any cytogenetic abnormalities in 20 analyzed metaphases, repeat bone marrow biopsy eight days later demonstrated this translocation. Initial cytogenetic analysis of 20 metaphases was therefore insufficient to make the diagnosis of hypocellular acute myeloid leukemia. We discuss that further complementary molecular tests, such as CGH, would likely provide a more robust diagnosis of hematopoietic diseases. PMID:25003026

Purev, Enkhtsetseg; Dumitriu, Bogdan; Hourigan, Christopher S.; Young, Neal S.; Townsley, Danielle M.

2014-01-01

86

Detection of cytogenetic aberrations both in CD90 (Thy1)-positive and (Thy1)-negative stem cell (CD34) subfractions of patients with acute and chronic myeloid leukemias  

Microsoft Academic Search

Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are thought to arise from malignant hematopoietic progenitor cells representing early and undifferentiated stem cell clones. In CML there is evidence for a progenitor cell subset free of leukemic clones, depending on the course of the disease. Additionally, it has been suggested that in AML, the early stem cell compartment (CD34+\\/90+)

C Brendel; B Mohr; C Schimmelpfennig; J Müller; M Bornhäuser; M Schmidt; M Ritter; G Ehninger; A Neubauer

1999-01-01

87

Development of Pluripotent Hematopoietic Progenitor Cells in the Human Fetus  

Microsoft Academic Search

Pluripotent hematopoietic progenitor cells (CFU-GEMM), myeloid progenitor cells (CFU-GM), and erythroid progeni- tors (BFU-E) were studied in midtrimester human fetuses using the mixed colony assay. All three progenitor cell populations were detected at high levels in the fetal liver from 1 2 to 23 wk of gestation. Stem cells were first observed in the bone marrow at 1 5-1 6

I. M. Hann; M. P. Bodger; A. V. Hoffbrand

2010-01-01

88

What Is Chronic Myeloid Leukemia?  

MedlinePLUS

... about chronic myeloid leukemia? What is chronic myeloid leukemia? Chronic myeloid leukemia (CML), also known as chronic ... and start making antibodies to fight them. How leukemia starts Any blood-forming or lymphoid cells can ...

89

CCR1 plays a critical role in modulating pain through hematopoietic and non-hematopoietic cells.  

PubMed

Inflammation is associated with immune cells infiltrating into the inflammatory site and pain. CC chemokine receptor 1 (CCR1) mediates trafficking of leukocytes to sites of inflammation. However, the contribution of CCR1 to pain is incompletely understood. Here we report an unexpected discovery that CCR1-mediated trafficking of neutrophils and CCR1 activity on non-hematopoietic cells both modulate pain. Using a genetic approach (CCR1-/- animals) and pharmacological inhibition of CCR1 with selective inhibitors, we show significant reductions in pain responses using the acetic acid-induced writhing and complete Freund's adjuvant-induced mechanical hyperalgesia models. Reductions in writhing correlated with reduced trafficking of myeloid cells into the peritoneal cavity. We show that CCR1 is highly expressed on circulating neutrophils and their depletion decreases acetic acid-induced writhing. However, administration of neutrophils into the peritoneal cavity did not enhance acetic acid-induced writhing in wild-type (WT) or CCR1-/- mice. Additionally, selective knockout of CCR1 in either the hematopoietic or non-hematopoietic compartments also reduced writhing. Together these data suggest that CCR1 functions to significantly modulate pain by controlling neutrophil trafficking to the inflammatory site and having an unexpected role on non-hematopoietic cells. As inflammatory diseases are often accompanied with infiltrating immune cells at the inflammatory site and pain, CCR1 antagonism may provide a dual benefit by restricting leukocyte trafficking and reducing pain. PMID:25170619

Lewis, Nuruddeen D; Muthukumarana, Akalushi; Fogal, Steven E; Corradini, Laura; Stefanopoulos, Dimitria E; Adusumalli, Prathima; Pelletier, Josephine; Panzenbeck, Mark; Berg, Karen; Canfield, Melissa; Cook, Brian N; Razavi, Hossein; Kuzmich, Daniel; Anderson, Shawn; Allard, Devan; Harrison, Paul; Grimaldi, Christine; Souza, Donald; Harcken, Christian; Fryer, Ryan M; Modis, Louise K; Brown, Maryanne L

2014-01-01

90

Common Developmental Pathway for Primitive Erythrocytes and Multipotent Hematopoietic Progenitors in Early Mouse Development  

PubMed Central

Summary Development of the hematopoietic system proceeds in a multistep manner. Primitive erythrocytes are the first hematopoietic cells to be observed that were produced transiently in developing embryos. Multilineage lymphohematopoiesis occurs after the primitive erythropoiesis. However, the lineage relationship of cells that comprise embryonic hematopoietic system is not well characterized. To clarify this process, careful analyses of the embryonic cells that differentiate into these cell lineages are necessary. We identified the common precursors of primitive erythrocytes and multipotent hematopoietic cells in mouse embryonic stem cell cultures and mouse embryos. A subset defined as CD45?CD41+AA4.1? cells showed bipotential capability to produce primitive erythrocytes and lymphomyeloid cells at the single-cell level. The cell population was present in vivo before hematopoietic stem cells (HSCs) appeared. Our results show that primitive erythrocytes and lymphomyeloid cells are not completely separate cell lineages, and these precursors comprise the embryonic hematopoietic system before HSC emergence. PMID:24371812

Yamane, Toshiyuki; Washino, Aya; Yamazaki, Hidetoshi

2013-01-01

91

A Case of Inguinal Sparganosis Mimicking Myeloid Sarcoma  

PubMed Central

We report here a case of inguinal sparganosis, initially regarded as myeloid sarcoma, diagnosed in a patient undergone allogeneic hematopoietic transplantation (HSCT). A 56-year-old male patient having myelodysplastic syndrome was treated with allogeneic HSCT after myeloablative conditioning regimen. At day 5 post-HSCT, the patient complained of a painless palpable mass on the left scrotum and inguinal area. Pelvic magnetic resonance imaging and computed tomography revealed suspected myeloid sarcoma. Gun-biopsy was performed, and the result revealed eosinophilic infiltrations without malignancy. Subsequent serologic IgG antibody test was positive for sparganum. Excisional biopsy as a therapeutic diagnosis was done, and the diagnosis of sparganosis was confirmed eventually. This is the first report of sparganosis after allogeneic HSCT mimicking myeloid sarcoma, giving a lesson that the physicians have to consider the possibility of sparganosis in this clinical situation and perform adequate diagnostic and therapeutic approaches. PMID:23230335

Yeo, Jin Yeob; Han, Jee Young; Lee, Jung Hwan; Park, Young Hoon; Lim, Joo Han; Lee, Moon Hee; Kim, Chul Soo

2012-01-01

92

Redefining the Hematopoietic Microenvironment.  

National Technical Information Service (NTIS)

Hematopoietic stem cells (HSC) and their progeny reside in specialized niches of the microenvironment (ME) in the bone marrow. The ME niches control HSC self-renewal, differentiation, and maturation. The ME niche cells are derived from non-hematopoietic c...

M. Iwata

2013-01-01

93

Radiation dose determines the degree of myeloid engraftment after nonmyeloablative stem cell transplantation  

Microsoft Academic Search

A multivariate analysis of 121 dogs conditioned with 200, 100, or 50 cGy of total body irradiation (TBI) followed by hematopoietic stem cell transplantation from matched littermates showed that TBI dose was the only factor examined that was statistically significantly associated with the percentage of donor myeloid engraftment in stable long-term chimeras (P = .008). To understand the direct effects

Christoph Kahl; Marco Mielcarek; Mineo Iwata; Michael A. Harkey; Barry Storer; Beverly Torok-Storb

2004-01-01

94

Myeloid-specific expression of human lysosomal acid lipase corrects malformation and malfunction of myeloid-derived suppressor cells in lal-/- mice.  

PubMed

Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. LAL deficiency causes expansion of CD11b(+)Gr-1(+) immature myeloid cells, loss of T cells, and impairment of T cell function. To test how myeloid cell LAL controls myelopoiesis and lymphopoiesis, a myeloid-specific doxycycline-inducible transgenic system was used to reintroduce human lysosomal acid lipase (hLAL) expression into LAL gene knockout (lal(-/-)) mice. Expression of hLAL in myeloid cells of lal(-/-) mice reversed abnormal myelopoiesis in the bone marrow starting at the granulocyte-monocyte progenitor stage and reduced systemic expansion of myeloid-derived suppressor cells (MDSCs). Myeloid hLAL expression inhibited reactive oxygen species production and arginase expression in CD11b(+)Gr-1(+) cells of lal(-/-) mice. Structural organization of the thymus and spleen was partially restored in association with reduced infiltration of CD11b(+)Gr-1(+) cells in these mice. In the thymus, reconstitution of myeloid cell LAL restored development of thymocytes at the double-negative DN3 stage. Myeloid cell LAL expression improved the proliferation and function of peripheral T cells. In vitro coculture experiments showed that myeloid hLAL expression in lal(-/-) mice reversed CD11b(+)Gr-1(+) myeloid cell suppression of CD4(+) T cell proliferation, T cell signaling activation, and lymphokine secretion. Blocking stat3 and NF-?B p65 signaling by small-molecule inhibitors in MDSCs achieved a similar effect. Injection of anti-Gr-1 Ab into lal(-/-) mice to deplete MDSCs restored T cell proliferation. These studies demonstrate that LAL in myeloid cells plays a critical role in maintaining normal hematopoietic cell development and balancing immunosuppression and inflammation. PMID:21900179

Qu, Peng; Yan, Cong; Blum, Janice S; Kapur, Reuben; Du, Hong

2011-10-01

95

Immunotherapy for acute myeloid leukemia.  

PubMed

Immunotherapeutic strategies have become part of standard cancer treatment. Chimeric and humanized antibodies have demonstrated activity against a variety of tumors. Although the humanized anti-CD33 antibody HuM195 has only modest activity against overt acute myeloid leukemia (AML), it can eliminate minimal residual disease in acute promyelocytic leukemia. High-dose radioimmunotherapy with b-particle-emitting isotopes targeting CD33, CD45, and CD66 can potentially allow intensification of antileukemic therapy before hematopoietic stem cell transplantation. Conversely, a-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumor cell kill while sparing surrounding normal tissues. Targeted chemotherapy with the anti-CD33- calicheamicin construct gemtuzumab ozogamicin has produced remissions in relapsed AML and appears promising when used in combination with standard chemotherapy for newly diagnosed AML. T-cell recognition of peptide antigens presented on the cell surface in combination with major histocompatibility complex antigen provides another potentially promising approach for the treatment of AML. PMID:16091194

Jurcic, Joseph G

2005-09-01

96

Epigenetic control of dendritic cell development and fate determination of common myeloid progenitor by Mysm1.  

PubMed

The mechanisms controlling the development of dendritic cells (DCs) remain incompletely understood. Using an Mysm1 knockout (Mysm1(-/-)) mouse model, we identified the histone H2A deubiquitinase Mysm1, as a critical regulator in DC differentiation. Mysm1(-/-) mice showed a global reduction of DCs in lymphoid organs, whereas development of granulocytes and macrophages were not severely affected. Hematopoietic progenitors and DC precursors were significantly decreased in Mysm1(-/-) mice and defective in Fms-like tyrosine kinase-3(Flt3) ligand-induced, but not in granulocyte macrophage-colony-stimulating factor (GM-CSF)-induced DC differentiation in vitro. Molecular studies demonstrated that the developmental defect of DCs from common myeloid progenitor (CMP) in Mysm1(-/-) mice is associated with decreased Flt3 expression and that Mysm1 derepresses transcription of the Flt3 gene by directing histone modifications at the Flt3 promoter region. Two molecular mechanisms were found to be responsible for the selective role of Mysm1 in lineage determination of DCs from CMPs: the selective expression of Mysm1 in a subset of CMPs and the different requirement of Mysm1 for PU.1 recruitment to the Flt3 locus vs GM-CSF-? and macrophage-colony-stimulating factor receptor loci. In conclusion, this study reveals an essential role of Mysm1 in epigenetic regulation of Flt3 transcription and DC development, and it provides a novel mechanism for lineage determination from CMP. PMID:25217698

Won, Haejung; Nandakumar, Vijayalakshmi; Yates, Peter; Sanchez, Suzi; Jones, Lindsey; Huang, Xue F; Chen, Si-Yi

2014-10-23

97

Crk-associated substrate lymphocyte type regulates myeloid cell motility and suppresses the progression of leukemia induced by p210Bcr/Abl.  

PubMed

The p210Bcr/Abl and p190Bcr/Abl fusion oncoproteins are known to cause chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Bcr/Abl phosphorylates several proteins that can lead to leukemogenesis. Crk-associated substrate lymphocyte type (Cas-L)/human enhancer of filamentation-1 (HEF1)/neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) is an adapter protein at focal adhesions known to be associated with solid tumor metastasis. Crk-associated substrate lymphocyte type has also been reported to be tyrosine phosphorylated by p190Bcr/Abl. We demonstrated that Cas-L was expressed in murine granulocytes, as well as in lymphocytes, and that Cas-L-deficient (Cas-L(-/-) ) granulocytes had increased migratory activity and decreased adhesiveness. To examine whether Cas-L was involved in leukemogenesis by p210Bcr/Abl, we generated Cas-L(-/-) p210Bcr/Abl transgenic mice. The mice displayed early development of myeloproliferative neoplasm seen in the chronic phase of CML, which resulted in the early death of the mice. Pathologically, increased infiltration of myeloid cells into several tissues was detected in the absence of Cas-L. In a hematopoietic reconstitution assay, Cas-L(-/-) p210Bcr/Abl transgenic cells showed a low population in the spleen, although only their myeloid cell population was normal. Thus, Cas-L seems to regulate the progression of CML in a negative way, presumably by attenuating extramedullary hyperplasia. PMID:21848808

Seo, Sachiko; Nakamoto, Tetsuya; Takeshita, Masataka; Lu, Jun; Sato, Tomohiko; Suzuki, Takahiro; Kamikubo, Yasuhiko; Ichikawa, Motoshi; Noda, Masaki; Ogawa, Seishi; Honda, Hiroaki; Oda, Hideaki; Kurokawa, Mineo

2011-12-01

98

Donor Cell Myeloid Sarcoma  

PubMed Central

Donor cell derived malignancies are a rare and interesting complication of allogeneic bone marrow transplantation. We present a case of a 56-year-old male with donor cell myeloid sarcoma of the stomach and myocardium. PMID:24822132

Walshauser, Mark A.; Sojitra, Payal

2014-01-01

99

HOXA9 promotes hematopoietic commitment of human embryonic stem cells.  

PubMed

The molecular determinants regulating the specification of human embryonic stem cells (hESCs) into hematopoietic cells remain elusive. HOXA9 plays a relevant role in leukemogenesis and hematopoiesis. It is highly expressed in hematopoietic stem and progenitor cells (HSPCs) and is downregulated upon differentiation. Hoxa9-deficient mice display impaired hematopoietic development, and deregulation of HOXA9 expression is frequently associated with acute leukemia. Analysis of the genes differentially expressed in cord blood HSPCs vs hESC-derived HSPCs identified HOXA9 as the most downregulated gene in hESC-derived HSPCs, suggesting that expression levels of HOXA9 may be crucial for hematopoietic differentiation of hESC. Here we show that during hematopoietic differentiation of hESCs, HOXA9 expression parallels hematopoietic development, but is restricted to the hemogenic precursors (HEP) (CD31(+)CD34(+)CD45(-)), and diminishes as HEPs differentiate into blood cells (CD45(+)). Different gain-of-function and loss-of-function studies reveal that HOXA9 enhances hematopoietic differentiation of hESCs by specifically promoting the commitment of HEPs into primitive and total CD45(+) blood cells. Gene expression analysis suggests that nuclear factor-?B signaling could be collaborating with HOXA9 to increase hematopoietic commitment. However, HOXA9 on its own is not sufficient to confer in vivo long-term engraftment potential to hESC-hematopoietic derivatives, reinforcing the idea that additional molecular regulators are needed for the generation of definitive in vivo functional HSPCs from hESC. PMID:25185710

Ramos-Mejía, Veronica; Navarro-Montero, Oscar; Ayllón, Verónica; Bueno, Clara; Romero, Tamara; Real, Pedro J; Menendez, Pablo

2014-11-13

100

How I treat pediatric acute myeloid leukemia  

PubMed Central

Acute myeloid leukemia is a heterogeneous disease that accounts for approximately 20% of acute leukemias in children and adolescents. Despite the lack of targeted therapy for most subtypes and a dearth of new agents, survival rates have reached approximately 60% for children treated on clinical trials in developed countries. Most of the advances have been accomplished by better risk classification, the implementation of excellent supportive care measures, adaptation of therapy on the basis of each patient's response to therapy, and improvements in allogeneic hematopoietic stem cell transplantation. However, it is unlikely that further gains can be made through these measures alone. In this regard, high-resolution, genome-wide analyses have led to greater understanding of the pathogenesis of this disease and the identification of molecular abnormalities that are potential targets of new therapies. The development of molecularly targeted agents, some of which are already in clinical trials, holds great promise for the future. PMID:22566607

2012-01-01

101

BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups  

PubMed Central

Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207+ dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207+ DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c+ and CD14+ fractions and in bone marrow (BM) CD34+ hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207+ DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs. PMID:24638167

Berres, Marie-Luise; Lim, Karen Phaik Har; Peters, Tricia; Price, Jeremy; Takizawa, Hitoshi; Salmon, Helene; Idoyaga, Juliana; Ruzo, Albert; Lupo, Philip J.; Hicks, M. John; Shih, Albert; Simko, Stephen J.; Abhyankar, Harshal; Chakraborty, Rikhia; Leboeuf, Marylene; Beltrao, Monique; Lira, Sergio A.; Heym, Kenneth M.; Bigley, Venetia; Collin, Matthew; Manz, Markus G.; McClain, Kenneth

2014-01-01

102

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes.  

PubMed

Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia. PMID:23388639

Pang, Wendy W; Pluvinage, John V; Price, Elizabeth A; Sridhar, Kunju; Arber, Daniel A; Greenberg, Peter L; Schrier, Stanley L; Park, Christopher Y; Weissman, Irving L

2013-02-19

103

Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation.  

PubMed

The decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC aging and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging. PMID:22560076

Florian, Maria Carolina; Dörr, Karin; Niebel, Anja; Daria, Deidre; Schrezenmeier, Hubert; Rojewski, Markus; Filippi, Marie-Dominique; Hasenberg, Anja; Gunzer, Matthias; Scharffetter-Kochanek, Karin; Zheng, Yi; Geiger, Hartmut

2012-05-01

104

Minimal Residual Disease Following Allogeneic Hematopoietic Stem Cell Transplantation  

PubMed Central

Minimal residual disease (MRD), both before and after transplant, is a clinically important yet relatively poorly defined aspect of allogeneic hematopoietic stem cell transplantation (alloHSCT). The clinical relevance of MRD in the context of alloHSCT has been demonstrated by its association with the development of clinical relapse. However, with the possible exception of chronic myeloid leukemia, the specific techniques, timing, frequency and clinical utility, relative to improvement in patient outcomes, for monitoring MRD in the setting of alloHSCT has yet to be clearly defined. A concise overview of monitoring techniques for detecting MRD, as well as treatment strategies and biologic and clinical research initiatives for MRD suggested by the National Cancer Institute 1st International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation, is covered in this paper. PMID:21047560

Kroger, Nicolaus; Miyamura, Koichi; Bishop, Michael R.

2010-01-01

105

In vivo evidence for an instructive role of fms-like tyrosine kinase-3 (FLT3) ligand in hematopoietic development.  

PubMed

Cytokines are essential regulators of hematopoiesis, acting in an instructive or permissive way. Fms-like tyrosine kinase 3 ligand (FLT3L) is an important cytokine for the development of several hematopoietic populations. Its receptor (FLT3) is expressed on both myeloid and lymphoid progenitors and deletion of either the receptor or its ligand leads to defective developmental potential of hematopoietic progenitors. In vivo administration of FLT3L promotes expansion of progenitors with combined myeloid and lymphoid potential. To investigate further the role of this cytokine in hematopoietic development, we generated transgenic mice expressing high levels of human FLT3L. These transgenic mice displayed a dramatic expansion of dendritic and myeloid cells, leading to splenomegaly and blood leukocytosis. Bone marrow myeloid and lymphoid progenitors were significantly increased in numbers but retained their developmental potential. Furthermore, the transgenic mice developed anemia together with a reduction in platelet numbers. FLT3L was shown to rapidly reduce the earliest erythroid progenitors when injected into wild-type mice, indicating a direct negative role of the cytokine on erythropoiesis. We conclude that FLT3L acts on multipotent progenitors in an instructive way, inducing their development into myeloid/lymphoid lineages while suppressing their megakaryocyte/erythrocyte potential. PMID:24463214

Tsapogas, Panagiotis; Swee, Lee Kim; Nusser, Anja; Nuber, Natko; Kreuzaler, Matthias; Capoferri, Giuseppina; Rolink, Hannie; Ceredig, Rhodri; Rolink, Antonius

2014-04-01

106

Interferons Regulate the in vitro Differentiation of Multilineage Lympho-Myeloid Stem Cells in Hairy Cell Leukemia  

Microsoft Academic Search

In vitro 14-day cultures of peripheral blood mononuclear cells from hairy cell leukemia patients consistently showed the presence of hematopoietic stem cells giving rise to multilineage colonies containing a high proportion of lymphoid cells associated with the myeloid and erythroid progenitors. These stem cells are not the hairy cells but appear to be pluripotent lymphomyeloid primitive stem cells persisting in

Rita Michalevicz; Michel Revel

1987-01-01

107

Dendritic cell differentiation from hematopoietic CD34+ progenitor cells.  

PubMed

Dendritic cells (DC) are the most powerful antigen presenting cells (APC) and play a pivotal role in initiating the immune response. In light of their unique properties, DC have been proposed as a tool to enhance immunity against infectious agents and in anticancer vaccine strategies. In the last few years, the development of DC has been extensively investigated. The present paper summarizes the most recent findings on the differentiation of myeloid DC from hematopoietic CD34+ progenitors and methods for DC generation in vitro. A better understanding of DC function has important implications for their use in clinical settings. PMID:11388744

Curti, A; Fogli, M; Ratta, M; Biasco, G; Tura, S; Lemoli, R M

2001-01-01

108

STAT5 in hematopoietic stem cell biology and transplantation  

PubMed Central

Signal transducer and activator of transcription 5 (STAT5) regulates normal lympho-myeloid development through activation downstream of early-acting cytokines, their receptors, and Janus kinases (JAKs). Despite a general understanding of the role of STAT5 in hematopoietic stem cell (HSC) proliferation, survival, and self-renewal, the transcriptional targets and mechanisms of gene regulation that control multi-lineage engraftment following transplantation for the most part remain to be understood. In this review, we focus on the role of STAT5 in HSC transplantation and recent developments toward identifying the relevant downstream target genes and their role as part of a pleiotropic STAT5 mediated signaling response. PMID:24498540

Wang, Zhengqi; Bunting, Kevin D

2013-01-01

109

Hematopoietic microenvironment. Origin, lineage, and transplantability of the stromal cells in long-term bone marrow cultures from chimeric mice  

Microsoft Academic Search

Studies of bone marrow transplant patients have suggested that the stromal cells of the in vitro hematopoietic microenvironment are transplantable into conditioned recipients. Moreover, in patients with myeloproliferative disorders, all of the stromal cells, which include presumptive endothelial cells, appear to be derived from hematopoietic precursors. To confirm these findings, we have constructed two chimeric mouse models: (a) traditional radiation

S. Perkins; R. A. Fleischman

1988-01-01

110

Ectopic bone formation in severely combat-injured orthopedic patients -- a hematopoietic niche.  

PubMed

Combat-related heterotopic ossification (HO) has emerged as a common and problematic complication of modern wartime extremity injuries, contributing to substantial patient morbidity and loss of function. We have previously reported that HO-forming patients exhibit a more pronounced systemic and local inflammatory response very early in the wound healing process. Moreover, traumatized muscle-derived mesenchymal progenitor cells from these patients have a skewed differentiation potential toward bone. Here, we demonstrate that HO lesions excised from this patient population contain highly vascularized, mature, cancellous bone containing adipogenic marrow. Histologic analysis showed immature hematopoietic cells located within distinct foci in perivascular regions. The adipogenic marrow often contained low numbers of functional erythroid (BFU-E), myeloid (CFU-GM, CFU-M) and multilineage (CFU-GEMM) colony-forming hematopoietic progenitor cells (HPCs). Conversely, tissue from control muscle and non-HO traumatic wound granulation tissue showed no evidence of hematopoietic progenitor cell activity. In summary, our findings suggest that ectopic bone can provide an appropriate hematopoietic microenvironment for supporting the proliferation and differentiation of HPCs. This reactive and vibrant cell population may help maintain normal hematopoietic function, particularly in those with major extremity amputations who have sustained both massive blood loss, prompting systemic marrow stimulation, as well as loss of available native active marrow space. These findings begin to characterize the functional biology of ectopic bone and elucidate the interactions between HPC and non-hematopoietic cell types within the ectopic intramedullary hematopoietic microenvironmental niche identified. PMID:23727270

Davis, Thomas A; Lazdun, Yelena; Potter, Benjamin K; Forsberg, Jonathan A

2013-09-01

111

[Role of ASXL1 mutation in myeloid malignancies].  

PubMed

Additional sex comb-like 1 ( ASXL1) is an enhancer of Trithorax and Polycomb family, which are necessary for the maintenance of stable repression of homeotic and other loci. Recently, alterations of ASXL1 gene were identified in the hematopoietic cells from patients with a variety of myeloid malignancies, including chronic myelomonocytic leukemia (CMML, 43% of cases), myelodysplastic syndrome (MDS, 20%), myeloproliferative neoplasms (MPN, 10%) and acute myeloid leukemia (AML, 20%). The majority of ASXL1 mutations are frameshift and nonsense mutations. These clinical data suggest an important role of ASXL1 in the pathogenesis and/or transformation of myeloid malignancies. However, the role of ASXL1 in the pathogenesis of myeloid malignancies and in normal hematopoiesis in vivo, as well as the underlying mechanisms remains unknown. This article reviews the structure and function of ASXL1, the clinical characteristic and prognostic significance of ASXL1 mutation, the association of ASXL1 with other gene mutation, as well as ASXL1 knock-down or silence in vitro and in vivo models. PMID:25130853

Sheng, Meng-Yao; Zhou, Yuan; Xu, Ming-Jiang; Yang, Feng-Chun

2014-08-01

112

Expression profile of CREB knockdown in myeloid leukemia cells  

PubMed Central

Background The cAMP Response Element Binding Protein, CREB, is a transcription factor that regulates cell proliferation, differentiation, and survival in several model systems, including neuronal and hematopoietic cells. We demonstrated that CREB is overexpressed in acute myeloid and leukemia cells compared to normal hematopoietic stem cells. CREB knockdown inhibits leukemic cell proliferation in vitro and in vivo, but does not affect long-term hematopoietic reconstitution. Methods To understand downstream pathways regulating CREB, we performed expression profiling with RNA from the K562 myeloid leukemia cell line transduced with CREB shRNA. Results By combining our expression data from CREB knockdown cells with prior ChIP data on CREB binding we were able to identify a list of putative CREB regulated genes. We performed extensive analyses on the top genes in this list as high confidence CREB targets. We found that this list is enriched for genes involved in cancer, and unexpectedly, highly enriched for histone genes. Furthermore, histone genes regulated by CREB were more likely to be specifically expressed in hematopoietic lineages. Decreased expression of specific histone genes was validated in K562, TF-1, and primary AML cells transduced with CREB shRNA. Conclusion We have identified a high confidence list of CREB targets in K562 cells. These genes allow us to begin to understand the mechanisms by which CREB contributes to acute leukemia. We speculate that regulation of histone genes may play an important role by possibly altering the regulation of DNA replication during the cell cycle. PMID:18801183

Pellegrini, Matteo; Cheng, Jerry C; Voutila, Jon; Judelson, Dejah; Taylor, Julie; Nelson, Stanley F; Sakamoto, Kathleen M

2008-01-01

113

Hematopoietic Surgery Codes  

Cancer.gov

Hematopoietic/Reticuloendothelial/ Immunoproliferative/Myeloproliferative Disease C420, C421, C423, C424 (with any histology) or M9727, 9733, 9741-9742, 9764-9809, 9832, 9840-9931, 9945-9946, 9950-9967, 9975-9992) (with any site) Codes 98 All

114

Myeloid-Specific Expression of Human Lysosomal Acid Lipase Corrects Malformation and Malfunction of Myeloid-derived Suppressive Cells in lal?/? Mice  

PubMed Central

Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. LAL deficiency causes expansion of CD11b+GR-1+ immature myeloid cells, loss of T cells and impairment of T cell function. To test how myeloid cell LAL controls myelopoiesis and lymphopoiesis, a myeloid-specific doxycycline-inducible transgenic system was used to re-introduce human LAL (hLAL) expression into LAL gene knock-out (lal?/?)mice. Expression of hLAL in myeloid cells of lal?/? mice reversed abnormal myelopoiesis in the bone marrow starting at the granulocyte-macrophage precursors (GMP) stage and reduced systemic expansion of myeloid-derived suppressor cells (MDSCs). Myeloid hLAL expression inhibited reactive oxygen species production and arginase expression in CD11b+GR-1+ cells of lal?/? mice. Structural organization of the thymus and spleen was partially restored in association with reduced infiltration of CD11b+GR-1+ cells in these mice. In the thymus, reconstitution of myeloid cell LAL restored development of thymocytes at the double-negative DN3 stage. Myeloid cell LAL expression improved the proliferation and function of peripheral T cells. In vitro co-culture experiments showed that myeloid hLAL expression in lal?/? mice reversed CD11b+GR-1+ myeloid cell suppression of CD4+ T cell proliferation, T cell signaling activation, and lymphokine secretion. Blocking Stat3 and NF?B p65 signaling by small molecule inhibitors in MDSCs achieved the similar effect. Injection of anti-Gr-1 antibody into lal?/? mice to deplete MDSCs restored T cell proliferation. These studies demonstrate that LAL in myeloid cells plays a critical role in maintaining normal hematopietic cell development and balancing immunosuppression and inflammation. PMID:21900179

Qu, Peng; Yan, Cong; Blum, Janice S.; Kapur, Reuben; Du, Hong

2011-01-01

115

O6 alkylguanine-DNA alkyltransferase activity in human myeloid cells.  

PubMed Central

The association between alkylating agent exposure and acute nonlymphocytic leukemia in humans indicates that myeloid cells may be particularly susceptible to mutagenic damage. Alkylating agent mutagenesis is frequently mediated through formation and persistence of a particular DNA base adduct, O6alkylguanine, which preferentially mispairs with thymine rather than cytosine, leading to point mutations. O6alkylguanine is repaired by O6alkylguanine-DNA alkyltransferase (alkyltransferase), a protein that removes the adduct, leaving an intact guanine base in DNA. We measured alkyltransferase activity in myeloid precursors and compared it with levels in other cells and tissues. In peripheral blood granulocytes, monocytes, T lymphocytes, and B lymphocytes, there was an eightfold range of activity between individuals but only a twofold range in the mean activity between cell types. Normal donors maintained stable levels of alkyltransferase activity over time. In bone marrow T lymphocytes and myeloid precursors, there was an eightfold range of alkyltransferase activity between donors. Alkyltransferase activity in the two cell types was closely correlated in individual donors, r = 0.69, P less than 0.005, but was significantly higher in the T lymphocytes than the myeloid precursors, P less than 0.05. Liver contained the highest levels of alkyltransferase of all tissues tested. By comparison, small intestine contained 34%, colon 14%, T lymphocytes 11%, brain 11%, and myeloid precursors 6.6% of the activity found in liver. Thus, human myeloid precursors have low levels of O6alkylguanine-DNA alkyltransferase compared with other tissues. Low levels of this DNA repair protein may increase the susceptibility of myeloid precursors to malignant transformation after exposure to certain alkylating agents. PMID:3878366

Gerson, S L; Miller, K; Berger, N A

1985-01-01

116

Acute Myeloid Leukemia  

Cancer.gov

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. An acute leukemia can become worse quickly if it is not treated and can result in death within months. AML is the most common type of acute leukemia in American adults and the average age of a patient with AML is 67.

117

Pediatric secondary chronic myeloid leukemia following cardiac transplantation for anthracycline-induced cardiomyopathy.  

PubMed

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cell that is exceptionally rare in the first five years of life, particularly as a secondary malignancy. This report describes a case of secondary CML in a four-year-old female occurring after AML treatment. Interestingly, CML developed while on immunosuppression for a heart transplant due to anthracycline-induced cardiomyopathy. Pediatr Blood Cancer 2015;62:166-168. © 2014 Wiley Periodicals, Inc. PMID:25175922

Menon, Neethu Mohan; Katsanis, Emmanuel; Khalpey, Zain; Whitlow, Puja

2015-01-01

118

Hematopoietic stem cell transplantation  

PubMed Central

More than 25,000 hematopoietic stem cell transplantations (HSCTs) are performed each year for the treatment of lymphoma, leukemia, immune-deficiency illnesses, congenital metabolic defects, hemoglobinopathies, and myelodysplastic and myeloproliferative syndromes. Before transplantation, patients receive intensive myeloablative chemoradiotherapy followed by stem cell “rescue.” Autologous HSCT is performed using the patient’s own hematopoietic stem cells, which are harvested before transplantation and reinfused after myeloablation. Allogeneic HSCT uses human leukocyte antigen (HLA)-matched stem cells derived from a donor. Survival after allogeneic transplantation depends on donor–recipient matching, the graft-versus-host response, and the development of a graft versus leukemia effect. This article reviews the biology of stem cells, clinical efficacy of HSCT, transplantation procedures, and potential complications. PMID:24198516

Hatzimichael, Eleftheria; Tuthill, Mark

2010-01-01

119

New answers to old questions from genome-wide maps of DNA methylation in hematopoietic cells.  

PubMed

DNA methylation is a well-studied epigenetic modification essential for efficient cellular differentiation. Aberrant DNA methylation patterns are a characteristic feature of cancer, including myeloid malignancies such as acute myeloid leukemia. Recurrent mutations in DNA-modifying enzymes were identified in acute myeloid leukemia and linked to distinct DNA methylation signatures. In addition, discovery of Tet enzymes provided new mechanisms for the reversal of DNA methylation. Advances in base-resolution profiling of DNA methylation have enabled a more comprehensive understanding of the methylome landscape in the genome. This review will summarize and discuss the key questions in the function of DNA methylation in the hematopoietic system, including where and how DNA methylation regulates diverse biological processes in the genome as elucidated by recent studies. PMID:24993071

Jeong, Mira; Goodell, Margaret A

2014-08-01

120

How Is Chronic Myeloid Leukemia Diagnosed?  

MedlinePLUS

... chronic myeloid leukemia classified? How is chronic myeloid leukemia diagnosed? Many people with CML do not have ... of samples used to test for chronic myeloid leukemia If signs and symptoms suggest you may have ...

121

Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors  

PubMed Central

Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients. PMID:23975177

Zuurbier, Linda; Gutierrez, Alejandro; Mullighan, Charles G.; Cante-Barrett, Kirsten; Gevaert, A. Olivier; de Rooi, Johan; Li, Yunlei; Smits, Willem K.; Buijs-Gladdines, Jessica G.C.A.M.; Sonneveld, Edwin; Look, A. Thomas; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

2014-01-01

122

TIM-family molecules in embryonic hematopoiesis: fetal liver TIM-4(lo) cells have myeloid potential.  

PubMed

Trans-membrane (or T cell) immunoglobulin and mucin (TIM) molecules are known regulators of immune response whose function in hematopoiesis is unknown. Earlier, we found that tim-1 and tim-4 are expressed by CD45(+) cells in the para-aortic region of chicken embryo. Because the para-aortic region is a known site for hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) differentiation and expansion, we hypothesize that TIM molecules have a role in hematopoiesis. To study this role further, we analyzed TIM expression more precisely in chicken para-aortic region and mouse fetal liver hematopoietic cells. Additionally, we examined the hematopoietic potential of TIM-4(+) mouse fetal liver cells with a colony-forming assay. tim-1 gene expression was detected in chicken and mouse embryos in the aorta-gonads-mesonephros-region at the time of HSC emergence, whereas tim-3 mRNA was widely expressed in different tissues. tim-4 expression was restricted to fetal liver CD45(+)F4/80(+) cells. Moreover, two TIM-4(+) populations were distinguished: F4/80(hi)TIM-4(hi) and F4/80(lo)TIM-4(lo). F4/80(hi)TIM-4(hi) cells had no hematopoietic potential and were morphologically similar to mature macrophages, suggesting that they are yolk sac-derived macrophages. Instead, many of the F4/80(lo)TIM-4(lo) cells were c-kit(+) and Sca-1(+) and had primitive morphology and multilineage colony-forming ability. In addition, F4/80(lo)TIM-4(lo) cells included a considerable population expressing ER-MP12, a known marker for macrophage colony-forming cells and other myeloid progenitors. We conclude that TIM molecules are expressed in embryonic hematopoietic tissues in chicken and mouse and that in fetal liver, TIM-4 is expressed by myeloid progenitor cells. PMID:24316337

Syrjänen, Riikka; Petrov, Petar; Glumoff, Virpi; Fang, Shentong; Salven, Petri; Savolainen, Eeva-Riitta; Vainio, Olli; Uchida, Tatsuya

2014-03-01

123

Sox17 as a candidate regulator of myeloid restricted differentiation potential.  

PubMed

Sry related high mobility group box 17 (Sox17), which is a marker of endodermal cells and a transcriptional regulator, has a critical role in the maintenance of fetal and neonatal hematopoietic stem cells (HSC). Sox17 has been identified as a key regulator of the development and differentiation of fetal hematopoietic progenitors from the aorta-gonad-mesonephros (AGM) region. The co-culture of Sox17-transduced hematopoietic progenitor cells (CD45(low) c-Kit(high) cells) from AGM regions on OP9 stromal cells gives rise to multipotential hematopoietic stem/progenitor cells. Here, we show that in a primary transplantation experiment, Sox17-transduction in CD45(low) c-Kit(high) cells of embryonic day (E) 10.5 AGM increased the absolute number of common myeloid progenitors (CMPs) in the bone marrow (BM) of recipient mice in comparison to that of granulocyte/macrophage progenitors (GMPs) and the megakaryocyte/erythroid progenitors (MEPs). When Sox17-transduced cells were cultured with OP9 stromal cells, Sox17-transduced GMPs (Sox17-GMPs), Sox17-transduced CMPs (Sox17-CMPs), and Sox17-transduced MEPs (Sox17-MEPs) were generated. Sox17-GMPs and Sox17-CMPs maintained their self-renewal capacity and the hematopoietic ability upon co-culture with the OP9 stromal cells for some passages. Moreover, Sox17-GMPs exhibited the increase in expression of c-Mpl and GATA-2 in comparison to GMPs of BM and Sox17-CMPs showed the increase in expression of c-Mpl, NF-E2, and ?-globin genes in comparison to CMPs of BM. Furthermore, when Sox17-transduced cells were cultured in methylcellulose to examine the colony-forming ability, Sox17-GMPs and Sox17-CMPs maintained the formation of mixed colonies for some passages. Taken together, Sox17 is suggested to regulate the maintenance and differentiation of hematopoietic progenitors derived from AGM regions at midgestation, in particular myeloid progenitors. PMID:25093513

Anani, Maha; Nobuhisa, Ikuo; Osawa, Mitsujiro; Iwama, Atsushi; Harada, Kaho; Saito, Kiyoka; Taga, Tetsuya

2014-08-01

124

FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model  

Microsoft Academic Search

FLT3 receptor tyrosine kinase is ex- pressed on lymphoid and myeloid pro- genitors in the hematopoietic system. Ac- tivating mutations in FLT3 have been identified in approximately 30% of pa- tients with acute myelogenous leukemia, making it one of the most common muta- tions observed in this disease. Frequently, the mutation is an in-frame internal tan- dem duplication (ITD) in

Louise M. Kelly; Qing Liu; Jeffrey L. Kutok; Ifor R. Williams; Christina L. Boulton; D. Gary

125

Post-remission therapy for acute myeloid leukemia  

PubMed Central

Induction followed by post-remission therapy including intensive chemotherapy with high-dose cytarabine, autologous and allogeneic hematopoietic stem cell transplantation is recognized as the main road towards cure in acute myeloid leukemia. In recent years, also a renaissance of maintenance therapy after completion of intensive consolidation has been observed with the introduction of kinase inhibitors and demethylating agents in clinical trials. Greater insight into the genetic background of the disease fostered the extension of disease classification and pretreatment risk-categorization by gene mutations. In addition, the pre-treatment risk-defining parameters have been supplemented by markers evaluated at distinct time points during treatment and follow up. In this context, minimal residual disease assessment is increasingly used to dynamically fine tune treatment recommendations. Currently, the gold standard to counterbalance a higher risk of relapse by treatment strategies based on hematopoietic stem cell transplantation with grafts from matched related or unrelated donors is still valuable, whereas autologous hematopoietic stem cell transplantation showed promising results especially in patients categorized as low-risk. Nonetheless, more targeted approaches including kinase inhibitors and demethylating agents in combination with or sequentially before or after intensive chemotherapy are currently in clinical evaluation and may lead to more genotype- instead of purely risk-adapted treatment strategies.

Schlenk, Richard F.

2014-01-01

126

A highly conserved regulatory element controls hematopoietic expression of GATA-2 in zebrafish  

PubMed Central

Background GATA-2 is a transcription factor required for hematopoietic stem cell survival as well as for neuronal development in vertebrates. It has been shown that specific expression of GATA-2 in blood progenitor cells requires distal cis-acting regulatory elements. Identification and characterization of these elements should help elucidating transcription regulatory mechanisms of GATA-2 expression in hematopoietic lineage. Results By pair-wise alignments of the zebrafish genomic sequences flanking GATA-2 to orthologous regions of fugu, mouse, rat and human genomes, we identified three highly conserved non-coding sequences in the genomic region flanking GATA-2, two upstream of GATA-2 and another downstream. Using both transposon and bacterial artificial chromosome mediated germline transgenic zebrafish analyses, one of the sequences was established as necessary and sufficient to direct hematopoietic GFP expression in a manner that recapitulates that of GATA-2. In addition, we demonstrated that this element has enhancer activity in mammalian myeloid leukemia cell lines, thus validating its functional conservation among vertebrate species. Further analysis of potential transcription factor binding sites suggested that integrity of the putative HOXA3 and LMO2 sites is required for regulating GATA-2/GFP hematopoietic expression. Conclusion Regulation of GATA-2 expression in hematopoietic cells is likely conserved among vertebrate animals. The integrated approach described here, drawing on embryological, transgenesis and computational methods, should be generally applicable to analyze tissue-specific gene regulation involving distal DNA cis-acting elements. PMID:17708765

Yang, Zhongan; Jiang, Hong; Zhao, Fang; Shankar, Deepa B; Sakamoto, Kathleen M; Zhang, Michael Q; Lin, Shuo

2007-01-01

127

Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia.  

PubMed

Cell fate can be controlled through asymmetric division and segregation of protein determinants, but the regulation of this process in the hematopoietic system is poorly understood. Here we show that the dynein-binding protein Lis1 is critically required for hematopoietic stem cell function and leukemogenesis. Conditional deletion of Lis1 (also known as Pafah1b1) in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, real-time imaging revealed that loss of Lis1 caused defects in spindle positioning and inheritance of cell fate determinants, triggering accelerated differentiation. Finally, deletion of Lis1 blocked the propagation of myeloid leukemia and led to a marked improvement in survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells and mark its directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development. PMID:24487275

Zimdahl, Bryan; Ito, Takahiro; Blevins, Allen; Bajaj, Jeevisha; Konuma, Takaaki; Weeks, Joi; Koechlein, Claire S; Kwon, Hyog Young; Arami, Omead; Rizzieri, David; Broome, H Elizabeth; Chuah, Charles; Oehler, Vivian G; Sasik, Roman; Hardiman, Gary; Reya, Tannishtha

2014-03-01

128

Production and differentiation of myeloid cells driven by proinflammatory cytokines in response to acute pneumovirus infection in mice.  

PubMed

Respiratory virus infections are often pathogenic, driving severe inflammatory responses. Most research has focused on localized effects of virus infection and inflammation. However, infection can induce broad-reaching, systemic changes that are only beginning to be characterized. In this study, we assessed the impact of acute pneumovirus infection in C57BL/6 mice on bone marrow hematopoiesis. We hypothesized that inflammatory cytokine production in the lung upregulates myeloid cell production in response to infection. We demonstrate a dramatic increase in the percentages of circulating myeloid cells, which is associated with pronounced elevations in inflammatory cytokines in serum (IFN-?, IL-6, CCL2), bone (TNF-?), and lung tissue (TNF-?, IFN-?, IL-6, CCL2, CCL3, G-CSF, osteopontin). Increased hematopoietic stem/progenitor cell percentages (Lineage(-)Sca-I(+)c-kit(+)) were also detected in the bone marrow. This increase was accompanied by an increase in the proportions of committed myeloid progenitors, as determined by colony-forming unit assays. However, no functional changes in hematopoietic stem cells occurred, as assessed by competitive bone marrow reconstitution. Systemic administration of neutralizing Abs to either TNF-? or IFN-? blocked expansion of myeloid progenitors in the bone marrow and also limited virus clearance from the lung. These findings suggest that acute inflammatory cytokines drive production and differentiation of myeloid cells in the bone marrow by inducing differentiation of committed myeloid progenitors. Our findings provide insight into the mechanisms via which innate immune responses regulate myeloid cell progenitor numbers in response to acute respiratory virus infection. PMID:25200951

Maltby, Steven; Hansbro, Nicole G; Tay, Hock L; Stewart, Jessica; Plank, Maximilian; Donges, Bianca; Rosenberg, Helene F; Foster, Paul S

2014-10-15

129

Early postradition recovery of hematopoietic stromal precursor cells  

SciTech Connect

The aim of this investigation was an immunohistochemical study of alpha-endorphin-producing cells and also a study of rat mast cells (MC in the antral mucosa of the human stomach. Men aged 18 to 30 years undergoing in-patient treatment wre studied. According to the results of radioimmunoassay, antibodies against alpha-endorphin did not react with enkephalins, beta-endorphin, or the C-terminal fragment of beta-endorphin, but had cross reactivity of about 10% with gammaendorphin. Results were subjected to statistical analysis by Student's test at a 85% level of significance and they are shown. The facts presented here suggest that MC of human gastric mucosa include argyrophilic cells which contain alpha-endorphin.

Todriya, T.V.

1985-04-01

130

FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance  

Microsoft Academic Search

FLT3 is a receptor tyrosine kinase in- volved in the proliferation and differentia- tion of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3\\/ITDs) are reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3\\/ITDs in 11.5% of 234 chil- dren with de novo AML. FLT3\\/ITD-positive patients were significantly older and had higher percentages of normal cytoge-

Christian M. Zwaan; Soheil Meshinchi; Jerald P. Radich; Anjo J. P. Veerman; Dieuwke R. Huismans; Leonhard Munske; Martina Podleschny; Karel Hahlen; Rob Pieters; Martin Zimmermann; Dirk Reinhardt; Jochen Harbott; Ursula Creutzig; Gertjan J. L. Kaspers; Frank Griesinger

2003-01-01

131

TC1(C8orf4) Regulates Hematopoietic Stem/Progenitor Cells and Hematopoiesis  

PubMed Central

Hematopoiesis is a complex process requiring multiple regulators for hematopoietic stem/progenitor cells (HSPC) and differentiation to multi-lineage blood cells. TC1(C8orf4) is implicated in cancers, hematological malignancies and inflammatory activation. Here, we report that Tc1 regulates hematopoiesis in mice. Myeloid and lymphoid cells are increased markedly in peripheral blood of Tc1–deleted mice compared to wild type controls. Red blood cells are small-sized but increased in number. The bone marrow of Tc1?/? mice is normocellular histologically. However, Lin?Sca-1+c-Kit+ (LSK) cells are expanded in Tc1?/? mice compared to wild type controls. The expanded population mostly consists of CD150?CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells. Colony forming units (CFU) are increased in Tc1?/? mice bone marrow cells compared to controls. In wild type mice bone marrow, Tc1 is expressed in a limited population of HSPC but not in differentiated cells. Major myeloid transcriptional regulators such as Pu.1 and Cebp? are not up-regulated in Tc1?/? mice bone marrow. Our findings indicate that TC1 is a novel hematopoietic regulator. The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown. PMID:24937306

Lee, Soyoung; Kim, Jungtae; Park, Surim; Song, Kyuyoung; Lee, Inchul

2014-01-01

132

Childhood Acute Myeloid Leukaemia  

PubMed Central

Summary Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation. PMID:22966788

Rubnitz, Jeffrey E.; Inaba, Hiroto

2012-01-01

133

[Chronic myeloid leukemia].  

PubMed

More than 10 years have passed since imatinib as a first developed BCR-ABL tyrosine kinase inhibitor (TKI) introduced in treatment of patients with chronic myeloid leukemia (CML). In globally, there are tremendous numbers of patients on imatinib therapy. Based upon randomized trials comparing second generation TKIs such as dasatinib and nilotinib versus imatinib, both TKIs produce faster and deeper response than imatinib and they can be selected as first-line therapy for newly diagnosed chronic phase of CML (CP-CML) as imatinib. Bosutinib is a potent for imatinib resistant/intolerant CP-CML and can be used as second or third-line therapy. Ponatinib is the only clinically available TKI that has activity against the T315 mutation that is resistant to all other TKIs. Currently, a choice among these potent TKIs should take into consideration the drug side effect profiles and the patient's comorbidities. PMID:25016806

Usui, Noriko

2014-06-01

134

Detection of FLT3 Oncogene Mutations in Acute Myeloid Leukemia Using Conformation Sensitive Gel Electrophoresis  

E-print Network

Abstract: FLT3 (fms-related tyrosine kinase 3) is a receptor tyrosine kinase class III that is expressed on by early hematopoietic progenitor cells and plays an important role in hematopoietic stem cell proliferation, differentiation and survival. FLT3 is also expressed on leukemia blasts in most cases of acute myeloid leukemia (AML). In order to determine the frequency of FLT3 oncogene mutations, we analyzed genomic DNA of adult de novo acute myeloid leukemia (AML). Polymerase chain reaction (PCR) and conformation-sensitive gel electrophoresis (CSGE) were used for FLT3 exons 11, 14, and 15, followed by direct DNA sequencing. Two different types of functionally important FLT 3 mutations have been identified. Those mutations were unique to patients with inv(16), t(15:17) or t(8;21) and comprised fifteen cases with internal tandem duplication (ITD) mutation in the juxtamembrane domain and eleven cases with point mutation (exon 20, Asp835Tyr). The high frequency of the flt3 proto-oncogene mutations in acute myeloid leukemia AML suggests a key role for the receptor function. The association ofInt. J. Mol. Sci. 2008, 9

Mamdooh Gari; Adel Abuzenadah; Adeel Chaudhary; Mohammed Al-qahtani; Waseem Ahmad; Fatin Al-sayes; Sahira Lary; Ghazi Damanhouri

2008-01-01

135

The glutathione disulfide mimetic NOV-002 inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress.  

PubMed

The oxidized glutathione mimetic NOV-002 is a unique anti-tumor agent that not only has the ability to inhibit tumor cell proliferation, survival, and invasion, but in some settings can also ameliorate cytotoxic chemotherapy-induced hematopoietic and immune suppression. However, the mechanisms by which NOV-002 protects the hematopoietic and immune systems against the cytotoxic effects of chemotherapy are not known. Therefore, in this study we investigated the mechanisms of action of NOV-002 using a mouse model in which hematopoietic and immune suppression was induced by cyclophosphamide (CTX) treatment. We found that NOV-002 treatment in a clinically comparable dose regimen attenuated CTX-induced reduction in bone marrow hematopoietic stem and progenitor cells (HSPCs) and reversed the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), which led to a significant improvement in hematopoietic and immune functions. These effects of NOV-002 may be attributable to its ability to modulate cellular redox. This suggestion is supported by the finding that NOV-002 treatment upregulated the expression of superoxide dismutase 3 and glutathione peroxidase 2 in HSPCs, inhibited CTX-induced increases in reactive oxygen species production in HSPCs and MDSCs, and attenuated CTX-induced reduction of the ratio of reduced glutathione to oxidized glutathione in splenocytes. These findings provide a better understanding of the mechanisms whereby NOV-002 modulates chemotherapy-induced myelosuppression and immune dysfunction and a stronger rationale for clinical utilization of NOV-002 to reduce chemotherapy-induced hematopoietic and immune suppression. PMID:22343421

Diaz-Montero, C Marcela; Wang, Yong; Shao, Lijian; Feng, Wei; Zidan, Abdel-Aziz; Pazoles, Christopher J; Montero, Alberto J; Zhou, Daohong

2012-05-01

136

PXD101 in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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; Untreated Adult Acute Myeloid Leukemia

2014-10-08

137

The origin and evolution of mutations in Acute Myeloid Leukemia  

PubMed Central

Summary Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability, driving clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of AML samples with a known initiating event (PML-RARA) vs. normal karyotype AML samples, and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse. PMID:22817890

Welch, John S.; Ley, Timothy J.; Link, Daniel C.; Miller, Christopher A.; Larson, David E.; Koboldt, Daniel C.; Wartman, Lukas D.; Lamprecht, Tamara L.; Liu, Fulu; Xia, Jun; Kandoth, Cyriac; Fulton, Robert S.; McLellan, Michael D.; Dooling, David J.; Wallis, John W.; Chen, Ken; Harris, Christopher C.; Schmidt, Heather K.; Kalicki-Veizer, Joelle M.; Lu, Charles; Zhang, Qunyuan; Lin, Ling; O'Laughlin, Michelle D.; McMichael, Joshua F.; Delehaunty, Kim D.; Fulton, Lucinda A.; Magrini, Vincent J.; McGrath, Sean D.; Demeter, Ryan T.; Vickery, Tammi L.; Hundal, Jasreet; Cook, Lisa L.; Swift, Gary W.; Reed, Jerry P.; Alldredge, Patricia A.; Wylie, Todd N.; Walker, Jason R.; Watson, Mark A.; Heath, Sharon E.; Shannon, William D.; Varghese, Nobish; Nagarajan, Rakesh; Payton, Jacqueline E.; Baty, Jack D.; Kulkarni, Shashikant; Klco, Jeffery M.; Tomasson, Michael H.; Westervelt, Peter; Walter, Matthew J.; Graubert, Timothy A.; DiPersio, John F.; Ding, Li; Mardis, Elaine R.; Wilson, Richard K.

2012-01-01

138

Hematopoietic Neoplasias in Horses: Myeloproliferative and Lymphoproliferative Disorders  

PubMed Central

Leukemia, i.e., the neoplasia of one or more cell lines of the bone marrow, although less common than in other species, it is also reported in horses. Leukemia can be classified according to the affected cells (myeloproliferative or lymphoproliferative disorders), evolution of clinical signs (acute or chronic) and the presence or lack of abnormal cells in peripheral blood (leukemic, subleukemic and aleukemic leukemia). The main myeloproliferative disorders in horses are malignant histiocytosis and myeloid leukemia, the latter being classified as monocytic and myelomonocytic, granulocytic, primary erythrocytosis or polycythemia vera and megakaryocytic leukemia. The most common lymphoproliferative disorders in horses are lymphoid leukemia, plasma cell or multiple myeloma and lymphoma. Lymphoma is the most common hematopoietic neoplasia in horses and usually involves lymphoid organs, without leukemia, although bone marrow may be affected after metastasis. Lymphoma could be classified according to the organs involved and four main clinical categories have been established: generalized-multicentric, alimentary-gastrointestinal, mediastinal-thymic-thoracic and cutaneous. The clinical signs, hematological and clinical pathological findings, results of bone marrow aspirates, involvement of other organs, prognosis and treatment, if applicable, are presented for each type of neoplasia. This paper aims to provide a guide for equine practitioners when approaching to clinical cases with suspicion of hematopoietic neoplasia. PMID:24833969

MUÑOZ, Ana; RIBER, Cristina; TRIGO, Pablo; CASTEJÓN, Francisco

2010-01-01

139

Mll5 contributes to hematopoietic stem cell fitness and homeostasis  

PubMed Central

MLL5 is a novel trithorax group gene and a candidate tumor suppressor gene located within a 2.5-Mb interval of chromosome band 7q22 that frequently is deleted in human myeloid malignancy. Here we show that inactivation of the Mll5 gene in mice results in a 30% reduction in the average representation of hematopoietic stem cells and in functional impairment of long-term hematopoietic repopulation potential under competitive conditions. Bone marrow cells from Mll5-deficient mice were defective in spleen colony-forming assays, and the mutant mice showed enhanced susceptibility to 5-fluorouracil–induced myelosuppression. Heterozygous and homozygous Mll5 mutant mice did not spontaneously develop hematologic cancers, and loss of Mll5 did not alter the phenotype of a fatal myeloproliferative disorder induced by oncogenic Kras in vivo. Collectively, the data reveal an important role for Mll5 in HSC homeostasis and provide a basis for further studies to explore its role in leukemogenesis. PMID:18818388

Zhang, Yan; Wong, Jasmine; Klinger, Mark; Tran, Mary T.; Shannon, Kevin M.

2009-01-01

140

Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors  

PubMed Central

Nonviral conversion of skin or blood cells into clinically useful human induced pluripotent stem cells (hiPSC) occurs in only rare fractions (?0.001%–0.5%) of donor cells transfected with non-integrating reprogramming factors. Pluripotency induction of developmentally immature stem-progenitors is generally more efficient than differentiated somatic cell targets. However, the nature of augmented progenitor reprogramming remains obscure, and its potential has not been fully explored for improving the extremely slow pace of non-integrated reprogramming. Here, we report highly optimized four-factor reprogramming of lineage-committed cord blood (CB) myeloid progenitors with bulk efficiencies of ?50% in purified episome-expressing cells. Lineage-committed CD33+CD45+CD34? myeloid cells and not primitive hematopoietic stem-progenitors were the main targets of a rapid and nearly complete non-integrated reprogramming. The efficient conversion of mature myeloid populations into NANOG+TRA-1-81+ hiPSC was mediated by synergies between hematopoietic growth factor (GF), stromal activation signals, and episomal Yamanaka factor expression. Using a modular bioinformatics approach, we demonstrated that efficient myeloid reprogramming correlated not to increased proliferation or endogenous Core factor expressions, but to poised expression of GF-activated transcriptional circuits that commonly regulate plasticity in both hematopoietic progenitors and embryonic stem cells (ESC). Factor-driven conversion of myeloid progenitors to a high-fidelity pluripotent state was further accelerated by soluble and contact-dependent stromal signals that included an implied and unexpected role for Toll receptor-NF?B signaling. These data provide a paradigm for understanding the augmented reprogramming capacity of somatic progenitors, and reveal that efficient induced pluripotency in other cell types may also require extrinsic activation of a molecular framework that commonly regulates self-renewal and differentiation in both hematopoietic progenitors and ESC. PMID:22905176

Park, Tea Soon; Huo, Jeffrey S.; Peters, Ann; Talbot, C. Conover; Verma, Karan; Zimmerlin, Ludovic; Kaplan, Ian M.; Zambidis, Elias T.

2012-01-01

141

Differential regulation of myeloid leukemias by the bone marrow microenvironment  

PubMed Central

Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM)1, and may be the cause of relapse following chemotherapy.2 Targeting the niche is a novel strategy to eliminate persistent and drug-resistant LSC. CD443,4 and IL-65 have been implicated previously in the LSC niche. Transforming growth factor (TGF)-?1 is released during bone remodeling6 and plays a role in maintenance of CML LSCs7, but a role for TGF-?1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor8,9 attenuates BCR-ABL1-induced CML-like myeloproliferative neoplasia (MPN)10 but enhances MLL-AF9-induced AML11 in mouse transplantation models, possibly through opposing effects of increased TGF-?1 on the respective LSC. PTH treatment caused a 15-fold decrease in LSCs in wildtype mice with CML-like MPN, and reduced engraftment of immune deficient mice with primary human CML cells. These results demonstrate that LSC niches in chronic and acute myeloid leukemias are distinct, and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSC, a prerequisite for the cure of CML. PMID:24162813

Krause, Daniela S.; Fulzele, Keertik; Catic, Andre; Sun, Chia Chi; Dombkowski, David; Hurley, Michael P.; Lezeau, Sanon; Attar, Eyal; Wu, Joy Y.; Lin, Herbert Y.; Divieti-Pajevic, Paola; Hasserjian, Robert P.; Schipani, Ernestina; Van Etten, Richard A.; Scadden, David T.

2013-01-01

142

MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny.  

PubMed

The MLL-AF9 fusion gene is associated with aggressive leukemias of both the myeloid and lymphoid lineage in infants, whereas in adults, this translocation is mainly associated with acute myeloid leukemia. These observations suggest that differences exist between fetal and adult tissues in terms of the 'cell of origin' from which the leukemia develops. Here we show that depending on extrinsic cues, human neonatal CD34(+) cells are readily immortalized along either the myeloid or lymphoid lineage upon MLL-AF9 expression and give rise to mainly lymphoid leukemia in immunocompromised mice. In contrast, immortalization of adult bone marrow CD34(+) cells is more difficult to achieve and is myeloid-biased, even when MLL-AF9 is expressed in purified hematopoietic stem cells (HSCs). Transcriptome analysis identified enrichment of HSC but not progenitor gene signatures in MLL-AF9-expressing cells. Although not observed in adult cells, neonatal cells expressing MLL-AF9 were enriched for gene signatures associated with poor prognosis, resistance to chemotherapeutic agents and MYC signaling. These results indicate that neonatal cells are inherently more prone to MLL-AF9-mediated immortalization than adult cells and suggest that intrinsic properties of the cell of origin, in addition to extrinsic cues, dictate lineage of the immortalized cell. PMID:23178754

Horton, S J; Jaques, J; Woolthuis, C; van Dijk, J; Mesuraca, M; Huls, G; Morrone, G; Vellenga, E; Schuringa, J J

2013-04-01

143

Functional integration of acute myeloid leukemia into the vascular niche.  

PubMed

Vascular endothelial cells are a critical component of the hematopoietic microenvironment that regulates blood cell production. Recent studies suggest the existence of functional cross-talk between hematologic malignancies and vascular endothelium. Here we show that human acute myeloid leukemia (AML) localizes to the vasculature in both patients and in a xenograft model. A significant number of vascular tissue-associated AML cells (V-AML) integrate into vasculature in vivo and can fuse with endothelial cells. V-AML cells acquire several endothelial cell-like characteristics, including the upregulation of CD105, a receptor associated with activated endothelium. Remarkably, endothelial-integrated V-AML shows an almost fourfold reduction in proliferative activity compared with non-vascular-associated AML. Primary AML cells can be induced to downregulate the expression of their hematopoietic markers in vitro and differentiate into phenotypically and functionally defined endothelial-like cells. After transplantation, these leukemia-derived endothelial cells are capable of giving rise to AML. These novel functional interactions between AML cells and normal endothelium along with the reversible endothelial cell potential of AML suggest that vascular endothelium may serve as a previously unrecognized reservoir for AML. PMID:24637335

Cogle, C R; Goldman, D C; Madlambayan, G J; Leon, R P; Al Masri, A; Clark, H A; Asbaghi, S A; Tyner, J W; Dunlap, J; Fan, G; Kovacsovics, T; Liu, Q; Meacham, A; Hamlin, K L; Hromas, R A; Scott, E W; Fleming, W H

2014-10-01

144

Myeloid leukemia after hematotoxins  

SciTech Connect

One of the most serious consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can now be distinguished. Classic therapy-related myeloid leukemia typically occurs 5 to 7 years after exposure to alkylating agents and/or irradiation, has a myelodysplastic phase with trilineage involvement, and is characterized by abnormalities of the long arms of chromosomes 5 and/or 7. Response to treatment is poor, and allogeneic bone marrow transplantation is recommended. Leukemia following treatment with agents that inhibit topoisomerase 11, however, has a shorter latency, no preleukemic phase, a monoblastic, myelomonocytic, or myeloblastic phenotype, and balanced translocations, most commonly involving chromosome bands 11 q23 or 21 q22. The MLL gene at 11 q23 or the AML1 gene at 21 q22 are almost uniformly rearranged. MLL is involved with many fusion gene partners. Therapy-related acute lymphoblastic leukemia also occurs with 1 1 q23 rearrangements. Therapy-related leukemias with 11 q23 or 21 q22 rearrangements, inv(16) or t(15;17), have a more favorable response to treatment and a clinical course similar to their de novo counterparts. 32 refs., 4 tabs.

Larson, R.A.; LeBeau, M.M.; Vardiman, J.W.; Rowley, J.D. [Univ. of Chicago, IL (United States)

1996-12-01

145

Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations  

PubMed Central

Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1, IGH@/MYC, ETV6(TEL)/RUNX1(AML1), 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies. PMID:16354839

Andersson, Anna; Olofsson, Tor; Lindgren, David; Nilsson, Bjorn; Ritz, Cecilia; Eden, Patrik; Lassen, Carin; Rade, Johan; Fontes, Magnus; Morse, Helena; Heldrup, Jesper; Behrendtz, Mikael; Mitelman, Felix; Hoglund, Mattias; Johansson, Bertil; Fioretos, Thoas

2005-01-01

146

Genetic deletion of JAM-C reveals a role in myeloid progenitor generation  

PubMed Central

Hematopoietic stem cells (HSCs) have the capacity to self-renew and continuously differentiate into all blood cell lineages throughout life. At each branching point during differentiation, interactions with the environment are key in the generation of daughter cells with distinct fates. Here, we examined the role of the cell adhesion molecule JAM-C, a protein known to mediate cellular polarity during spermatogenesis, in hematopoiesis. We show that murine JAM-C is highly expressed on HSCs in the bone marrow (BM). Expression correlates with self-renewal, the highest being on long-term repopulating HSCs, and decreases with differentiation, which is maintained longest among myeloid committed progenitors. Inclusion of JAM-C as a sole marker on lineage-negative BM cells yields HSC enrichments and long-term multilineage reconstitution when transferred to lethally irradiated mice. Analysis of Jam-C–deficient mice showed that two-thirds die within 48 hours after birth. In the surviving animals, loss of Jam-C leads to an increase in myeloid progenitors and granulocytes in the BM. Stem cells and myeloid cells from fetal liver are normal in number and homing to the BM. These results provide evidence that JAM-C defines HSCs in the BM and that JAM-C plays a role in controlling myeloid progenitor generation in the BM. PMID:19109565

McBride, Jacqueline M.; Chiu, Henry; Rangell, Linda; Cabote, Lorena; Lee, Wyne P.; Cupp, James; Danilenko, Dimitry M.; Fong, Sherman

2009-01-01

147

MicroRNAs in Acute Myeloid Leukemia and Other Blood Disorders  

PubMed Central

Common blood disorders include hematopoietic cell malignancies or leukemias and plasma cell dyscrasia, all of which have associated microRNA abnormalities. In this paper, we discuss several leukemias including acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) and identify altered microRNAs and their targets. Immune disorders with altered blood levels of antibodies include autoimmune disorders, such as systemic lupus erythematosus (SLE) with associated anti-self-autoantibodies and immunoglobulin A nephropathy (IgAN) also have related microRNA abnormalities. The alterations in microRNAs may serve as therapeutic targets in these blood disorders. PMID:23259069

Yuan, Yao; Kasar, Siddha; Underbayev, Chingiz; Prakash, Sindhuri; Raveche, Elizabeth

2012-01-01

148

Anti-infective prophylaxis in pediatric patients with acute myeloid leukemia.  

PubMed

Pediatric patients undergoing treatment for acute myeloid leukemia (AML) are at high risk for infectious complications, predominantly due to Gram-negative bacteria, viridans group streptococci and fungal pathogens. In order to prevent infections in these patients, most institutions have implemented a number of non-pharmacological approaches to supportive care. In addition, antibiotic prophylaxis reduces bacterial infection, but may increase the emergence of resistance. Antifungal prophylaxis is generally recommended for children with AML. Whereas the use of hematopoietic growth factors has not resulted in improved survival, the efficacy of prophylactic granulocyte transfusions has to be determined. PMID:25359519

Lehrnbecher, Thomas; Sung, Lillian

2014-12-01

149

Rearrangement and expression of the immunoglobulin ?-chain gene in human myeloid cells.  

PubMed

Immunoglobulin (Ig), a characteristic marker of B cells, has been reported to be expressed in epithelial cells, with a suggested role in their growth and survival. We have previously reported that IgG heavy chain is expressed in acute myeloid leukemia (AML), but not in the monocytes or neutrophils from patients with non-hematopoietic neoplasms or healthy controls. In the present study, we assessed IgM heavy chain expression and repertoire in human myeloid cells. We detected VH?DJH? rearrangement and expression in 7/7 AML cell lines, 7/14 primary myeloblasts from AML patients, and interestingly, 8/20 monocytes and 3/20 neutrophils from patients with non-hematopoietic neoplasms and healthy individuals. We also found evidence of somatic hypermutation of the variable (V) gene segments in AML-derived IgM gene rearrangements but not in IgM from monocytes or neutrophils from patients with non-hematopoietic neoplasms and healthy individuals. Furthermore, IgM VH?DJH? gene rearrangements in AML cell lines, primary myeloblasts, and monocytes and neutrophils from patients with non-hematopoietic neoplasms showed a restricted V usage and repertoire, whereas the VH?DJH? gene rearrangements in monocytes and neutrophils from healthy individuals displayed more diversity. Anti-human IgM inhibited cell proliferation, but did not induce apoptosis in AML cell lines. Our findings suggest that AML-derived IgM might be a novel AML-related molecule that is involved in leukemogenesis and AML progression and might serve as a useful molecular marker for designing targeted therapy and monitoring minimal residual disease. PMID:24141767

Huang, Jing; Sun, Xiaoping; Gong, Xiaoting; He, Zhiqiao; Chen, Lei; Qiu, Xiaoyan; Yin, C Cameron

2014-01-01

150

Gemtuzumab Ozogamicin in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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

2013-09-23

151

Localization of hematopoietic cells in the bullfrog (Lithobates catesbeianus).  

PubMed

Amphibians represent the first phylogenetic group to possess hematopoietic bone marrow. However, adult amphibian hematopoiesis has only been described in a few species and with conflicting data. Bone marrow, kidney, spleen, liver, gut, stomach, lung, tegument, and heart were therefore collected from adult Lithobates catesbeianus and investigated by light microscopy and immunohistochemical methods under confocal laser microscopy. Our study demonstrated active hematopoiesis in the bone marrow of vertebrae, femur, and fingers and in the kidney, but no hematopoietic activity inside other organs including the spleen and liver. Blood cells were identified as a heterogeneous cell population constituted by heterophils, basophils, eosinophils, monocytes, erythrocytic cells, lymphocytes, and their precursors. Cellular islets of the thrombocytic lineage occurred near sinusoids of the bone marrow. Antibodies against CD34, CD117, stem cell antigen, erythropoietin receptor, and the receptor for granulocyte colony-stimulating factor identified some cell populations, and some circulating immature cells were seen in the bloodstream. Thus, on the basis of these phylogenetic features, we propose that L. catesbeianus can be used as an important model for hematopoietic studies, since this anuran exhibits hematopoiesis characteristics both of lower vertebrates (renal hematopoiesis) and of higher vertebrates (bone marrow hematopoiesis). PMID:19449034

de Abreu Manso, Pedro Paulo; de Brito-Gitirana, Lycia; Pelajo-Machado, Marcelo

2009-08-01

152

Graft-versus-host disease causes broad suppression of hematopoietic primitive cells and blocks megakaryocyte differentiation in a murine model.  

PubMed

Cytopenia and delayed immune reconstitution with acute graft-versus-host disease (aGVHD) indicate a poor prognosis. However, how donor-derived cell hematopoiesis is impaired in aGVHD is not well understood. We addressed this issue by studying the kinetics of hematopoiesis and the functions of hematopoietic stem and progenitor cells in an aGVHD model with haplo-MHC-matched murine bone marrow transplantation. Although hematopoiesis was progressively suppressed during aGVHD, the hematopoietic regenerative potential of donor-derived hematopoietic stem cells remains intact. There was a dramatic reduction in primitive hematopoietic cells and a defect in the ability of these cells to generate common myeloid progenitors (CMPs) and megakaryocyte/erythrocyte progenitors (MEPs). These effects were observed along with a concomitant increase in granulocyte/macrophage progenitors, suggesting that differentiation into MEPs is blocked during aGVHD. Interestingly, cyclosporine A was able to partially reverse the hematopoietic suppression as well as the differentiation blockage of CMPs. These data provide new insights into the pathogenesis of aGVHD and may improve the clinical management of aGVHD. PMID:24846295

Lin, Yan; Hu, Xiaoxia; Cheng, Hui; Pang, Yakun; Wang, Libing; Zou, Lin; Xu, Sheng; Zhuang, Xiaomeng; Jiang, Chuanhe; Yuan, Weiping; Cheng, Tao; Wang, Jianmin

2014-09-01

153

Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis  

PubMed Central

Immunosuppressive therapy is the treatment for aplastic anemia patients ineligible for transplantation. The role of hematopoietic growth factors as adjunct to treatment in these patients is unclear. We conducted a systematic review and meta-analysis of randomized controlled trials comparing treatment with immunosuppressive therapy and hematopoietic growth factors to immunosuppressive therapy alone in patients with aplastic anemia. Two reviewers appraised the quality of trials and extracted data. For each trial, results were expressed as relative risks with 95% confidence intervals (CI) for dichotomous data. The addition of hematopoietic growth factors yielded no difference in overall mortality at 100 days, one year and five years [relative risks 1.33 (95% CI 0.56–3.18), relative risks 0.90 (95% CI 0.50–1.63) and relative risks 0.89 (95% CI 0.55–1.46), respectively]. There was no difference in overall hematologic response and in the occurrence of infections. HGF significantly decreased the risk for relapse, relative risks 0.45 (95% CI 0.30–0.68, 3 trials). Hematopoietic growth factors were not associated with higher occurrence of myelodysplastic syndrome and acute myeloid leukemia or paroxysmal nocturnal hemoglobinuria. The addition of hematopoietic growth factors does not affect mortality, response rate or infections occurrence. Therefore, it should not be recommended routinely as an adjunct to the immunosuppressive therapy for patients with aplastic anemia. PMID:19336743

Gurion, Ronit; Gafter-Gvili, Anat; Paul, Mical; Vidal, Liat; Ben-Bassat, Isaac; Yeshurun, Moshe; Shpilberg, Ofer; Raanani, Pia

2009-01-01

154

A fast and simple approach for the simultaneous detection of hematopoietic chimerism, NPM1, and FLT3-ITD mutations after allogeneic stem cell transplantation.  

PubMed

Hematopoietic chimerism can be used as a tool for patient management after allogeneic hematopoietic stem cell transplantation (HSCT). An increase in the proportion of recipient cells after transplantation is strongly associated with relapse in chronic myeloid leukemia. However, in acute myeloid leukemia (AML) the significance of increasing mixed chimerism (MC) as a predictive marker for relapse is less clear. Several mutations frequently found in AML have been employed for minimal residual disease detection and relapse prediction. Therefore, a combined analysis of hematopoietic chimerism and of the molecular aberrations found in AML could be used to improve MC characterization. We developed a multiplex PCR for use in the simultaneous detection of hematopoietic chimerism and mutations in nucleophosmin (NPM1) and fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD). A total of 303 samples from 20 AML patients were analyzed after HSCT. The microsatellite markers used for hematopoietic chimerism detection were D1S80, D7S1517, D4S2366, THO1, and SE33. A total of 149 samples from 18 patients showed MC with a mean detection time of 9.7 months. From the 18 patients with MC, in 6 of the patients, no FLT3-ITD or NPM1 mutation was found at any time point tested, and these patients remained in complete hematological remission. In 12 patients with MC, FLT3-ITD and NPM1 mutations were found, and these patients showed signs of hematological relapse. Our combined analysis of NPM1/FLT3-ITD mutations and hematopoietic chimerism improved the characterization of patients with MC after HSCT. The present approach may be further expanded by combining additional mutations found in AML with hematopoietic chimerism detection. PMID:23907410

Waterhouse, Miguel; Bertz, Hartmut; Finke, Juergen

2014-02-01

155

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation  

PubMed Central

Inherited or sporadic heterozygous mutations in the transcription factor GATA2 lead to a clinical syndrome characterized by non-tuberculous mycobacterial and other opportunistic infections, a severe deficiency in monocytes, B cells and natural killer cells, and progression from a hypocellular myelodysplastic syndrome to myeloid leukemias. To identify acquired somatic mutations associated with myeloid transformation in patients with GATA2 mutations, we sequenced the region of the ASXL1 gene previously associated with transformation from myelodysplasia to myeloid leukemia. Somatic, heterozygous ASXL1 mutations were identified in 14/48 (29%) of patients with GATA2 deficiency, including four out of five patients who developed a proliferative chronic myelomonocytic leukemia. Although patients with GATA2 mutations had a similarly high incidence of myeloid transformation when compared to previously described patients with ASXL1 mutations, GATA2 deficiency patients with acquired ASXL1 mutation were considerably younger, almost exclusively female, and had a high incidence of transformation to a proliferative chronic myelomonocytic leukemia. These patients may benefit from allogeneic hematopoietic stem cell transplantation before the development of acute myeloid leukemia or chronic myelomonocytic leukemia. (ClinicalTrials.gov identifier NCT00018044, NCT00404560, NCT00001467, NCT00923364.) PMID:24077845

West, Robert R.; Hsu, Amy P.; Holland, Steven M.; Cuellar-Rodriguez, Jennifer; Hickstein, Dennis D.

2014-01-01

156

Myelodysplastic syndromes/neoplasms: recent classification system based on World Health Organization Classification of Tumors - International Agency for Research on Cancer for Hematopoietic and Lymphoid Tissues  

PubMed Central

The myelodysplastic Syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective hematopoiesis, and increased risk of development of acute myeloid leukemia. The classification and the diagnostic criteria have been redefined by the recent World Health Organization Classification of Tumors – International Agency for Research on Cancer for Hematopoietic and Lymphoid Tissues. The myelodysplastic syndromes are now classified into the following categories – refractory cytopenia with unilineage dysplasia, refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, myelodysplastic syndrome associated with isolated del (5q), myelodysplastic syndrome – unclassifiable, and childhood myelodysplastic syndrome. The clinicopathologic features, morphology, differential diagnosis, immunophenotyping, cytogenetics, prognosis and predictive factors are presented in the light of recent World Health Organization Classification of Tumors – International Agency for Research on Cancer. PMID:22282696

Gupta, Geetanjali; Singh, Reecha; Kotasthane, Dhananjay S; Kotasthane, Vaishali D

2010-01-01

157

MIP-1?/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia.  

PubMed

In the initiation process of chronic myeloid leukemia (CML), a small number of transformed leukemia-initiating cells (LICs) coexist with a large number of normal hematopoietic cells, gradually increasing thereafter and eventually predominating in the hematopoietic space. However, the interaction between LICs and normal hematopoietic cells at the early phase has not been clearly delineated because of the lack of a suitable experimental model. In this study, we succeeded in causing a marked leukocytosis resembling CML from restricted foci of LICs in the normal hematopoietic system by direct transplantation of BCR-ABL gene-transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL(+)lineage(-)c-kit(-) immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1?/CCL3, which promoted the development of CML. Conversely, ablation of the CCL3 gene in LICs dramatically inhibited the development of CML and concomitantly reduced recurrence after the cessation of a short-term tyrosine kinase inhibitor treatment. Finally, normal hematopoietic stem/progenitor cells can directly impede the maintenance of LICs in BM in the absence of CCL3 signal. PMID:24166712

Baba, Tomohisa; Naka, Kazuhito; Morishita, Soji; Komatsu, Norio; Hirao, Atsushi; Mukaida, Naofumi

2013-11-18

158

Adult neurogenesis in the decapod crustacean brain: a hematopoietic connection?  

PubMed

New neurons are produced and integrated into circuits in the adult brains of many organisms, including crustaceans. In some crustacean species, the first-generation neuronal precursors reside in a niche exhibiting characteristics analogous to mammalian neurogenic niches. However, unlike mammalian niches where several generations of neuronal precursors co-exist, the lineage of precursor cells in crayfish is spatially separated allowing the influence of environmental and endogenous regulators on specific generations in the neuronal precursor lineage to be defined. Experiments also demonstrate that the first-generation neuronal precursors in the crayfish Procambarus clarkii are not self-renewing. A source external to the neurogenic niche must therefore provide cells that replenish the first-generation precursor pool, because although these cells divide and produce a continuous efflux of second-generation cells from the niche, the population of first-generation niche precursors is not diminished with growth and aging. In vitro studies show that cells extracted from the hemolymph, but not other tissues, are attracted to and incorporated into the neurogenic niche, a phenomenon that appears to involve serotonergic mechanisms. We propose that, in crayfish, the hematopoietic system may be a source of cells that replenish the niche cell pool. These and other studies reviewed here establish decapod crustaceans as model systems in which the processes underlying adult neurogenesis, such as stem cell origins and transformation, can be readily explored. Studies in diverse species where adult neurogenesis occurs will result in a broader understanding of fundamental mechanisms and how evolutionary processes may have shaped the vertebrate/mammalian condition. PMID:21929622

Beltz, Barbara S; Zhang, Yi; Benton, Jeanne L; Sandeman, David C

2011-09-01

159

Adult neurogenesis in the decapod crustacean brain: A hematopoietic connection?  

PubMed Central

New neurons are produced and integrated into circuits in the adult brains of many organisms, including crustaceans. In some crustacean species, the 1st- generation neuronal precursors reside in a niche exhibiting characteristics analogous to mammalian neurogenic niches. However, unlike mammalian niches where several generations of neuronal precursors coexist, the lineage of precursor cells in crayfish is spatially separated allowing the influence of environmental and endogenous regulators on specific generations in the neuronal precursor lineage to be defined. Experiments also demonstrate that the 1st-generation neuronal precursors in the crayfish Procambarus clarkii are not self-renewing. A source external to the neurogenic niche must therefore provide cells that replenish the 1st-generation precursor pool, because although these cells divide and produce a continuous efflux of 2nd-generation cells from the niche, the population of 1st-generation niche precursors is not diminished with growth and aging. In vitro studies show that cells extracted from the hemolymph, but not other tissues, are attracted to and incorporated into the neurogenic niche, a phenomenon that appears to involve serotonergic mechanisms. We propose that in crayfish, the hematopoietic system may be a source of cells that replenish the niche cell pool. These and other studies reviewed here establish decapod crustaceans as model systems in which the processes underlying adult neurogenesis, such as stem cell origins and transformation, can be readily explored. Studies in diverse species where adult neurogenesis occurs will result in a broader understanding of fundamental mechanisms and how evolutionary processes may have shaped the vertebrate/mammalian condition. PMID:21929622

Beltz, Barbara S.; Zhang, Yi; Benton, Jeanne L.; Sandeman, David C.

2011-01-01

160

Expression and role of mannose receptor\\/terminal high-mannose type oligosaccharide on osteoclast precursors during osteoclast formation  

Microsoft Academic Search

Osteoclasts are formed from hematopoietic precursors via cell-cell fusion. We have previously reported that man- nose residues are expressed on the outer membranes of monocytes during osteoclast differentiation. In the present study, we have attempted to demonstrate the pattern of expression levels of terminal high-mannose type oligo- saccharide and to show that the mannose receptor is expressed on osteoclast precursor

S Morishima; I Morita; T Tokushima; H Kawashima; M Miyasaka; K Omura; S Murota

2003-01-01

161

T-, B and NK-lymphoid, but not myeloid cells arise from human CD34+CD38?CD7+ common lymphoid progenitors expressing lymphoid-specific genes  

Microsoft Academic Search

Hematopoietic stem cells in the bone marrow (BM) give rise to all blood cells. According to the classic model of hematopoiesis, the differentiation paths leading to the myeloid and lymphoid lineages segregate early. A candidate ‘common lymphoid progenitor’ (CLP) has been isolated from CD34+CD38? human cord blood cells based on CD7 expression. Here, we confirm the B- and NK-differentiation potential

I Hoebeke; M De Smedt; F Stolz; K Pike-Overzet; F J T Staal; J Plum; G Leclercq

2007-01-01

162

Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice  

PubMed Central

Tissue factor (TF) is the primary activator of the coagulation cascade. During endotoxemia, TF expression leads to disseminated intravascular coagulation. However, the relative contribution of TF expression by different cell types to the activation of coagulation has not been defined. In this study, we investigated the effect of either a selective inhibition of TF expression or cell type-specific deletion of the TF gene (F3) on activation of coagulation in a mouse model of endotoxemia. We found that inhibition of TF on either hematopoietic or nonhematopoietic cells reduced plasma thrombin-antithrombin (TAT) levels 8 hours after administration of bacterial lipopolysaccharide (LPS). In addition, plasma TAT levels were significantly reduced in endotoxemic mice lacking the TF gene in either myeloid cells (TFflox/flox,LysMCre mice) or in both endothelial cells (ECs) and hematopoietic cells (TFflox/flox,Tie-2Cre mice). However, deletion of the TF gene in ECs alone had no effect on LPS-induced plasma TAT levels. Similar results were observed in mice lacking TF in vascular smooth muscle cells. Finally, we found that mouse platelets do not express TF pre-mRNA or mRNA. Our data demonstrate that in a mouse model of endotoxemia activation of the coagulation cascade is initiated by TF expressed by myeloid cells and an unidentified nonhematopoietic cell type(s). PMID:20410508

Pawlinski, Rafal; Wang, Jian-Guo; Owens, A. Phillip; Williams, Julie; Antoniak, Silvio; Tencati, Michael; Luther, Thomas; Rowley, Jesse W.; Low, Elizabeth N.; Weyrich, Andrew S.

2010-01-01

163

Allogeneic Hematopoietic Stem Cell Transplantation for a BCR-FGFR1 Myeloproliferative Neoplasm Presenting as Acute Lymphoblastic Leukemia.  

PubMed

Hematopoietic myeloproliferative neoplasms (MPNS) with rearrangements of the receptor tyrosine kinase FGFR1 gene, located on chromosome 8p11, are uncommon and associated with diverse presentations such as atypical chronic myeloid leukemia, acute myeloid leukemia, or an acute T- or B-lymphoblastic leukemia, reflecting the hematopoietic stem cell origin of the disease. A review of MPN patients with the t(8;22) translocation that results in a chimeric BCR-FGFR1 fusion gene reveals that this disease either presents or rapidly transforms into an acute leukemia that is generally unresponsive to currently available chemotherapeutic regimens including tyrosine kinase inhibitors (TKIS). The first case of a rare BCR-FGFR1 MPN presenting in a B-acute lymphoblastic phase who underwent allogeneic hematopoietic stem cell transplantation (HSCT) with a subsequent sustained complete molecular remission is described. Allogeneic HSCT is currently the only available therapy capable of achieving long-term remission in BCR-FGFR1 MPN patients. PMID:23082258

Haslam, Karl; Langabeer, Stephen E; Kelly, Johanna; Coen, Natasha; O'Connell, Niamh M; Conneally, Eibhlin

2012-01-01

164

Allogeneic Hematopoietic Stem Cell Transplantation for a BCR-FGFR1 Myeloproliferative Neoplasm Presenting as Acute Lymphoblastic Leukemia  

PubMed Central

Hematopoietic myeloproliferative neoplasms (MPNS) with rearrangements of the receptor tyrosine kinase FGFR1 gene, located on chromosome 8p11, are uncommon and associated with diverse presentations such as atypical chronic myeloid leukemia, acute myeloid leukemia, or an acute T- or B-lymphoblastic leukemia, reflecting the hematopoietic stem cell origin of the disease. A review of MPN patients with the t(8;22) translocation that results in a chimeric BCR-FGFR1 fusion gene reveals that this disease either presents or rapidly transforms into an acute leukemia that is generally unresponsive to currently available chemotherapeutic regimens including tyrosine kinase inhibitors (TKIS). The first case of a rare BCR-FGFR1 MPN presenting in a B-acute lymphoblastic phase who underwent allogeneic hematopoietic stem cell transplantation (HSCT) with a subsequent sustained complete molecular remission is described. Allogeneic HSCT is currently the only available therapy capable of achieving long-term remission in BCR-FGFR1 MPN patients. PMID:23082258

Haslam, Karl; Langabeer, Stephen E.; Kelly, Johanna; Coen, Natasha; O'Connell, Niamh M.; Conneally, Eibhlin

2012-01-01

165

Gfi-1 regulates the erythroid transcription factor network through Id2 repression in murine hematopoietic progenitor cells.  

PubMed

Growth factor independence 1 (Gfi-1) is a part of the transcriptional network that regulates the development of adult hematopoietic stem and progenitor cells. Gfi-1-null (Gfi-1(-/-)) mice have reduced numbers of hematopoietic stem cells (HSCs), impaired radioprotective function of hematopoietic progenitor cells (HPCs), and myeloid and erythroid hyperplasia. We found that the development of HPCs and erythropoiesis, but not HSC function, was rescued by reducing the expression of inhibitor of DNA-binding protein 2 (Id2) in Gfi-1(-/-) mice. Analysis of Gfi-1(-/-);Id2(+/-) mice revealed that short-term HSCs, common myeloid progenitors (CMPs), erythroid burst-forming units, colony-forming units in spleen, and more differentiated red cells were partially restored by reducing Id2 levels in Gfi-1(-/-) mice. Moreover, short-term reconstituting cells, and, to a greater extent, CMP and megakaryocyte-erythroid progenitor development, and red blood cell production (anemia) were rescued in mice transplanted with Gfi-1(-/-);Id2(+/-) bone marrow cells (BMCs) in comparison with Gfi-1(-/-) BMCs. Reduction of Id2 expression in Gfi-1(-/-) mice increased the expression of Gata1, Eklf, and EpoR, which are required for proper erythropoiesis. Reducing the levels of other Id family members (Id1 and Id3) in Gfi-1(-/-) mice did not rescue impaired HPC function or erythropoiesis. These data provide new evidence that Gfi-1 is linked to the erythroid gene regulatory network by repressing Id2 expression. PMID:25051963

Kim, Wonil; Klarmann, Kimberly D; Keller, Jonathan R

2014-09-01

166

Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia  

PubMed Central

The ETS transcription factor ERG plays a central role in definitive hematopoiesis, and its overexpression in acute myeloid leukemia (AML) is associated with a stem cell signature and poor prognosis. Yet how ERG causes leukemia is unclear. Here we show that pan-hematopoietic ERG expression induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and to human AML with high ERG expression. This transcriptional program was associated with activation of RAS that was required for leukemia cells growth in vitro and in vivo. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel hematopoietic enhancer validated in transgenic mice and human CD34+ normal and leukemic cells. Pim1 inhibition disrupts growth and induces apoptosis of ERG-expressing leukemic cells. The importance of the ERG/PIM1 axis is further underscored by the poorer prognosis of AML highly expressing ERG and PIM1. Thus, integrative genomic analysis demonstrates that ERG causes myeloid progenitor leukemia characterized by an induction of leukemia stem cell transcriptional programs. Pim1 and the RAS pathway are potential therapeutic targets of these high-risk leukemias. PMID:23974202

Goldberg, Liat; Tijssen, Marloes R.; Birger, Yehudit; Hannah, Rebecca L.; Kinston, Sarah J.; Schutte, Judith; Beck, Dominik; Knezevic, Kathy; Schiby, Ginette; Jacob-Hirsch, Jasmine; Biran, Anat; Kloog, Yoel; Marcucci, Guido; Bloomfield, Clara D.; Aplan, Peter D.; Pimanda, John E.

2013-01-01

167

Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens.  

PubMed

The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown. We compared the outcome of allogeneic hematopoietic cell transplantation in children with acute myeloid leukemia using RIC regimens with those receiving myeloablative-conditioning (MAC) regimens. A total of 180 patients were evaluated (39 with RIC and 141 with MAC regimens). Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-versus-host disease, leukemia-free, and overall survival between treatment groups. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%; P = .95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; P = .73). After carefully controlled analyses, we found that in this relatively modest study population, the data supported a role for RIC regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provided justification for designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population. PMID:24435046

Bitan, Menachem; He, Wensheng; Zhang, Mei-Jie; Abdel-Azim, Hisham; Ayas, Mouhab Fakhreddine; Bielorai, Bella; Carpenter, Paul A; Cairo, Mitchell S; Diaz, Miguel Angel; Horan, John T; Jodele, Sonata; Kitko, Carrie L; Schultz, Kirk R; Kletzel, Morris; Kasow, Kimberly A; Lehmann, Leslie E; Mehta, Parinda A; Shah, Nirali; Pulsipher, Michael A; Prestidge, Tim; Seber, Adriana; Shenoy, Shalini; Woolfrey, Ann E; Yu, Lolie C; Davies, Stella M

2014-03-01

168

RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.  

PubMed

Hematopoietic stem cells (HSCs) sustain lifelong production of all blood cell types through finely balanced divisions leading to self-renewal and differentiation. Although several genes influencing HSC self-renewal have been identified, to date no gene has been described that, when activated, enhances HSC self-renewal and, when inactivated [corrected] promotes HSC differentiation. We observe that the retinoic acid receptor (RAR)gamma is selectively expressed in primitive hematopoietic precursors and that the bone marrow of RARgamma knockout mice exhibit markedly reduced numbers of HSCs associated with increased numbers of more mature progenitor cells compared with wild-type mice. In contrast, RARalpha is widely expressed in hematopoietic cells, but RARalpha knockout mice do not exhibit any HSC or progenitor abnormalities. Primitive hematopoietic precursors overexpressing RARalpha differentiate predominantly to granulocytes in short-term culture, whereas those overexpressing RARgamma exhibit a much more undifferentiated phenotype. Furthermore, loss of RARgamma abrogated the potentiating effects of all-trans retinoic acid on the maintenance of HSCs in ex vivo culture. Finally, pharmacological activation of RARgamma ex vivo promotes HSC self-renewal, as demonstrated by serial transplant studies. We conclude that the RARs have distinct roles in hematopoiesis and that RARgamma is a critical physiological and pharmacological regulator of the balance between HSC self-renewal and differentiation. PMID:16682494

Purton, Louise E; Dworkin, Sebastian; Olsen, Gemma Haines; Walkley, Carl R; Fabb, Stewart A; Collins, Steven J; Chambon, Pierre

2006-05-15

169

Drosophila as a model for the two myeloid blood cell systems in vertebrates.  

PubMed

Fish, mice, and humans rely on two coexisting myeloid blood cell systems. One is sustained by hematopoietic progenitor cells, which reside in specialized microenvironments (niches) in hematopoietic organs and give rise to cells of the monocyte lineage. The other system corresponds to the independent lineage of self-renewing tissue macrophages, which colonize organs during embryonic development and are maintained during later life by proliferation in local tissue microenvironments. However, little is known about the nature of these microenvironments and their regulation. Moreover, many vertebrate tissues contain a mix of both tissue-resident and monocyte-derived macrophages, posing a challenge to the study of lineage-specific regulatory mechanisms and function. This review highlights how research in the simple model organism Drosophila melanogaster can address many of these outstanding questions in the field. Drawing parallels between hematopoiesis in Drosophila and vertebrates, we illustrate the evolutionary conservation of the two myeloid systems across animal phyla. Much like vertebrates, Drosophila possesses a lineage of self-renewing tissue-resident macrophages, which we refer to as tissue hemocytes, as well as a "definitive" lineage of macrophages that derive from hematopoiesis in the progenitor-based lymph gland. We summarize key findings from Drosophila hematopoiesis that illustrate how local microenvironments, systemic signals, immune challenges, and nervous inputs regulate adaptive responses of tissue-resident macrophages and progenitor-based hematopoiesis to maximize fitness of the animal. PMID:24946019

Gold, Katrina S; Brückner, Katja

2014-08-01

170

Transduction of human NOD/SCID-repopulating cells with both lymphoid and myeloid potential by foamy virus vectors.  

PubMed

The efficiency of gene transfer into human hematopoietic stem cells by oncoretroviral vectors is too low for effective gene therapy of most hematologic diseases. Retroviral vectors based on the nonpathogenic foamy viruses (FV) are an alternative gene-transfer system. In this study, human umbilical cord blood CD34(+) cells were transduced with FV vectors by a single 10-h exposure to vector stocks and then injected into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice. At 5-7 weeks after transplantation, high transgene expression rates were observed in engrafted human hematopoietic cells, including over 60% of clonogenic progenitors. Significant transgene silencing did not occur. We developed an approach for expanding human cell populations derived from transplanted mice to show that multiple SCID repopulating cells (SRCs) had been transduced, including some that were capable of both lymphoid and myeloid differentiation. These findings demonstrate for the first time that human pluripotent (lympho-myeloid) hematopoietic stem cells repopulate NOD/SCID mice and can be efficiently transduced by FV vectors. PMID:12060773

Josephson, Neil C; Vassilopoulos, George; Trobridge, Grant D; Priestley, Greg V; Wood, Brent L; Papayannopoulou, Thalia; Russell, David W

2002-06-11

171

Genetics Home Reference: Familial acute myeloid leukemia with mutated CEBPA  

MedlinePLUS

... OMIM Genetic disorder catalog Conditions > Familial acute myeloid leukemia with mutated CEBPA On this page: Description Genetic ... Reviewed May 2012 What is familial acute myeloid leukemia with mutated CEBPA? Familial acute myeloid leukemia with ...

172

Genetics Home Reference: Cytogenetically normal acute myeloid leukemia  

MedlinePLUS

... PubMed Recent literature Conditions > Cytogenetically normal acute myeloid leukemia On this page: Description Genetic changes Inheritance Diagnosis ... January 2014 What is cytogenetically normal acute myeloid leukemia? Cytogenetically normal acute myeloid leukemia (CN-AML) is ...

173

Hematopoietic Stem Cells: Inferences-from In Vivo Assays  

E-print Network

Hematopoietic Stem Cells: Inferences-from In Vivo Assays CONNIEEAVES,CINDYMILLER,JOHANNE CASHMAN Columbia, Canada Key Words.Hematopoietic stem cells Transplantation Cord blood. Expansion Growthfactors murine hematopoietic stem cells to be quantitated. Measurements of murine CRU have shown

Zandstra, Peter W.

174

Characterizing the human hematopoietic CDome  

PubMed Central

In this study, we performed extensive semi-automated data collection from the primary and secondary literature in an effort to characterize the expression of all membrane proteins within the CD scheme on hematopoietic cells. Utilizing over 6000 data points across 305 CD molecules on 206 cell types, we seek to give a preliminary characterization of the “human hematopoietic CDome.” We encountered severe gaps in the knowledge of CD protein expression, mostly resulting from incomplete and unstructured data generation, which we argue inhibit both basic research as well as therapies seeking to target membrane proteins. We detail these shortcomings and propose strategies to overcome these issues. Analyzing the available data, we explore the functional characteristics of the CD molecules both individually and across the groups of hematopoietic cells on which they are expressed. We compare protein and mRNA data for a subset of CD molecules, and explore cell functions in the context of CD protein expression. We find that the presence and function of CD molecules serve as good indicators for the overall function of the cells that express them, suggesting that increasing our knowledge about the cellular CDome may serve to stratify cells on a more functional level. PMID:25309582

Barnkob, Mike Stein; Simon, Christian; Olsen, Lars R?nn

2014-01-01

175

Cohesin mutations in myeloid malignancies: underlying mechanisms  

PubMed Central

Recently, whole genome sequencing approaches have pinpointed mutations in genes that were previously not associated with cancer. For Acute Myeloid Leukaemia (AML), and other myeloid disorders, these approaches revealed a high prevalence of mutations in genes encoding the chromosome cohesion complex, cohesin. Cohesin mutations represent a novel genetic pathway for AML, but how AML arises from these mutations is unknown. This review will explore the potential mechanisms by which cohesin mutations contribute to AML and other myeloid malignancies. PMID:24904756

2014-01-01

176

Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease  

PubMed Central

BACKGROUND Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease. METHODS Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward. RESULTS All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (±SE) donor–recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3±8.6% and 83.3±10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0±0.3 and 12.6±0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient. CONCLUSIONS A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor–recipient chimerism and reverse the sickle cell phenotype. PMID:20007560

Hsieh, Matthew M.; Kang, Elizabeth M.; Fitzhugh, Courtney D.; Link, M. Beth; Bolan, Charles D.; Kurlander, Roger; Childs, Richard W.; Rodgers, Griffin P.; Powell, Jonathan D.; Tisdale, John F.

2013-01-01

177

Azacitidine and Sonidegib in Treating Patients With Myeloid Malignancies  

ClinicalTrials.gov

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); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2014-09-12

178

PRL-2 increases Epo and IL-3 responses in hematopoietic cells  

PubMed Central

Dual specificity protein tyrosine phosphatase PRL-2 is over-expressed in pediatric acute myeloid leukemia (AML) and is located at human chromosome 1p35, a region often rearranged or amplified in malignant lymphoma and B cell-chronic lymphocytic leukemia (B-CLL). Little is known of the significance of PRL-2 expression in hematopoietic malignancies. Herein we demonstrated that ectopic expression of PRL-2 in murine pre-B cell line BaF3ER and mouse bone marrow cells induced key features associated with malignant progression and metastasis. PRL-2 transfected Baf3ER cells had augmented growth responses to hematopoietic growth factors Epo or IL-3 with shortened cell cycle, reduced requirement (5x) for Epo in cell survival, increased cell migration (3x), reduced cell adhesion (5x) and conversion to an immature cell morphology in association with increased expression (3x) of stem cell marker Bmi-1. When transduced into mouse bone marrow cells, PRL-2 increased Epo-induced colony formation (4x) and gave rise to larger colonies. These observations provide evidences implicating PRL-2 as a pathogenic molecule in hematopoietic malignancies and suggest its potential as a novel therapeutic target. PMID:20226699

Akiyama, Shoko; Yi, Taolin

2010-01-01

179

Lineage Tracing of Pf4-Cre Marks Hematopoietic Stem Cells and Their Progeny  

PubMed Central

The development of a megakaryocyte lineage specific Cre deleter, using the Pf4 (CXCL4) promoter (Pf4-Cre), was a significant step forward in the specific analysis of platelet and megakaryocyte cell biology. However, in the present study we have employed a sensitive reporter-based approach to demonstrate that Pf4-Cre also recombines in a significant proportion of both fetal liver and bone marrow hematopoietic stem cells (HSCs), including the most primitive fraction containing the long-term repopulating HSCs. Consequently, we demonstrate that Pf4-Cre activity is not megakaryocyte lineage-specific but extends to other myeloid and lymphoid lineages at significant levels between 15–60%. Finally, we show for the first time that Pf4 transcripts are present in adult HSCs and primitive hematopoietic progenitor cells. These results have fundamental implications for the use of the Pf4-Cre mouse model and for our understanding of a possible role for Pf4 in the development of the hematopoietic lineage. PMID:23300543

Schachtner, Hannah; Watson, Steve P.; Holyoake, Tessa L.; Kranc, Kamil R.; Machesky, Laura M.

2012-01-01

180

Metabolic Regulation by the Mitochondrial Phosphatase PTPMT1 Is Required for Hematopoietic Stem Cell Differentiation  

PubMed Central

SUMMARY The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell (HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, a PTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resulted in hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs. Surprisingly, the HSC pool was increased by ~40-fold in PTPMT1 knockout mice. Reintroduction of wild-type PTPMT1, but not catalytically deficient PTPMT1 or truncated PTPMT1 lacking mitochondrial localization, restored differentiation capabilities of PTPMT1 knockout HSCs. Further analyses demonstrated that PTPMT1 deficiency altered mitochondrial metabolism and that phosphatidylinositol phosphate substrates of PTPMT1 directly enhanced fatty-acid-induced activation of mitochondrial uncoupling protein 2. Intriguingly, depletion of PTPMT1 from myeloid, T lymphoid, or B lymphoid progenitors did not cause any defects in lineage-specific knockout mice. This study establishes a crucial role of PTPMT1 in the metabolic regulation of HSC function. PMID:23290137

Yu, Wen-Mei; Liu, Xia; Shen, Jinhua; Jovanovic, Olga; Pohl, Elena E.; Gerson, Stanton L.; Finkel, Toren; Broxmeyer, Hal E.; Qu, Cheng-Kui

2013-01-01

181

Preleukemic hematopoietic hyperplasia induced by Moloney murine leukemia virus is an indirect consequence of viral infection.  

PubMed Central

We previously showed that neonatal mice inoculated with Moloney murine leukemia virus (M-MuLV) exhibit a preleukemic state characterized by splenomegaly and increased numbers of hematopoietic progenitors. An M-MuLV variant with greatly reduced leukemogenic potential, Mo+PyF101 M-MuLV, does not generally induce this preleukemic state. In order to investigate the mechanism involved in M-MuLV induction of preleukemic hyperplasia, we tested the CFU-mixed myeloid and erythroid (CFUmix) from M-MuLV- and Mo+PyF101 M-MuLV-inoculated mice for the presence of virus by antibody staining and for the release of infectious virus. The majority of CFUmix colonies from both M-MuLV- and Mo+PyF101 M-MuLV-inoculated mice contained infectious virus even though M-MuLV-inoculated mice showed elevated levels of CFUmix while the Mo+PyF101 M-MuLV-inoculated mice did not. This indicates that direct infection of hematopoietic progenitors was not sufficient to induce hyperplasia. Rather, hematopoietic hyperplasia may result indirectly from infection of some other cell type. Images PMID:2200891

Brightman, B K; Davis, B R; Fan, H

1990-01-01

182

Effects of Mobilization Regimens in Donors on Outcomes of Hematopoietic Cell Transplantation in Miniature Swine  

PubMed Central

Toxicities and complications associated with hematopoietic cell transplantation currently limit this potentially curative therapy for malignant and nonmalignant blood disorders. Miniature swine provide a clinically relevant model for studies to improve posttransplantation outcomes. Miniature swine recipients of high-dose haploidentical hepatopoietic cell transplantation after reduced-intensity conditioning consisting of low-dose (100 cGy) total-body irradiation, partial T-cell depletion by using a CD3 immunotoxin, and a 45-d course of cyclosporine A typically successfully engraft without graft-versus-host disease. We recently observed broad variability in engraftment outcomes that correlates with the occurrence of adverse reactions in donors after cytokine treatment to mobilize hematopoietic progenitor cells from the bone marrow to the peripheral blood for collection. Haploidentical recipients (n = 16) of cells from donors remaining healthy during cytokine treatment engrafted with multilineage chimerism, did not develop graft-versus-host disease, and did not require any blood products. In comparison, identically conditioned recipients of cells from donors that had severe reactions during cytokine treatment had adverse outcomes, including the development of clinically significant thrombocytopenia requiring blood product support in 8 of 11 swine. Furthermore, all 11 recipients lost peripheral blood myeloid chimerism (indicating lack of engraftment of donor stem cells). These data suggest that posttransplantation complications in swine are influenced by the health status of the donor before and during the collection of hematopoietic cells by leukapheresis. PMID:23561882

Matar, Abraham J; Crepeau, Rebecca L; Pathiraja, Vimukthi; Robson, Simon; Fishman, Jay A; Spitzer, Thomas R; Sachs, David H; Huang, Christene A; Duran-Struuck, Raimon

2012-01-01

183

Integration of adeno-associated virus vectors in CD34+ human hematopoietic progenitor cells after transduction.  

PubMed

Gene transfer vectors based on adeno-associated virus (AAV) appear promising because of their high transduction frequencies regardless of cell cycle status and ability to integrate into chromosomal DNA. We tested AAV-mediated gene transfer into a panel of human bone marrow or umbilical cord-derived CD34+ hematopoietic progenitor cells, using vectors encoding several transgenes under the control of viral and cellular promoters. Gene transfer was evaluated by (1) chromosomal integration of vector sequences and (2) analysis of transgene expression. Southern hybridization and fluorescence in situ hybridization analysis of transduced CD34 genomic DNA showed the presence of integrated vector sequences in chromosomal DNA in a portion of transduced cells and showed that integrated vector sequences were replicated along with cellular DNA during mitosis. Transgene expression in transduced CD34 cells in suspension cultures and in myeloid colonies differentiating in vitro from transduced CD34 cells approximated that predicted by the multiplicity of transduction. This was true in CD34 cells from different donors, regardless of the transgene or selective pressure. Comparisons of CD34 cell transduction either before or after cytokine stimulation showed similar gene transfer frequencies. Our findings suggest that AAV transduction of CD34+ hematopoietic progenitor cells is efficient, can lead to stable integration in a population of transduced cells, and may therefore provide the basis for safe and efficient ex vivo gene therapy of the hematopoietic system. PMID:8695797

Fisher-Adams, G; Wong, K K; Podsakoff, G; Forman, S J; Chatterjee, S

1996-07-15

184

BCR-ABL1-Associated Reduction of Beta Catenin Antagonist Chibby1 in Chronic Myeloid Leukemia  

PubMed Central

Beta Catenin signaling is critical for the self-renewal of leukemic stem cells in chronic myeloid leukemia. It is driven by multiple events, enhancing beta catenin stability and promoting its transcriptional co-activating function. We investigated the impact of BCR-ABL1 on Chibby1, a beta catenin antagonist involved in cell differentiation and transformation. Relative proximity of the Chibby1 encoding gene (C22orf2) on chromosome 22q12 to the BCR breakpoint (22q11) lets assume its involvement in beta catenin activation in chronic myeloid leukemia as a consequence of deletions of distal BCR sequences encompassing one C22orf2 allele. Forty patients with chronic myeloid leukemia in chronic phase were analyzed for C22orf2 relocation and Chibby1 expression. Fluorescent in situ hybridization analyses established that the entire C22orf2 follows BCR regardless of chromosomes involved in the translocation. In differentiated hematopoietic progenitors (bone marrow mononuclear cell fractions) of 30/40 patients, the expression of Chibby1 protein was reduced below 50% of the reference value (peripheral blood mononuclear cell fractions of healthy persons). In such cell context, Chibby1 protein reduction is not dependent on C22orf2 transcriptional downmodulation; however, it is strictly dependent upon BCR-ABL1 expression because it was not observed at the moment of major molecular response under tyrosine kinase inhibitor therapy. Moreover, it was not correlated with the disease prognosis or response to therapy. Most importantly, a remarkable Chibby1 reduction was apparent in a putative BCR-ABL1+ leukemic stem cell compartment identified by a CD34+ phenotype compared to more differentiated hematopoietic progenitors. In CD34+ cells, Chibby1 reduction arises from transcriptional events and is driven by C22orf2 promoter hypermethylation. These results advance low Chibby1 expression associated with BCR-ABL1 as a component of beta catenin signaling in leukemic stem cells. PMID:24339928

Aluigi, Michela; Luatti, Simona; Castagnetti, Fausto; Testoni, Nicoletta; Soverini, Simona; Santucci, Maria Alessandra; Martinelli, Giovanni

2013-01-01

185

Targeted alpha-particle immunotherapy for acute myeloid leukemia.  

PubMed

Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ((213)Bi)-labeled lintuzumab. In a subsequent study, (213)Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of (213)Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ((225)Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that (225)Ac-lintuzumab is safe at doses of 3 ?Ci/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose (225)Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using (213)Bi- and astatine-211 ((211)At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios. PMID:24857092

Jurcic, Joseph G; Rosenblat, Todd L

2014-01-01

186

Transcriptional fine-tuning of microRNA-223 levels directs lineage choice of human hematopoietic progenitors.  

PubMed

MicroRNAs (miRNAs) regulate cell proliferation, differentiation and death during development and postnatal life. The expression level of mature miRNAs results from complex molecular mechanisms, including the transcriptional regulation of their genes. MiR-223 is a hematopoietic-specific miRNA participating in regulatory signaling networks involving lineage-specific transcription factors (TFs). However, the transcriptional mechanisms governing its expression levels and its functional role in lineage fate decision of human hematopoietic progenitors (HPCs) have not yet been clarified. We found that in CD34(+)HPCs undergoing unilineage differentiation/maturation, miR-223 is upregulated more than 10-fold during granulopoiesis, 3-fold during monocytopoiesis and maintained at low levels during erythropoiesis. Chromatin immunoprecipitation and promoter luciferase assays showed that the lineage-specific expression level of mature miR-223 is controlled by the coordinated binding of TFs to their DNA-responsive elements located in 'distal' and 'proximal' regulatory regions of the miR-223 gene, differentially regulating the transcription of two primary transcripts (pri-miRs). All this drives myeloid progenitor maturation into specific lineages. Accordingly, modulation of miR-223 activity in CD34(+)HPCs and myeloid cell lines significantly affects their differentiation/maturation into erythroid, granulocytic and monocytic/macrophagic lineages. MiR-223 overexpression increases granulopoiesis and impairs erythroid and monocytic/macrophagic differentiation. Its knockdown, meanwhile, impairs granulopoiesis and facilitates erythropoiesis and monocytic/macrophagic differentiation. Overall, our data reveal that transcriptional pathways acting on the differential regulation of two pri-miR transcripts results in the fine-tuning of a single mature miRNA expression level, which dictates the lineage fate decision of hematopoietic myeloid progenitors. PMID:24141720

Vian, L; Di Carlo, M; Pelosi, E; Fazi, F; Santoro, S; Cerio, A M; Boe, A; Rotilio, V; Billi, M; Racanicchi, S; Testa, U; Grignani, F; Nervi, C

2014-02-01

187

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

PubMed Central

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

Moreno-Martinez, Daniel; Nomdedeu, Meritxell; Lara-Castillo, Maria Carmen; Etxabe, Amaia; Pratcorona, Marta; Tesi, Niccolo; Diaz-Beya, Marina; Rozman, Maria; Montserrat, Emili; Urbano-Ispizua, Alvaro; Esteve, Jordi; Risueno, Ruth M.

2014-01-01

188

Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia.  

PubMed

FMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPCs) but its role during embryogenesis is unclear. In acute myeloid leukemia (AML), internal tandem duplication (ITD) of FLT3 at the juxtamembrane (JMD) and tyrosine kinase (TKD) domains (FLT3-ITD(+)) occurs in 30% of patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD(+)) occur in 5% of cases. We made use of zebrafish to examine the role of flt3 in developmental hematopoiesis and model human FLT3-ITD(+) and FLT3-TKD(+) AML. Zebrafish flt3 JMD and TKD were remarkably similar to their mammalian orthologs. Morpholino knockdown significantly reduced the expression of l-plastin (pan-leukocyte), csf1r, and mpeg1 (macrophage) as well as that of c-myb (definitive HSPCs), lck, and rag1 (T-lymphocyte). Expressing human FLT3-ITD in zebrafish embryos resulted in expansion and clustering of myeloid cells (pu.1(+), mpo(+), and cebp?(+)) which were ameliorated by AC220 and associated with stat5, erk1/2, and akt phosphorylation. Human FLT3-TKD (D835Y) induced significant, albeit modest, myeloid expansion resistant to AC220. This study provides novel insight into the role of flt3 during hematopoiesis and establishes a zebrafish model of FLT3-ITD(+) and FLT3-TKD(+) AML that may facilitate high-throughput screening of novel and personalized agents. PMID:24591202

He, Bai-Liang; Shi, Xiangguo; Man, Cheuk Him; Ma, Alvin C H; Ekker, Stephen C; Chow, Howard C H; So, Chi Wai Eric; Choi, William W L; Zhang, Wenqing; Zhang, Yiyue; Leung, Anskar Y H

2014-04-17

189

HDAC1 and Klf4 interplay critically regulates human myeloid leukemia cell proliferation  

PubMed Central

Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain unclear. General histone deacetylase (HDAC) inhibitors have been used in blood cancers including AML, but the lack of gene specificity greatly limits their anti-cancer effects and clinical applications. Here, we found that HDAC1 expression was negatively correlated with that of Krüppel-like factor 4 (Klf4) and that AML patients with lower HDAC1 level had better prognosis. Further, knockdown of HDAC1 in leukemia cells K562, HL-60, and U937 significantly increased Klf4 expression and inhibited cell cycle progression and cell proliferation, similar results were found for HDAC inhibitors (VPA and mocetinostat). Moreover, overexpression or knockdown of Klf4 could markedly block the effects of HDAC1 overexpression or knockdown on leukemia cells in vitro and in vivo, respectively. Mechanistic analyses demonstrated that HDAC1 and Klf4 competitively bound to the promoter region of Klf4 and oppositely regulated Klf4 expression in myeloid leukemia. We identified HDAC1 as a potential specific target for repressing cell proliferation and inducing cell cycle arrest through interplay and modulation of Klf4 expression, suggests that HDAC1 and Klf4 are potential new molecular markers and targets for clinical diagnosis, prognosis, and treatment of myeloid leukemia. PMID:25341045

Huang, Y; Chen, J; Lu, C; Han, J; Wang, G; Song, C; Zhu, S; Wang, C; Li, G; Kang, J; Wang, J

2014-01-01

190

CD47 is up-regulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis  

PubMed Central

Summary Macrophages clear pathogens and damaged or aged cells from the blood stream via phagocytosis. Cell-surface CD47 interacts with its receptor on macrophages, SIRP?, to inhibit phagocytosis of normal, healthy cells. We find that mobilizing cytokines and inflammatory stimuli cause CD47 to be transiently up-regulated on mouse hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo. CD47 is also constitutively up-regulated on mouse and human myeloid leukemias and over-expression of CD47 on a myeloid leukemia line increases its pathogenicity by allowing it to evade phagocytosis. We conclude that CD47 up-regulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing. PMID:19632178

Jaiswal, Siddhartha; Jamieson, Catriona H.M.; Pang, Wendy W.; Park, Chris Y.; Chao, Mark P.; Majeti, Ravindra; Traver, David; van Rooijen, Nico; Weissman, Irving L.

2009-01-01

191

Identification of hematopoietic-specific regulatory elements from the CD45 gene and use for lentiviral tracking of transplanted cells.  

PubMed

The development of a hematopoietic reporter is crucial for determining the fate of lineages derived from cell-based therapies. A marking system will enable safer embryonic stem and induced pluripotent stem cell-based derivation of blood lineages and facilitate the development of efficient cellular reprogramming strategies based on direct fibroblast conversion. Here we report that the protein tyrosine phosphatase CD45 is an ideal candidate gene on which to base a hematopoietic reporter. CD45 regulatory elements were discovered by analyzing transcription factor chromatin occupancy (ChIP-seq) and promoter nuclease sensitivity (DNase-seq) to identify minimally sufficient sequences required for expression. After cloning the CD45 regulatory elements into an attenuated lentiviral backbone, we found that two transcriptional initiation regions were essential for high-level expression. Expressing CD45 promoters containing these regions and tethered to green fluorescent protein (GFP) in a primary B-cell differentiation assay and a transplantation model resulted in high levels of GFP in lymphoid, myeloid, and nucleated erythroid cells in mouse and human blood cell lineages. Moreover, GFP levels remained high 5 months after secondary transplantation, indicating persistence of the reporter. No CD45-driven GFP expression is observed after fibroblast or embryonic stem cell transduction. The GFP reporter is seen only after embryonic stem cells differentiate into hematopoietic cell progenitors and lineages, suggesting that this hematopoietic reporter system could be useful in validating potential autologous blood cell therapies. PMID:24852660

Duong, Khanh L; Das, Satyabrata; Yu, Shuyang; Barr, Jennifer Y; Jena, Snehalata; Kim, Eunmi; Zavazava, Nicolas; Colgan, John D; Xue, Hai-Hui; Levasseur, Dana N

2014-09-01

192

Histocompatibility and Hematopoietic Transplantation in the Zebrafish  

PubMed Central

The zebrafish has proven to be an excellent model for human disease, particularly hematopoietic diseases, since these fish make similar types of blood cells as humans and other mammals. The genetic program that regulates the development and differentiation of hematopoietic cells is highly conserved. Hematopoietic stem cells (HSCs) are the source of all the blood cells needed by an organism during its lifetime. Identifying an HSC requires a functional assay, namely, a transplantation assay consisting of multilineage engraftment of a recipient and subsequent serial transplant recipients. In the past decade, several types of hematopoietic transplant assays have been developed in the zebrafish. An understanding of the major histocompatibility complex (MHC) genes in the zebrafish has lagged behind transplantation experiments, limiting the ability to perform unbiased competitive transplantation assays. This paper summarizes the different hematopoietic transplantation experiments performed in the zebrafish, both with and without immunologic matching, and discusses future directions for this powerful experimental model of human blood diseases. PMID:22778744

de Jong, Jill L. O.; Zon, Leonard I.

2012-01-01

193

Myeloid-derived suppressor cells  

PubMed Central

While conventional anticancer therapies, including surgical resection, radiotherapy, and/or chemotherapy, are relatively efficient at eliminating primary tumors, these treatment modalities are largely ineffective against metastases. At least in part, this reflects the rather inefficient delivery of conventional anticancer agents to metastatic lesions. We have recently demonstrated that myeloid-derived suppressor cells (MDSCs) can be used as cellular missiles to selectively deliver a radioisotope-coupled attenuated variant of Listeria monocytogenes to both primary and metastatic neoplastic lesions in mice with pancreatic cancer. This novel immunotherapeutic intervention robustly inhibited tumor growth while promoting a dramatic decrease in the number of metastases. PMID:24427545

Chandra, Dinesh; Gravekamp, Claudia

2013-01-01

194

Endothelial cells mediate the regeneration of hematopoietic stem cells  

Microsoft Academic Search

Recent studies suggest that endothelial cells are a critical component of the normal hematopoietic microenvironment. Therefore, we sought to determine whether primary endothelial cells have the capacity to repair damaged hematopoietic stem cells. Highly purified populations of primary CD31+ microvascular endothelial cells isolated from the brain or lung did not express the pan hematopoietic marker CD45, most hematopoietic lineage markers,

Bei Li; Alexis S. Bailey; Shuguang Jiang; Bin Liu; Devorah C. Goldman; William H. Fleming

2010-01-01

195

Bortezomib, Sorafenib Tosylate, and Decitabine in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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; Untreated Adult Acute Myeloid Leukemia

2014-09-30

196

Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia.  

PubMed

Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by somatic BRAFV600E mutations. The malignant cell in HCL has immunophenotypic features of a mature B cell, but no normal counterpart along the continuum of developing B lymphocytes has been delineated as the cell of origin. We find that the BRAFV600E mutation is present in hematopoietic stem cells (HSCs) in HCL patients, and that these patients exhibit marked alterations in hematopoietic stem/progenitor cell (HSPC) frequencies. Quantitative sequencing analysis revealed a mean BRAFV600E-mutant allele frequency of 4.97% in HSCs from HCL patients. Moreover, transplantation of BRAFV600E-mutant HSCs from an HCL patient into immunodeficient mice resulted in stable engraftment of BRAFV600E-mutant human hematopoietic cells, revealing the functional self-renewal capacity of HCL HSCs. Consistent with the human genetic data, expression of BRafV600E in murine HSPCs resulted in a lethal hematopoietic disorder characterized by splenomegaly, anemia, thrombocytopenia, increased circulating soluble CD25, and increased clonogenic capacity of B lineage cells-all classic features of human HCL. In contrast, restricting expression of BRafV600E to the mature B cell compartment did not result in disease. Treatment of HCL patients with vemurafenib, an inhibitor of mutated BRAF, resulted in normalization of HSPC frequencies and increased myeloid and erythroid output from HSPCs. These findings link the pathogenesis of HCL to somatic mutations that arise in HSPCs and further suggest that chronic lymphoid malignancies may be initiated by aberrant HSCs. PMID:24871132

Chung, Stephen S; Kim, Eunhee; Park, Jae H; Chung, Young Rock; Lito, Piro; Teruya-Feldstein, Julie; Hu, Wenhuo; Beguelin, Wendy; Monette, Sebastien; Duy, Cihangir; Rampal, Raajit; Telis, Leon; Patel, Minal; Kim, Min Kyung; Huberman, Kety; Bouvier, Nancy; Berger, Michael F; Melnick, Ari M; Rosen, Neal; Tallman, Martin S; Park, Christopher Y; Abdel-Wahab, Omar

2014-05-28

197

Hematopoietic effects of benzene inhalation assessed by long-term bone marrow culture  

SciTech Connect

The strong and long-lasting hematotoxic effect after benzene exposure in vivo (300 ppm, 6 hr/day, 5 days/week for 2 weeks) was assessed in mice with bone marrow cells grown in long-term bone marrow culture (LTBMC). Bone marrow cultures initiated 1 day after the last benzene exposure did not produce adequate numbers of hematopoietic cells over 3 weeks and, in most cases, no erythroid or myeloid clonogenic cells could be recovered. The adherent cell layer of these cultures had a lower capacity for supporting in vitro hematopoiesis after the second seeding with normal bone marrow cells compared with control cultures. Two weeks after the last benzene exposure, body weight, hematocrit, bone marrow cellularity, and committed hematopoietic progenitor content (BFU-E and CFU-GM) were regenerated to normal or subnormal values, whereas hematopoiesis in LTB MC was very poor. Over 8 weeks, little or no significant committed progenitor production was observed. Treatment of mice exposed to benzene with hemin (three doses of 3 {mu}g/g bw iv over 2 weeks for a total dose of 9 {mu}g/g) partially overcame the toxic effect of benzene on the hematopoietic system as measured by the LTBMC method. Cultures from mice treated with hemin had a modest recovery of BFU-E and CFU-GM clonogenic potential after 5 to 6 weeks in LTBMC. In contrast, little or no recovery was obtained for the adherent cell layer clonogenic capacity, even after hemin treatment. These results clearly indicate a strong, long-lasting toxic effect on the bone marrow stroma and a limited recovery of hematopoietic potential by clonogenic cells of the nonadherent population after in vivo hemin treatment. 35 refs., 3 figs., 1 tab.

Abraham, N.G. [Rockefeller Univ., New York, NY (United States)

1996-12-01

198

Therapy of chronic myeloid leukemia: twilight of the imatinib era?  

PubMed

Chronic myeloid leukemia (CML) results from the clonal expansion of pluripotent hematopoietic stem cells containing the active BCR/ABL fusion gene produced by a reciprocal translocation of the ABL1 gene to the BCR gene. The BCR/ABL protein displays a constitutive tyrosine kinase activity and confers on leukemic cells growth and proliferation advantage and resistance to apoptosis. Introduction of imatinib (IM) and other tyrosine kinase inhibitors (TKIs) has radically improved the outcome of patients with CML and some other diseases with BCR/ABL expression. However, a fraction of CML patients presents with resistance to this drug. Regardless of clinical profits of IM, there are several drawbacks associated with its use, including lack of eradication of the malignant clone and increasing relapse rate resulting from long-term therapy, resistance, and intolerance. Second and third generations of TKIs have been developed to break IM resistance. Clinical studies revealed that the introduction of second-generation TKIs has improved the overall survival of CML patients; however, some with specific mutations such as T315I remain resistant. Second-generation TKIs may completely replace imatinib in perspective CML therapy, and addition of third-generation inhibitors may overcome resistance induced by every form of point mutations. PMID:24634785

Trela, Ewelina; Glowacki, Sylwester; B?asiak, Janusz

2014-01-01

199

Therapy of Chronic Myeloid Leukemia: Twilight of the Imatinib Era?  

PubMed Central

Chronic myeloid leukemia (CML) results from the clonal expansion of pluripotent hematopoietic stem cells containing the active BCR/ABL fusion gene produced by a reciprocal translocation of the ABL1 gene to the BCR gene. The BCR/ABL protein displays a constitutive tyrosine kinase activity and confers on leukemic cells growth and proliferation advantage and resistance to apoptosis. Introduction of imatinib (IM) and other tyrosine kinase inhibitors (TKIs) has radically improved the outcome of patients with CML and some other diseases with BCR/ABL expression. However, a fraction of CML patients presents with resistance to this drug. Regardless of clinical profits of IM, there are several drawbacks associated with its use, including lack of eradication of the malignant clone and increasing relapse rate resulting from long-term therapy, resistance, and intolerance. Second and third generations of TKIs have been developed to break IM resistance. Clinical studies revealed that the introduction of second-generation TKIs has improved the overall survival of CML patients; however, some with specific mutations such as T315I remain resistant. Second-generation TKIs may completely replace imatinib in perspective CML therapy, and addition of third-generation inhibitors may overcome resistance induced by every form of point mutations. PMID:24634785

Glowacki, Sylwester; Blasiak, Janusz

2014-01-01

200

Leukemic Stem Cell Frequency: A Strong Biomarker for Clinical Outcome in Acute Myeloid Leukemia  

PubMed Central

Introduction Treatment failure in acute myeloid leukemia is probably caused by the presence of leukemia initiating cells, also referred to as leukemic stem cells, at diagnosis and their persistence after therapy. Specific identification of leukemia stem cells and their discrimination from normal hematopoietic stem cells would greatly contribute to risk stratification and could predict possible relapses. Results For identification of leukemic stem cells, we developed flow cytometric methods using leukemic stem cell associated markers and newly-defined (light scatter) aberrancies. The nature of the putative leukemic stem cells and normal hematopoietic stem cells, present in the same patient's bone marrow, was demonstrated in eight patients by the presence or absence of molecular aberrancies and/or leukemic engraftment in NOD-SCID IL-2R?-/- mice. At diagnosis (n?=?88), the frequency of the thus defined neoplastic part of CD34+CD38- putative stem cell compartment had a strong prognostic impact, while the neoplastic parts of the CD34+CD38+ and CD34- putative stem cell compartments had no prognostic impact at all. After different courses of therapy, higher percentages of neoplastic CD34+CD38- cells in complete remission strongly correlated with shorter patient survival (n?=?91). Moreover, combining neoplastic CD34+CD38- frequencies with frequencies of minimal residual disease cells (n?=?91), which reflect the total neoplastic burden, revealed four patient groups with different survival. Conclusion and Perspective Discrimination between putative leukemia stem cells and normal hematopoietic stem cells in this large-scale study allowed to demonstrate the clinical importance of putative CD34+CD38- leukemia stem cells in AML. Moreover, it offers new opportunities for the development of therapies directed against leukemia stem cells, that would spare normal hematopoietic stem cells, and, moreover, enables in vivo and ex vivo screening for potential efficacy and toxicity of new therapies. PMID:25244440

Terwijn, Monique; Zeijlemaker, Wendelien; Kelder, Angele; Rutten, Arjo P.; Snel, Alexander N.; Scholten, Willemijn J.; Pabst, Thomas; Verhoef, Gregor; Lowenberg, Bob; Zweegman, Sonja; Ossenkoppele, Gert J.; Schuurhuis, Gerrit J.

2014-01-01

201

Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors  

PubMed Central

Background: Chronic myeloid leukemia is a neoplasm characterized by clonal expansion of hematopoietic progenitor cells resulting from the (9:22)(q34,11) translocation. The tyrosine kinase abl fusion protein,the initial leukemogenic event in chronic myeloid leukemia, is constitutively activated thus inducing the production of reactive oxygen species. Of particular relevance is the fact that an increase in reactive oxygen species can facilitate genomic instability and may contribute to disease progression. Objetive: To evaluate oxidative stress by determining the levels of malondialdehyde and nitrite in chronic myeloid leukemia patients under treatment with 1st and 2nd generation tyrosine kinase inhibitors monitored at a referral hospital in Fortaleza, Ceará. Methods: A cross-sectional study was performed of 64 male and female adults. Patients were stratified according to treatment. The levels of malondialdehyde and nitrite were determined by spectrophotometry. Statistical differences between groups were observed using the Student t-test and Fisher's exact test. The results are expressed as mean ± standard error of mean. The significance level was set for a p-value < 0.05 in all analyses. Results: The results show significantly higher mean concentrations of nitrite and malondialdehyde in chronic myeloid leukemia patients using second-generation tyrosine kinase inhibitors compared to patients on imatinib. Conclusion: It follows that chronic myeloid leukemia patients present higher oxidative activity and that the increases in oxidative damage markers can indicate resistance to 1st generation tyrosine kinase inhibitors. PMID:23125543

Petrola, Maria Juracy; de Castro, Alana Joselina Montenegro; Pitombeira, Maria Helena da Silva; Barbosa, Maritza Cavalcante; Quixada, Acy Telles de Souza; Duarte, Fernando Barroso; Goncalves, Romelia Pinheiro

2012-01-01

202

Therapy-related Myeloid Leukemia  

PubMed Central

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

Godley, Lucy A.; Larson, Richard A.

2008-01-01

203

Chronic Myeloid Leukemia Presenting with Visual and Auditory Impairment in an Adolescent: An Insight to Management Strategies  

PubMed Central

A 15-year-old girl presented with progressive deterioration in vision and hearing over 1 week. A huge spleen was palpated below the left costal margin laying down to inguinal region. Blood count showed hyperleukocytosis with a white blood cell count of 455 × 109/l. Peripheral smear yielded myeloid precursor cells with basophilia. Bone marrow aspiration revealed a blast count of 5% morphologically and 4% by flow cytometry. Fundoscopic examination revealed bilateral retinal exudates, edema and hemorhages. Partial sensorioneural hearing loss was also detected on the right ear. The diagnosis of chronic myeloid leukemia was confirmed by positive t(9;22) by RT-PCR. After commencing on hydroxyurea and intrathecal methotrexate-prednisolone, progressive improvement in hearing and vision was obtained. In our brief report, we aimed to emphasize rare presentation with visual and hearing impairment of chronic myeloid leukemia during childhood, especially in “chronic phase”. PMID:21886391

Unal, Sule; Bayrakç?, Benan; Tuncer, Murat

2010-01-01

204

Homoharringtonine and omacetaxine for myeloid hematological malignancies  

PubMed Central

Homoharringtonine (HHT), a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action by preventing the initial elongation step of protein synthesis. HHT has been used widely in China for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Omacetaxine, a semisynthetic form of HHT, with excellent bioavailability by the subcutaneous route, has recently been approved by FDA of the United States for the treatment of CML refractory to tyrosine kinase inhibitors. This review summarized preclinical and clinical development of HHT and omacetaxine for myeloid hematological malignancies. PMID:24387717

2014-01-01

205

Radioimmunotherapy for hematopoietic cell transplantation.  

PubMed

Radioimmunotherapy (RIT) represents an attractive strategy to deliver radiation selectively to tumor and other target organs while minimizing toxicity to normal tissues. RIT with ?-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of conditioning before hematopoietic cell transplantation (HCT) in leukemia. Similarly, RIT directed against CD20 has shown promise in the setting of autologous and allogeneic HCT for B-cell lymphomas. ?-particle immunotherapy with isotopes such as bismuth-213, actinium-225 and astatinine-211 offers the possibility of more selective and efficient killing of target cells while sparing the surrounding normal cells. Pretargeting strategies may further improve target:normal organ dose ratios. While RIT has demonstrated significant antitumor activity, ultimately, randomized studies will be required to determine if conditioning regimens that include this therapeutic modality can improve patient outcomes after HCT. PMID:23557421

Jurcic, Joseph G

2013-04-01

206

Computational Modeling of the Hematopoietic Erythroid-Myeloid Switch Reveals Insights into  

E-print Network

Biology and Cell Therapy, Lund University, Lund, Sweden, 4 Computational Biology and Biological Physics et al. This is an open-access article distributed under the terms of the Creative Commons Attribution

Peterson, Carsten

207

Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia  

E-print Network

recurrent mutations (6, 7). Despite these advances, our fundamental understanding of both the genomics R. Quake3,+, and Ravindra Majeti1,2,+ 1Program in Cancer Biology, Cancer Institute, Institute (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute

Quake, Stephen R.

208

Engineering humanized mice for improved hematopoietic reconstitution  

E-print Network

Humanized mice are immunodeficient animals engrafted with human hematopoietic stem cells that give rise to various lineages of human blood cells throughout the life of the mouse. This article reviews recent advances in the ...

Drake, Adam

209

Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency.  

PubMed

XRCC4-like factor (XLF/Cernunnos) is a component of the nonhomologous end-joining (NHEJ) pathway of double-strand DNA break repair. XLF-deficient patients develop a severe progressive lymphocytopenia. Although NHEJ is required for V(D)J recombination and lymphocyte development, XLF-deficient mice have normal V(D)J recombination, highlighting the need for an alternative mechanism for the lymphocytopenia. Here, we report that XLF-deficient mice recapitulate the age-dependent lymphocytopenia of patients. We show that XLF deficiency leads to premature aging of hematopoietic stem cells (HSCs), measured by decreased functional capacity in transplantation assays, preferential myeloid reconstitution, and reduced self-renewal at a young age. We propose that premature aging of HSCs, together with previously reported defects in class-switch recombination and memory immune response, underlies the progressive and severe lymphocytopenia in XLF-deficient patients in the absence of measurable V(D)J recombination defects. PMID:25075129

Avagyan, Serine; Churchill, Michael; Yamamoto, Kenta; Crowe, Jennifer L; Li, Chen; Lee, Brian J; Zheng, Tian; Mukherjee, Siddhartha; Zha, Shan

2014-09-01

210

Two waves of distinct hematopoietic progenitor cells colonize the fetal thymus.  

PubMed

The generation of T cells depends on the migration of hematopoietic progenitor cells to the thymus throughout life. The identity of the thymus-settling progenitor cells has been a matter of considerable debate. Here we found that thymopoiesis was initiated by a first wave of T cell lineage-restricted progenitor cells with limited capacity for population expansion but accelerated differentiation into mature T cells. They gave rise to ?? and ?? T cells that constituted V?3(+) dendritic epithelial T cells. Thymopoiesis was subsequently maintained by less-differentiated progenitor cells that retained the potential to develop into B cells and myeloid cells. In that second wave, which started before birth, progenitor cells had high proliferative capacity but delayed differentiation capacity and no longer gave rise to embryonic ?? T cells. Our work reconciles conflicting hypotheses on the nature of thymus-settling progenitor cells. PMID:24317038

Ramond, Cyrille; Berthault, Claire; Burlen-Defranoux, Odile; de Sousa, Ana Pereira; Guy-Grand, Delphine; Vieira, Paulo; Pereira, Pablo; Cumano, Ana

2014-01-01

211

Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency  

PubMed Central

XRCC4-like factor (XLF/Cernunnos) is a component of the nonhomologous end-joining (NHEJ) pathway of double-strand DNA break repair. XLF-deficient patients develop a severe progressive lymphocytopenia. Although NHEJ is required for V(D)J recombination and lymphocyte development, XLF-deficient mice have normal V(D)J recombination, highlighting the need for an alternative mechanism for the lymphocytopenia. Here, we report that XLF-deficient mice recapitulate the age-dependent lymphocytopenia of patients. We show that XLF deficiency leads to premature aging of hematopoietic stem cells (HSCs), measured by decreased functional capacity in transplantation assays, preferential myeloid reconstitution, and reduced self-renewal at a young age. We propose that premature aging of HSCs, together with previously reported defects in class-switch recombination and memory immune response, underlies the progressive and severe lymphocytopenia in XLF-deficient patients in the absence of measurable V(D)J recombination defects. PMID:25075129

Avagyan, Serine; Churchill, Michael; Yamamoto, Kenta; Crowe, Jennifer L.; Li, Chen; Lee, Brian J.; Zheng, Tian; Mukherjee, Siddhartha

2014-01-01

212

Hematopoietic G-protein-coupled receptor kinase 2 deficiency decreases atherosclerotic lesion formation in LDL receptor-knockout mice  

PubMed Central

Leukocyte chemotaxis is deemed instrumental in initiation and progression of atherosclerosis. It is mediated by G-protein-coupled receptors (e.g., CCR2 and CCR5), the activity of which is controlled by G-protein-coupled receptor kinases (GRKs). In this study, we analyzed the effect of hematopoietic deficiency of a potent regulator kinase of chemotaxis (GRK2) on atherogenesis. LDL receptor-deficient (LDLr?/?) mice with heterozygous hematopoietic GRK2 deficiency, generated by bone marrow transplantation (n=15), displayed a dramatic attenuation of plaque development, with 79% reduction in necrotic core and increased macrophage content. Circulating monocytes decreased and granulocytes increased in GRK2+/? chimeras, which could be attributed to diminished granulocyte colony-forming units in bone marrow. Collectively, these data pointed to myeloid cells as major mediators of the impaired atherogenic response in GRK2+/? chimeras. LDLr?/? mice with macrophage/granulocyte-specific GRK2 deficiency (LysM-Cre GRK2flox/flox; n=8) failed to mimic the aforementioned phenotype, acquitting these cells as major responsible subsets for GRK2 deficiency-associated atheroprotection. To conclude, even partial hematopoietic GRK2 deficiency prevents atherosclerotic lesion progression beyond the fatty streak stage, identifying hematopoietic GRK2 as a potential target for intervention in atherosclerosis.—Otten, J. J. T., de Jager, S. C. A., Kavelaars, A., Seijkens, T., Bot, I., Wijnands, E., Beckers, L., Westra, M. M., Bot, M., Busch, M., Bermudez, B., van Berkel, T. J. C., Heijnen, C. J., Biessen, E. A. L. Hematopoietic G-protein-coupled receptor kinase 2 deficiency decreases atherosclerotic lesion formation in LDL receptor-knockout mice. PMID:23047899

Otten, Jeroen J. T.; de Jager, Saskia C. A.; Kavelaars, Annemieke; Seijkens, Tom; Bot, Ilze; Wijnands, Erwin; Beckers, Linda; Westra, Marijke M.; Bot, Martine; Busch, Matthias; Bermudez, Beatriz; van Berkel, Theo J. C.; Heijnen, Cobi J.; Biessen, Erik A. L.

2013-01-01

213

TGF? restores hematopoietic homeostasis after myelosuppressive chemotherapy  

PubMed Central

Myelosuppression is a life-threatening complication of antineoplastic therapy, but treatment is restricted to a few cytokines with unilineage hematopoietic activity. Although hematopoietic stem cells (HSCs) are predominantly quiescent during homeostasis, they are rapidly recruited into cell cycle by stresses, including myelosuppressive chemotherapy. Factors that induce HSCs to proliferate during stress have been characterized, but it is not known how HSC quiescence is then reestablished. In this study, we show that TGF? signaling is transiently activated in hematopoietic stem and progenitor cells (HSPCs) during hematopoietic regeneration. Blockade of TGF? signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. In contrast, TGF? blockade during homeostasis fails to induce cycling of HSPCs. We identified the cyclin-dependent kinase inhibitor Cdkn1c (p57) as a key downstream mediator of TGF? during regeneration because the recovery of chimeric mice, incapable of expressing p57 in HSPCs, phenocopies blockade of TGF? signaling after chemotherapy. This study demonstrates that context-dependent activation of TGF? signaling is central to an unrecognized counterregulatory mechanism that promotes homeostasis once hematopoiesis has sufficiently recovered from myelosuppressive chemotherapy. These results open the door to new, potentially superior, approaches to promote multilineage hematopoietic recovery by blocking the TGF? signaling that dampens regeneration. PMID:23440043

Brenet, Fabienne; Kermani, Pouneh; Spektor, Roman; Rafii, Shahin

2013-01-01

214

Recognizing familial myeloid leukemia in adults  

PubMed Central

Germline testing for familial cases of myeloid leukemia in adults is becoming more common with the recognition of multiple genetic syndromes predisposing people to bone marrow disease. Currently, Clinical Laboratory Improvement Amendments approved testing exists for several myeloid leukemia predisposition syndromes: familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML), caused by mutations in RUNX1; familial AML with mutated CEBPA; familial myelodysplastic syndrome and acute leukemia with mutated GATA2; and the inherited bone marrow failure syndromes, including dyskeratosis congenita, a disease of abnormal telomere maintenance. With the recognition of additional families with a genetic component to their leukemia, new predisposition alleles will likely be identified. We highlight how to recognize and manage these cases as well as outline the characteristics of the major known syndromes. We look forward to future research increasing our understanding of the scope of inherited myeloid leukemia syndromes. PMID:23926458

Nickels, Eric M.; Soodalter, Jesse; Churpek, Jane E.

2013-01-01

215

Hematopoietic Acute Radiation Syndrome (Bone marrow syndrome, Aplastic Anemia): Molecular Mechanisms of Radiation Toxicity.  

NASA Astrophysics Data System (ADS)

Key Words: Aplastic Anemia (AA), Pluripotential Stem Cells (PSC) Introduction: Aplastic Anemia (AA) is a disorder of the pluripotential stem cells involve a decrease in the number of cells of myeloid, erythroid and megakaryotic lineage [Segel et al. 2000 ]. The etiology of AA include idiopathic cases and secondary aplastic anemia after exposure to drugs, toxins, chemicals, viral infections, lympho-proliferative diseases, radiation, genetic causes, myelodisplastic syndromes and hypoplastic anemias, thymomas, lymphomas. [Brodskyet al. 2005.,Modan et al. 1975., Szklo et al. 1975]. Hematopoietic Acute Radiation Syndrome (or Bone marrow syndrome, or Radiation-Acquired Aplastic Anemia) is the acute toxic syndrome which usually occurs with a dose of irradiation between 0.7 and 10 Gy (70- 1000 rads), depending on the species irradiated. [Waselenko et al., 2004]. The etiology of bone morrow damage from high-level radiation exposure results depends on the radiosensitivity of certain bone marrow cell lines. [Waselenko et al. 2004] Aplastic anemia after radiation exposure is a clinical syndrome that results from a marked disorder of bone marrow blood cell production. [Waselenko et al. 2004] Radiation hematotoxicity is mediated via genotoxic and other specific toxic mechanisms, leading to aplasia, cell apoptosis or necrosis, initiation via genetic mechanisms of clonal disorders, in cases such as the acute radiation-acquired form of AA. AA results from radiation injury to pluripotential and multipotential stem cells in the bone marrow. The clinical signs displayed in reticulocytopenia, anemia, granulocytopenia, monocytopenia, and thrombocytopenia. The number of marrow CD34+ cells (multipotential hematopoietic progenitors) and their derivative colony-forming unit{granulocyte-macrophage (CFU-GM) and burst forming unit {erythroid (BFU{E) are reduced markedly in patients with AA. [Guinan 2011, Brodski et al. 2005, Beutler et al.,2000] Cells expressing CD34 (CD34+ cell) are normally found in the umbilical cord and bone marrow as hematopoietic cells, a subset of mesenchymal stem cells, endothelial progenitor cells, endothelial cells of blood vessels, etc. [Beutler et al. 2000 ] Potential mechanisms responsible for radiation-acquired marrow cell failure include direct toxicity , direct damage of hematopoietic multipotential cells or cellular or humoral immune suppression of the marrow multipotential cells. [ Beutler et al. 2000] Methods: These studies were conducted at several different research institutions and laboratories listed as follows: Kazan All-Union Scientific Research Veterinary, Biotechnology Centre of Russian Academy of Science (North Osetia), Institute Belarussian Scientific and Research Institute for Radiobiology in Gomel, the St. Petersburg Veterinary Institute, the Advanced Medical Technology and Systems Inc., Ontario, Canada. The studies were approved by the Animal Care and Use Committee for ethical animal research equivalent, at each institution. A critically important volume of purified Radiation Toxins (RT) was isolated from larger mammalian irradiated animals. Subsequently the RT were characterized chemically and biologically. The experimental design of later studies compared relative toxicity, potential for development of acute radiation hematopoietic syndrome, and potential cloning disorder of multipotential hematopoietic progenitors and their derivative and lethality after intravenous or intramuscular injections of SRD containing Hematopoietic Radiation Toxins. These experiments have employed a wide variety of experimental animals. The animals were irradiated in RUM-17, Puma, and Panorama devices. The dose varied from 0.7Gy to 100Gy. The methods of immune depletion, immuno-lympho plasmasabsorption, as well as direct extraction, were used to refine and purify the specific Radiation Toxins from the central lymph of animals with Hematopoietic forms of Radiation Toxins. Experiments include administration of Hematopoietic Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg;

Popov, Dmitri

216

Monochromatic precursor starts  

NASA Astrophysics Data System (ADS)

Whistler precursors are discrete emissions that precede two-hop whistlers, starting shortly after the one-hop delay. More evidence is presented that the precursor and associated whistler propagate through the same duct, and observations of a new type of precursor are presented. This new precursor has a monochromatic precursor start (MPS) which may or may not trigger a riser. Although MPS's may be emissions entrained by power line radiation (PLR), phase analysis of the starting frequencies shows that they are not simply related to harmonics of the power line frequencies in the two conjugate regions (50 Hz in New Zealand, 60 Hz in Alaska). If the MPS is due to entrainment by PLR, then previous theories of precursor generation need not be discarded. Forward triggering of a precursor at a power line harmonic by a hybrid whistler may occur.

Rietveld, M. T.

1980-05-01

217

Reconstitution of the myeloid and lymphoid compartments after the transplantation of autologous and genetically modified CD34+ bone marrow cells, following gamma irradiation in cynomolgus macaques  

PubMed Central

Background Prolonged, altered hematopoietic reconstitution is commonly observed in patients undergoing myeloablative conditioning and bone marrow and/or mobilized peripheral blood-derived stem cell transplantation. We studied the reconstitution of myeloid and lymphoid compartments after the transplantation of autologous CD34+ bone marrow cells following gamma irradiation in cynomolgus macaques. Results The bone marrow cells were first transduced ex vivo with a lentiviral vector encoding eGFP, with a mean efficiency of 72% ± 4%. The vector used was derived from the simian immunodeficiency lentivirus SIVmac251, VSV-g pseudotyped and encoded eGFP under the control of the phosphoglycerate kinase promoter. After myeloid differentiation, GFP was detected in colony-forming cells (37% ± 10%). A previous study showed that transduction rates did not differ significantly between colony-forming cells and immature cells capable of initiating long-term cultures, indicating that progenitor cells and highly immature hematopoietic cells were transduced with similar efficiency. Blood cells producingeGFP were detected as early as three days after transplantation, and eGFP-producing granulocyte and mononuclear cells persisted for more than one year in the periphery. Conclusion The transplantation of CD34+ bone marrow cells had beneficial effects for the ex vivo proliferation and differentiation of hematopoietic progenitors, favoring reconstitution of the T- and B-lymphocyte, thrombocyte and red blood cell compartments. PMID:18565229

Derdouch, Sonia; Gay, Wilfried; Negre, Didier; Prost, Stephane; Le Dantec, Mikael; Delache, Benoit; Auregan, Gwenaelle; Andrieu, Thibault; Leplat, Jean-Jacques; Cosset, Francois-Loic; Le Grand, Roger

2008-01-01

218

Hematopoietic miR155 Deficiency Enhances Atherosclerosis and Decreases Plaque Stability in Hyperlipidemic Mice  

PubMed Central

microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4+CD25+FoxP3+ regulatory T cells, and an increase in granulocytes (CD11b+Ly6G+) in blood of miR155?/? transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the ‘inflammatory’ monocyte subset (CD11b+Ly6G?Ly6Chi) and reduces ‘resident’ monocytes (CD11b+Ly6G?Ly6Clow) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155?/? transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced. In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation. PMID:22558252

Donners, Marjo M. P. C.; Wolfs, Ine M. J.; Stoger, Lauran J.; van der Vorst, Emiel P. C.; Pottgens, Chantal C. H.; Heymans, Stephane; Schroen, Blanche; Gijbels, Marion J. J.; de Winther, Menno P. J.

2012-01-01

219

Decitabine and Midostaurin in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia  

ClinicalTrials.gov

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-09-14

220

Early molecular diagnosis of aspergillosis in a patient with acute myeloid leukaemia.  

PubMed

Diagnosis of invasive fungal infection remains challenging. Here we report a case of early diagnosis of invasive aspergillosis in a neutropenic patient affected by acute myeloid leukaemia, achieved through the detection of Aspergillus fumigatus species-specific ribonucleic acid sequences by a sensitive multiplex real-time polymerase chain reaction-based molecular assay. Thanks to the early diagnosis, targeted therapy was promptly established and the severe fungal infection controlled, allowing the patient to subsequently receive allogeneic hematopoietic stem cell transplantation from a haploidentical donor, her only curative option. Also in this instance, targeted secondary antifungal prophylaxis with voriconazole avoided any other fungal infection afterwards. This report suggests how the implementation of molecular assays in combination with routine diagnostic procedures, can improve microbiological diagnosis in sepsis, particularly in case of fungal infection, difficult to detect with standard microbiological culture methods. PMID:25024994

Greco, R; Mancini, N; Peccatori, J; Cieri, N; Vago, L; Giglio, F; Morelli, M; Ghidoli, N; Carletti, S; Levati, G; Crucitti, L; Sala, E; Lupo Stanghellini, M T; Lorentino, F; Forcina, A; Pavesi, F; Carrabba, M; Marktel, S; Assanelli, A; Marcatti, M; Bernardi, M; Corti, C; Doglioni, C; Scarpellini, P; Burioni, R; Bonini, C; Clementi, M; Ciceri, F

2014-01-01

221

Practical issues surrounding the explosion of tyrosine kinase inhibitors for the management of chronic myeloid leukemia.  

PubMed

The advent of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment outcome of chronic myeloid leukemia (CML). Imatinib was the first TKI approved, and has been considered the standard of care for more than a decade. Second generation compounds, namely dasatinib and nilotinib, are highly effective in newly diagnosed patients as well as those who fail imatinib. Bosutinib and ponatinib have also become available as second line options. With five agents from which to choose, selecting a TKI has become a challenge. Multiple tests are now available to determine a patient's disease status, making the ideal monitoring strategy unclear. The gold standard for response to TKI therapy remains the achievement of complete cytogenetic response. This review will discuss the practical aspects of selecting a TKI and monitoring a patient once on therapy, including when to consider a treatment change. Other relevant issues, including cost, compliance, role of allogeneic hematopoietic cell transplantation, and discontinuation of TKIs will also be covered. PMID:24984571

Mathisen, Michael S; Kantarjian, Hagop M; Cortes, Jorge; Jabbour, Elias J

2014-09-01

222

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia  

PubMed Central

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML. PMID:23259070

Nestal de Moraes, Gabriela; Souza, Paloma Silva; Costas, Fernanda Casal de Faria; Vasconcelos, Flavia Cunha; Reis, Flaviana Ruade Souza; Maia, Raquel Ciuvalschi

2012-01-01

223

Precursor B Cells from Pax5 -deficient mice — Stem Cells for Macrophages, Granulocytes, Osteoclasts, Dendritic Cells, Natural Killer Cells, Thymocytes and T Cells  

Microsoft Academic Search

\\u000a At least three major cell differentiation lineages cooperate to build the system of lymphoid organs, each one derived from\\u000a a separate stem cell. Hematopoietic stem cells give rise to T-lymphoid cells in the thymus and to B-lymphoid and myeloid cells\\u000a in the bone marrow. Fibroblastic and epithelial stem cells seed the bone marrow and thymus to provide the stromal cell

A. G. Rolink; F. Melchers

224

[Allogeneic hematopoietic transplantation with stem cells extracted from peripheral blood].  

PubMed

Fifty three patients (pts) received an allogeneic hematopoietic transplant using peripheral blood progenitor cells (PBPC). Diagnosis were acute myeloid leukemia (AML) in 16 pts, acute lymphoblastic leukemia (ALL) in 15, chronic myeloid leukemia (CML) in first chronic phase in 12, aplastic anemia in 4, myelodysplasia in 3 and Hodgkin's disease, major thalasemia and Hunter's syndrome in one each. Mean age was 20 years-old (2-55), 28 males and 25 females. Conditioning regimens were total body irradiation with 1200 cGy and cyclophosphamide 120 mg/kg in 38 pts, busulfan 16 mg/kg and cyclophosphamide 120 mg/kg in 10 pts, total lymphoid irradiation and cyclophosphamide in 3, 2 pts received other chemotherapy based conditionings. PBPC were infused unmanipulated through a central catheter. Graft versus host disease (GVHD) prophylaxis was cyclosporin and short course methotrexate. Donors were 6/6 HLA compatible siblings in 52 cases and 5/6 match in one case. PBPC mobilization was done with G-CSF at a dose of 10 micrograms/kg/day subcutaneously for four days, pheresis started on day 5. Bone marrow harvest was also done in the first thirty cases. Mean cellularities for CD34, CD3, CD4, CD8, CD56, CD19 (cel x 10(6)/kg) were 4.12; 4.59; 2.57; 1.9; 0.55 and 0.68, respectively. Mean recovery of neutrophils > 500/microL was obtained on day +11 and platelets > 20,000/microL on day +13. Patients were hospitalized for a mean period of 26 days (range 18-39) and days with parenteral antibiotics were 12.2 (5-45). Two pts had venoocclusive disease of the liver. Transplant related mortality was 15%. Acute graft versus host disease (GVHD) was observed in 43.4% of pts, only 5 pts had acute GVHD III or IV. Mean time for aGVHD diagnosis was +23 (8-76). Forty three pts were evaluable for chronic GVHD with a mean follow-up of 18 months (4-39). Chronic GVHD was observed in 26.4% by day +240, only 2 pts developed severe cGVHD. The present experience demonstrates an acceptable incidence for cGVHD; however, taking into account recent reports showing an increase of this complication, it seems reasonable not to perform this procedure for non-malignant diseases in which graft versus malignancy effect is not to be expected. PMID:10962806

Kusminsky, G; Foncuberta, M C; Aversa, L; Drelichman, G; Freigeiro, D; Burgos, R; Irrazabal, C; Gonzalez, G; Dictar, M; Niborski, R; Kohan, A; Sanchez Avalos, J C

2000-01-01

225

P-selectin glycoprotein ligand-1 deficiency augments G-CSF induced myeloid cell mobilization.  

PubMed

The effect of granulocyte colony-stimulating factor (G-CSF) was investigated in P-selectin glycoprotein ligand-1 (PSGL-1) deficient (PSGL-1(-/-)) and wild-type (PSGL-1(+/+)) mice to establish the role of this mucin in myeloid cell mobilization. G-CSF activates tissue proteases that cleave adhesion molecules, thus enhances the mobilization of myeloid cells and haematopoietic stem cells. Cytopenia was induced with a single dose of cyclophosphamide. In PSGL-1(-/-) animals, we observed a delayed extravasation of mature myeloid cells from the peripheral vessels into the tissue compartments and their faster mobilization from the bone marrow. Subsequently, animals received G-CSF twice a day for 4 days. Neutrophil and monocyte counts increased upon completion of G-CSF treatment and both values were significantly higher in PSGL-1(-/-) mice; 47.7 versus 28.3 G/l for neutrophils and 4.1 versus 2.0 G/l for monocytes. The ratio of atypical myeloid cells was also elevated. Analyzing the causes of the above differences, we identified a 4-fold increase in the colony-forming unit (CFU-GM) counts of the peripheral blood in PSGL-1(-/-) mice, compared to wild-type animals. A significantly elevated number of CFU-GM was detected also in the femurs of PSGL-1(-/-) mice, 4 and 5 days after cyclophosphamide treatment and these values paralleled with the elevation of CD34+/CD117+ stem cell counts in the peripheral blood. Our data suggest, that in the absence of PSGL-1, G-CSF was more potent in elevating absolute myeloid cell numbers by acting on cell release from the bone marrow, maturation from circulating precursor cells in the peripheral blood and prolonged retainment in the circulation. PMID:24091681

Miszti-Blasius, Kornél; Felszeghy, Szabolcs; Kiss, Csongor; Benk?, Ilona; Géresi, Krisztina; Megyeri, Attila; Hevessy, Zsuzsanna; Kappelmayer, János

2014-02-01

226

Isolated duodenal myeloid sarcoma associated with the CBF?/MYH11 fusion gene followed by acute myeloid leukemia progression: A case report and literature review  

PubMed Central

Myeloid sarcoma (MS) is a rare disease that presents as an extramedullary tumorous mass of immature myeloid precursors. The majority of MS are identified in acute myeloid leukemia (AML) patients and rarely present as a primary isolated MS without AML. In addition, inversion of chromosome 16 [inv(16)] and the CBF?/MYH11 fusion gene are rarely associated with MS. The current study reports a female patient with an isolated duodenal MS, who developed AML-M4 associated with the CBF?/MYH11 fusion gene and 48,XX,inv(16),+13,+22. A review of previously reported cases of isolated MS with the CBF?/MYH11 fusion gene was also performed. Isolated MS with the CBF?/MYH11 fusion gene was often observed in abdominal lesions, with the intestinal tract being the predominantly involved site. In addition, patients with isolated MS with the CBF?/MYH11 fusion exhibited a high risk of developing systemic AML. The diagnosis of isolated MS may be particularly challenging and, therefore, determining the optimal standard treatment for isolated MS is required. PMID:25120702

HUANG, BO; YOU, PENG; ZHU, PING; DU, ZUNGUO; WU, BEIQIAN; XU, XIAOPING; CHEN, ZI

2014-01-01

227

Nitric oxide-induced murine hematopoietic stem cell fate involves multiple signaling proteins, gene expression, and redox modulation.  

PubMed

There are a growing number of reports showing the influence of redox modulation in cellular signaling. Although the regulation of hematopoiesis by reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been described, their direct participation in the differentiation of hematopoietic stem cells (HSCs) remains unclear. In this work, the direct role of nitric oxide (NO(•) ), a RNS, in the modulation of hematopoiesis was investigated using two sources of NO(•) , one produced by endothelial cells stimulated with carbachol in vitro and another using the NO(•) -donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) in vivo. Two main NO(•) effects were observed: proliferation of HSCs-especially of the short-term HSCs-and its commitment and terminal differentiation to the myeloid lineage. NO(•) -induced proliferation was characterized by the increase in the number of cycling HSCs and hematopoietic progenitor cells positive to BrdU and Ki-67, upregulation of Notch-1, Cx43, PECAM-1, CaR, ERK1/2, Akt, p38, PKC, and c-Myc. NO(•) -induced HSCs differentiation was characterized by the increase in granulocytic-macrophage progenitors, granulocyte-macrophage colony forming units, mature myeloid cells, upregulation of PU.1, and C/EBP? genes concomitantly to the downregulation of GATA-3 and Ikz-3 genes, activation of Stat5 and downregulation of the other analyzed proteins mentioned above. Also, redox status modulation differed between proliferation and differentiation responses, which is likely associated with the transition of the proliferative to differentiation status. Our findings provide evidence of the role of NO(•) in inducing HSCs proliferation and myeloid differentiation involving multiple signaling. Stem Cells 2014;32:2949-2960. PMID:24964894

Nogueira-Pedro, Amanda; Dias, Carolina C; Regina, Helena; Segreto, C; Addios, Priscilla C; Lungato, Lisandro; D'Almeida, Vania; Barros, Carlos C; Higa, Elisa M S; Buri, Marcus V; Ferreira, Alice T; Julian Paredes-Gamero, Edgar

2014-11-01

228

Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities.  

PubMed Central

PU.1 is a member of the ets family of transcription factors and is expressed exclusively in cells of the hematopoietic lineage. Mice homozygous for a disruption in the PU.1 DNA binding domain are born alive but die of severe septicemia within 48 h. The analysis of these neonates revealed a lack of mature macrophages, neutrophils, B cells and T cells, although erythrocytes and megakaryocytes were present. The absence of lymphoid commitment and development in null mice was not absolute, since mice maintained on antibiotics began to develop normal appearing T cells 3-5 days after birth. In contrast, mature B cells remained undetectable in these older mice. Within the myeloid lineage, despite a lack of macrophages in the older antibiotic-treated animals, a few cells with the characteristics of neutrophils began to appear by day 3. While the PU.1 protein appears not to be essential for myeloid and lymphoid lineage commitment, it is absolutely required for the normal differentiation of B cells and macrophages. Images PMID:8896458

McKercher, S R; Torbett, B E; Anderson, K L; Henkel, G W; Vestal, D J; Baribault, H; Klemsz, M; Feeney, A J; Wu, G E; Paige, C J; Maki, R A

1996-01-01

229

Isolated trisomy 2 in bone marrows of patients with suspected hematopoietic malignancies.  

PubMed

Isolated trisomy 2 in hematopoietic malignancies is rare, having been reported in only eight cases. Of these cases, the majority are older males. The underlying hematologic malignancies range from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). The molecular pathogenesis and prognostic significance of isolated trisomy 2 remains unknown. Herein, we report 11 cases of isolated trisomy 2 in hematologic disorders seen in the Mayo Clinic Cytogenetics laboratory from 1996-2012. The majority were older males between the ages of 63-93 years. The underlying bone marrow pathologic diagnoses ranged from no diagnostic features of malignancy to AML. Our data suggest that isolated trisomy 2 could represent an age-related phenomenon since all 11 cases were age 63 and over. It appears that isolated trisomy 2 harbors little prognostic significance and that, instead, the prognostic significance is driven by the underlying pathologic diagnosis. For example, whereas 3 of the cases with AML survived only 7-10 weeks post-bone marrow biopsy, 1 of the cases without diagnostic features of malignancy survived 10 additional years. Therefore, trisomy 2 as a sole abnormality should not be considered as definitive evidence for a myeloid neoplasm in the absence of diagnostic morphologic criteria. PMID:24736057

Aypar, Umut; Reichard, Kaaren K; Waltman, Lindsey A; Van Dyke, Daniel L

2014-04-01

230

A focused review of hematopoietic neoplasms occurring in the therapy-related setting  

PubMed Central

Hematological neoplasms developed in patients with a history of cytotoxic therapies comprise a group of diseases with a poor clinical outcome, and collectively categorized as “therapy-related myeloid neoplasms” (t-MN) in the 2008 World Health Organization (WHO) Classification. In recent years, numerous publications have emerged, and these studies have greatly expanded the scope of our understanding in this field. We here focused our review on several selected areas including secondary malignancies occurring in patients with autoimmune diseases; radiation therapy alone as a causative agent; the similarity and differences between therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); clinical behavior and treatment outcome of t-AML patients with favorable cytogenetics; the incidence and clinical features of myelodysplastic/myeloproliferative neoplasms, as well as acute lymphoblastic leukemia and myeloproliferative neoplasms in patients with prior cytotoxic exposure. These recent studies have shown that therapy-related hematopoietic neoplasms are heterogeneous, and may manifest in various forms, more complex than we have recognized previously. Cytogenetic abnormalities and underlying mutations are likely to be the major factors dictating prognosis. PMID:25120730

Zhang, Liping; Wang, Sa A

2014-01-01

231

NPM1-mutated acute myeloid leukemia of monocytic or myeloid origin exhibit distinct immunophenotypes.  

PubMed

Acute myeloid leukemia with mutated nucleophosmin (NPM1m+AML) is a heterogeneous entity. We investigated whether NPM1m+AML with monocytic or myeloid differentiation have distinct immunophenotype. The study included 160 NPM1m+AMLpatients and 178 AML patients without NPM1 mutation and recurrent cytogenetic abnormality (NPM1wt-AML). We analyzed the immunophenotype by flow cytometry. NPM1 mutation was detected by PCR. Compared with NPM1wt-AML patients, NPM1m+AML patients showed higher positive rates of CD33 and CD9 and lower positive rates of CD34, HLA-DR, CD7, CD15 and CD117 (all P<0.05). HLA-DR, CD64, CD14, CD11b, CD15, CD4, CD9 and CD10 were higher (P<0.001) and CD117 was lower (P<0.01) in monocytic NPM1m+AML compared with myeloid NPM1m+AML. Similar rates of lymphoid antigen (CD19, CD2, and CD7) and myeloid antigen (CD13, CD33) positivity were detected in monocytic and myeloid NPM1m+AML. Compared with NPM1wt-AML, CD34 expression was lower both in myeloid and monocytic NPM1m+AML subgroups, although HLA-DR was lower in NPM1m+AML compared with NPM1wt-AML only in myeloid subgroup. Comparisons of NPM1m+AML and NPM1wt-AML showed no differences in monocyte-associated markers such as CD14 and CD11b in myeloid and monocytic subgroup. Myeloid NPM1m+AML correlated with the female gender (P=0.001), lower WBC counts (P=0.04) and higher WT1 transcripts (P=0.006) compared with monocytic NPM1m+AML.These results suggested monocytic and myeloid-derived NPM1m+AML exhibit distinct immunophenotypes. PMID:23601747

Liu, Yan-Rong; Zhu, Hong-Hu; Ruan, Guo-Rui; Qin, Ya-Zhen; Shi, Hong-Xia; Lai, Yue-Yun; Chang, Yan; Wang, Ya-Zhe; Lu, Dan; Hao, Le; Li, Jin-Lan; Li, Ling-Di; Jiang, Bin; Huang, Xiao-Jun

2013-07-01

232

Cited2 is an essential regulator of adult hematopoietic stem cells.  

PubMed

The regulatory pathways necessary for the maintenance of adult hematopoietic stem cells (HSCs) remain poorly defined. By using loss-of-function approaches, we report a selective and cell-autonomous requirement for the p300/CBP-binding transcriptional coactivator Cited2 in adult HSC maintenance. Conditional deletion of Cited2 in the adult mouse results in loss of HSCs causing multilineage bone marrow failure and increased lethality. In contrast, conditional ablation of Cited2 after lineage specification in lymphoid and myeloid lineages has no impact on the maintenance of these lineages. Additional deletion of Ink4a/Arf (encoding p16(Ink4a) and p19(Arf)) or Trp53 (encoding p53, a downstream target of p19(Arf)) in a Cited2-deficient background restores HSC functionality and rescues mice from bone marrow failure. Furthermore, we show that the critical role of Cited2 in primitive hematopoietic cells is conserved in humans. Taken together, our studies provide genetic evidence that Cited2 selectively maintains adult HSC functions, at least in part, via Ink4a/Arf and Trp53. PMID:19951693

Kranc, Kamil R; Schepers, Hein; Rodrigues, Neil P; Bamforth, Simon; Villadsen, Ellen; Ferry, Helen; Bouriez-Jones, Tiphaine; Sigvardsson, Mikael; Bhattacharya, Shoumo; Jacobsen, Sten Eirik; Enver, Tariq

2009-12-01

233

Cited2 Is an Essential Regulator of Adult Hematopoietic Stem Cells  

PubMed Central

Summary The regulatory pathways necessary for the maintenance of adult hematopoietic stem cells (HSCs) remain poorly defined. By using loss-of-function approaches, we report a selective and cell-autonomous requirement for the p300/CBP-binding transcriptional coactivator Cited2 in adult HSC maintenance. Conditional deletion of Cited2 in the adult mouse results in loss of HSCs causing multilineage bone marrow failure and increased lethality. In contrast, conditional ablation of Cited2 after lineage specification in lymphoid and myeloid lineages has no impact on the maintenance of these lineages. Additional deletion of Ink4a/Arf (encoding p16Ink4a and p19Arf) or Trp53 (encoding p53, a downstream target of p19Arf) in a Cited2-deficient background restores HSC functionality and rescues mice from bone marrow failure. Furthermore, we show that the critical role of Cited2 in primitive hematopoietic cells is conserved in humans. Taken together, our studies provide genetic evidence that Cited2 selectively maintains adult HSC functions, at least in part, via Ink4a/Arf and Trp53. PMID:19951693

Kranc, Kamil R.; Schepers, Hein; Rodrigues, Neil P.; Bamforth, Simon; Villadsen, Ellen; Ferry, Helen; Bouriez-Jones, Tiphaine; Sigvardsson, Mikael; Bhattacharya, Shoumo; Jacobsen, Sten Eirik; Enver, Tariq

2009-01-01

234

Enrichment of functionally distinct mouse hematopoietic progenitor cell populations using CD62L1  

PubMed Central

The details of the bifurcation of the lymphoid and myeloid lineages following commitment by multipotent progenitor cells (MPP) remain a topic of controversy. We report that the surface glycoprotein CD62L can be characterized as a novel marker of this and other stages of early hematopoietic differentiation. Cell isolation and transplant studies demonstrated CD62Lneg/low long-term hematopoietic stem cells and CD62Lhigh MPP within the traditionally defined c-kitposLinneg/lowSca-1pos (KLS) stem/progenitor cellpopulation. Within the MPP population previously defined as KLS-Thy-1.1negFlt3pos, Sca-1 and CD62L resolved 4 populations and segregated Sca-1highCD62Lneg/low MPP from Sca-1highCD62Lhigh leukocyte-biased progenitors. Utilizing a novel transplantation method that allows tracking of erythroid and platelet engraftment as an alternative to the classical method of in vitro colony formation, we characterized Sca-1highCD62Lneg/low cells as MPP based on transient engraftment of these lineages. These data establish CD62L as a useful tool in the study of early hematopoiesis, and emphasize the power of tri-lineage engraftment studies in establishing the lineage potential of MPP subsets. PMID:21998453

Cho, Scott; Spangrude, Gerald J.

2011-01-01

235

Ubiquitous Expression of MAKORIN-2 in Normal and Malignant Hematopoietic Cells and Its Growth Promoting Activity  

PubMed Central

Makorin-2 (MKRN2) is a highly conserved protein and yet its functions are largely unknown. We investigated the expression levels of MKRN2 and RAF1 in normal and malignant hematopoietic cells, and leukemia cell lines. We also attempted to delineate the role of MKRN2 in umbilical cord blood CD34+ stem/progenitor cells and K562 cell line by over-expression and inhibition of MKRN2 through lentivirus transduction and shRNA nucleofection, respectively. Our results provided the first evidence on the ubiquitous expression of MKRN2 in normal hematopoietic cells, embryonic stem cell lines, primary leukemia and leukemic cell lines of myeloid, lymphoid, erythroid and megakaryocytic lineages. The expression levels of MKRN2 were generally higher in primary leukemia samples compared with those in age-matched normal BM cells. In all leukemia subtypes, there was no significant correlation between expression levels of MKRN2 and RAF1. sh-MKRN2-silenced CD34+ cells had a significantly lower proliferation capacity and decreased levels of the early stem/progenitor subpopulation (CFU-GEMM) compared with control cultures. Over-expression of MKRN2 in K562 cells increased cell proliferation. Our results indicated possible roles of MKRN2 in normal and malignant hematopoiesis. PMID:24675897

Lee, King Yiu; Chan, Kathy Yuen Yee; Tsang, Kam Sze; Chen, Yang Chao; Kung, Hsiang-fu; Ng, Pak Cheung; Li, Chi Kong; Leung, Kam Tong; Li, Karen

2014-01-01

236

Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors.  

PubMed

The Mixed Lineage Leukemia (MLL) gene is essential for embryonic hematopoietic stem cell (HSC) development, but its role during adult hematopoiesis is unknown. Using an inducible knockout model, we demonstrate that Mll is essential for the maintenance of adult HSCs and progenitors, with fatal bone marrow failure occurring within 3 weeks of Mll deletion. Mll-deficient cells are selectively lost from mixed bone marrow chimeras, demonstrating their failure to self-renew even in an intact bone marrow environment. Surprisingly, HSCs lacking Mll exhibit ectopic cell-cycle entry, resulting in the depletion of quiescent HSCs. In contrast, Mll deletion in myelo-erythroid progenitors results in reduced proliferation and reduced response to cytokine-induced cell-cycle entry. Committed lymphoid and myeloid cells no longer require Mll, defining the early multipotent stages of hematopoiesis as Mll dependent. These studies demonstrate that Mll plays selective and independent roles within the hematopoietic system, maintaining quiescence in HSCs and promoting proliferation in progenitors. PMID:18371366

Jude, Craig D; Climer, Leslie; Xu, Diyong; Artinger, Erika; Fisher, Jill K; Ernst, Patricia

2007-09-13

237

The role of PML in hematopoietic and leukemic stem cell maintenance  

PubMed Central

The tumor suppressor promyelocytic leukemia (PML) was first identified as a component of PML–RAR? fusion protein, one of the initiating cytogenetic abnormalities in acute promyelocytic leukemia. PML is now known to have diverse functions regulating the DNA-damage response, apoptosis, senescence, and angiogenesis. Recent investigations have identified PML as a regulator of metabolic pathways in stem cell compartments, including the hematopoietic system, and have provided researchers with new strategies for controlling stem cell maintenance and differentiation. Studies of PML in leukemia-initiating cells demonstrate that PML is also an essential component of their maintenance, which has drawn tremendous attention to PML from scientists in various stem cell fields. Here, we review research into PML and its associated pathways, including recent studies of PML as it relates to stem cell biology, as well as our finding that PML regulates fatty acid oxidation, which is essential to the maintenance of normal hematopoietic stem cells. We also discuss the therapeutic potential of controlling PML-associated pathways. In particular, we describe promising evidence for the use of arsenic trioxide in the treatment of chronic myeloid leukemia. PMID:24488785

Nakahara, Fumio; Weiss, Cary N.

2014-01-01

238

High avidity myeloid leukemia-associated antigen-specific CD8+ T cells preferentially reside in the bone marrow.  

PubMed

The activity of allogeneic CD8(+) T cells specific for leukemia-associated antigens (LAAs) is thought to mediate, at least in part, the curative effects of hematopoietic stem cell transplantation (HSCT) in myeloid malignancies. However, the identity and nature of clinically relevant LAA-specific CD8(+) T-cell populations have proven difficult to define. Here, we used a combination of coreceptor-mutated peptide-major histocompatibility complex class I (pMHCI) tetramers and polychromatic flow cytometry to examine the avidity profiles, phenotypic characteristics, and anatomical distribution of HLA A*0201-restricted CD8(+) T-cell populations specific for LAAs that are over-expressed in myeloid leukemias. Remarkably, LAA-specific CD8(+) T-cell populations, regardless of fine specificity, were confined almost exclusively to the bone marrow; in contrast, CD8(+) T-cell populations specific for the HLA A*0201-restricted cytomegalovirus (CMV) pp65(495-503) epitope were phenotypically distinct and evenly distributed between bone marrow and peripheral blood. Furthermore, bone marrow-resident LAA-specific CD8(+) T cells frequently engaged cognate antigen with high avidity; notably, this was the case in all tested bone marrow samples derived from patients who achieved clinical remission after HSCT. These data suggest that concomitant examination of bone marrow specimens in patients with myeloid leukemias might yield more definitive information in the search for immunologic prognosticators of clinical outcome. PMID:18997173

Melenhorst, J Joseph; Scheinberg, Phillip; Chattopadhyay, Pratip K; Gostick, Emma; Ladell, Kristin; Roederer, Mario; Hensel, Nancy F; Douek, Daniel C; Barrett, A John; Price, David A

2009-03-01

239

Disruption of the estrogen receptor ? gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis  

PubMed Central

Proliferation of pluripotent, bone marrow stem cells, which develop to lymphoid and myeloid progenitors, is negatively regulated by estrogen. Although in estrogen deficiency and in estrogen receptor knockout mice there is significant alteration in bone marrow hematopoiesis, the effects of aging on estrogen receptor deficiencies in mice have not been investigated yet. In this study we show that by 1.5 years of age, estrogen receptor ? knockout (ER?–/–) mice develop pronounced splenomegaly that is much more severe in females than in males. Further characterization of these mice revealed myelogenous hyperplasia in bone marrow, an increase in the number of granulocytes and B lymphocytes in blood, lymphadenopathy, and infiltration of leukocytes in the liver and lung. Analysis by flow cytometry of the bone marrow cells revealed that the percentage and total number of Gr-1hi/Mac-1hi-positive granulocytes were increased by 15–30% and 100%, respectively. The numbers of B cells in the bone marrow and spleen were significantly higher in ER?–/– mice than in WT littermates. Some of the ER?–/– mice also had a severe lymphoproliferative phenotype. Thus the absence of ER? results in a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis. Our results indicate a previously unknown role for ER? in regulating the differentiation of pluripotent hematopoietic progenitor cells and suggest that the ER?–/– mouse is a potential model for myeloid and lymphoid leukemia. Furthermore, we suggest that ER? agonists might have clinical value in the treatment of leukemia. PMID:12740446

Shim, Gil-Jin; Wang, Ling; Andersson, Sandra; Nagy, Noemi; Kis, Lorand Levente; Zhang, Qinghong; Makela, Sari; Warner, Margaret; Gustafsson, Jan-Ake

2003-01-01

240

What's New in Adult Acute Myeloid Leukemia Research and Treatment?  

MedlinePLUS

... Topic Additional resources for acute myeloid leukemia What’s new in acute myeloid leukemia research and treatment? Researchers ... against AML (see below). Gene expression profiling This new lab technique is being studied to help identify ...

241

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia  

PubMed Central

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 ? (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML. PMID:24616378

Jaras, Marcus; Miller, Peter G.; Chu, Lisa P.; Puram, Rishi V.; Fink, Emma C.; Schneider, Rebekka K.; Al-Shahrour, Fatima; Pena, Pablo; Breyfogle, L. Jordan; Hartwell, Kimberly A.; McConkey, Marie E.; Cowley, Glenn S.; Root, David E.; Kharas, Michael G.; Mullally, Ann

2014-01-01

242

The Promyelocytic Leukemia Zinc Finger Protein Affects Myeloid Cell Growth, Differentiation, and Apoptosis†  

PubMed Central

The promyelocytic leukemia zinc finger (PLZF) gene, which is disrupted in therapy-resistant, t(11;17)(q23;q21)-associated acute promyelocytic leukemia (APL), is expressed in immature hematopoietic cells and is down-regulated during differentiation. To determine the role of PLZF in myeloid development, we engineered expression of PLZF in murine 32Dcl3 cells. Expression of PLZF had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle and an increased incidence of apoptosis. PLZF-expressing pools also secreted a growth-inhibitory factor, which could explain the severe growth suppression of PLZF-expressing pools that occurred despite the fact that only half of the cells expressed high levels of PLZF. PLZF overexpression inhibited myeloid differentiation of 32Dcl3 cells in response to granulocyte and granulocyte-macrophage colony-stimulating factors. Furthermore, cells that expressed PLZF appeared immature as demonstrated by morphology, increased expression of Sca-1, and decreased expression of Gr-1. These findings suggest that PLZF is an important regulator of cell growth, death, and differentiation. Disruption of PLZF function associated with t(11;17) may be a critical event leading to APL. PMID:9710637

Shaknovich, Rita; Yeyati, Patricia L.; Ivins, Sarah; Melnick, Ari; Lempert, Cheryl; Waxman, Samuel; Zelent, Arthur; Licht, Jonathan D.

1998-01-01

243

Myeloid leukemia in a urine specimen: a case report and review of the literature.  

PubMed

Urinary tract cytology has a long history of utilization for the diagnosis and follow-up of tumors involving the urothelial tract. As expected, the most common tumor encountered in exfoliative urine cytology is urothelial carcinoma. While the sensitivity of urinary tract cytology for the diagnosis of low-grade urothelial carcinomas is low, its sensitivity and accuracy for high grade urothelial carcinomas is much higher. However, nonurothelial malignancies, such as hematopoietic malignancies, can also be encountered in urine specimens. Leukemic cells in urine can be diagnosed readily by cytological examination in cases where more invasive procedures are difficult to perform. Additionally, cell block sections can be utilized to determine the immunocytochemical profile of the tumor cells to confirm the diagnosis. Herein we report a case of a 75-year-old man with a past medical history of acute myeloid leukemia (AML), who presented with congested heart failure and painless macroscopic hematuria. AML relapse was diagnosed. Cytological examination of the urine using a ThinPrep® smear, cytospin preparation, and immunohistochemical stains performed on the cell block sections were examined. Findings were consistent with leukemic cells of myeloid origin in the bladder washing specimen. PMID:23749324

McCroskey, Zulfia; Mehta, Vikas; Wojcik, Eva M; Barkan, Güliz A

2014-08-01

244

Requirement for CDK6 in MLL-rearranged acute myeloid leukemia.  

PubMed

Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts. PMID:24764564

Placke, Theresa; Faber, Katrin; Nonami, Atsushi; Putwain, Sarah L; Salih, Helmut R; Heidel, Florian H; Krämer, Alwin; Root, David E; Barbie, David A; Krivtsov, Andrei V; Armstrong, Scott A; Hahn, William C; Huntly, Brian J; Sykes, Stephen M; Milsom, Michael D; Scholl, Claudia; Fröhling, Stefan

2014-07-01

245

C/EBP? Deficiency Sensitizes Mice to Ionizing Radiation-Induced Hematopoietic and Intestinal Injury  

PubMed Central

Knowledge of the mechanisms involved in the radiation response is critical for developing interventions to mitigate radiation-induced injury to normal tissues. Exposure to radiation leads to increased oxidative stress, DNA-damage, genomic instability and inflammation. The transcription factor CCAAT/enhancer binding protein delta (Cebpd; C/EBP? is implicated in regulation of these same processes, but its role in radiation response is not known. We investigated the role of C/EBP? in radiation-induced hematopoietic and intestinal injury using a Cebpd knockout mouse model. Cebpd?/? mice showed increased lethality at 7.4 and 8.5 Gy total-body irradiation (TBI), compared to Cebpd+/+ mice. Two weeks after a 6 Gy dose of TBI, Cebpd?/? mice showed decreased recovery of white blood cells, neutrophils, platelets, myeloid cells and bone marrow mononuclear cells, decreased colony-forming ability of bone marrow progenitor cells, and increased apoptosis of hematopoietic progenitor and stem cells compared to Cebpd+/+ controls. Cebpd?/? mice exhibited a significant dose-dependent decrease in intestinal crypt survival and in plasma citrulline levels compared to Cebpd+/+ mice after exposure to radiation. This was accompanied by significantly decreased expression of ?-H2AX in Cebpd?/? intestinal crypts and villi at 1 h post-TBI, increased mitotic index at 24 h post-TBI, and increase in apoptosis in intestinal crypts and stromal cells of Cebpd?/? compared to Cebpd+/+ mice at 4 h post-irradiation. This study uncovers a novel biological function for C/EBP? in promoting the response to radiation-induced DNA-damage and in protecting hematopoietic and intestinal tissues from radiation-induced injury. PMID:24747529

Chang, Jianhui; Wang, Wenze; Pathak, Rupak; Zhu, Xiaoyan; Wang, Junru; Hendrickson, Howard; Boerma, Marjan; Sterneck, Esta; Zhou, Daohong; Hauer-Jensen, Martin

2014-01-01

246

Concomitant JAK2 V617F-positive Polycythemia Vera and B-Cell Chronic Lymphocytic Leukemia in Three Patients Originating from Two Separate Hematopoietic Stem Cells  

PubMed Central

The simultaneous occurrence of polycythemia vera (PV) and chronic lymphocytic leukemia (CLL) is a rare event that offers a possibility to study their common origin. PV originates from self-renewing hematopoietic stem cells (HSC) with both lymphoid and myeloid potential(1–3). It has been reported that CLL also originates from self-renewing HSC with a potential for both lymphoid and myeloid differentiation(4, 5). We report 3 females with concomitant CLL and PV whose X-chromosome inactivation patterns of the neoplastic cells revealed that granulocytes/platelets and B-lymphocytes used different X-chromosome alleles. These data indicate that both PV and CLL have arisen independently and from different HSC. PMID:23280542

Swierczek, Sabina; Nausova, Jitka; Jelinek, Jaroslav; Liu, Enli; Roda, Paul; Kucerova, Jana; Jarosova, Marie; Urbankova, Helena; Indrak, Karel; Prchal, Josef T.; Divoky, Vladimir

2013-01-01

247

Delayed Hematopoietic Development in Osteopetrotic (op\\/op) Mice  

Microsoft Academic Search

Summary Changes in structure, cellularity, hematopoietic progenitor cell and macrophage content, and osteoclast activity were investigated in the hematopoietic organs of the colony-stimulating factor l(CSF-1)-less osteopetrotic (op\\/op) mouse. The data indicated that op\\/op mice undergo an age- related hematopoietic recovery and resolution of osteopetrosis, suggesting that the hematopoietic system has the capacity to use alternative mechanisms to compensate for the

Susan K. Begg; John M. Radley; Jeffrey W. Pollard; Orin T. Chisholm; E. Richard Stanley; Ivan Bertoncello

248

Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors.  

PubMed

TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid malignancies, including myeloproliferative neoplasms. Here we show that the level of 5-hmC is decreased in granulocyte DNA from myeloproliferative neoplasm patients with TET2 mutations compared with granulocyte DNA from healthy patients. Inhibition of TET2 by RNA interference decreases 5-hmC levels in both human leukemia cell lines and cord blood CD34(+) cells. These results confirm the enzymatic function of TET2 in human hematopoietic cells. Knockdown of TET2 in cord blood CD34(+) cells skews progenitor differentiation toward the granulomonocytic lineage at the expense of lymphoid and erythroid lineages. In addition, by monitoring in vitro granulomonocytic development we found a decreased granulocytic differentiation and an increase in monocytic cells. Our results indicate that TET2 disruption affects 5-hmC levels in human myeloid cells and participates in the pathogenesis of myeloid malignancies through the disturbance of myeloid differentiation. PMID:21734233

Pronier, Elodie; Almire, Carole; Mokrani, Hayat; Vasanthakumar, Aparna; Simon, Audrey; da Costa Reis Monte Mor, Barbara; Massé, Aline; Le Couédic, Jean-Pierre; Pendino, Frédéric; Carbonne, Bruno; Larghero, Jérôme; Ravanat, Jean-Luc; Casadevall, Nicole; Bernard, Olivier A; Droin, Nathalie; Solary, Eric; Godley, Lucy A; Vainchenker, William; Plo, Isabelle; Delhommeau, François

2011-09-01

249

Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors  

PubMed Central

TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid malignancies, including myeloproliferative neoplasms. Here we show that the level of 5-hmC is decreased in granulocyte DNA from myeloproliferative neoplasm patients with TET2 mutations compared with granulocyte DNA from healthy patients. Inhibition of TET2 by RNA interference decreases 5-hmC levels in both human leukemia cell lines and cord blood CD34+ cells. These results confirm the enzymatic function of TET2 in human hematopoietic cells. Knockdown of TET2 in cord blood CD34+ cells skews progenitor differentiation toward the granulomonocytic lineage at the expense of lymphoid and erythroid lineages. In addition, by monitoring in vitro granulomonocytic development we found a decreased granulocytic differentiation and an increase in monocytic cells. Our results indicate that TET2 disruption affects 5-hmC levels in human myeloid cells and participates in the pathogenesis of myeloid malignancies through the disturbance of myeloid differentiation. PMID:21734233

Pronier, Elodie; Almire, Carole; Mokrani, Hayat; Vasanthakumar, Aparna; Simon, Audrey; da Costa Reis Monte Mor, Barbara; Masse, Aline; Le Couedic, Jean-Pierre; Pendino, Frederic; Carbonne, Bruno; Larghero, Jerome; Ravanat, Jean-Luc; Casadevall, Nicole; Bernard, Olivier A.; Droin, Nathalie; Solary, Eric; Godley, Lucy A.; Vainchenker, William; Plo, Isabelle

2011-01-01

250

t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients.  

PubMed

Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature. PMID:24441146

Sandahl, Julie Damgaard; Coenen, Eva A; Forestier, Erik; Harbott, Jochen; Johansson, Bertil; Kerndrup, Gitte; Adachi, Souichi; Auvrignon, Anne; Beverloo, H Berna; Cayuela, Jean-Michel; Chilton, Lucy; Fornerod, Maarten; de Haas, Valérie; Harrison, Christine J; Inaba, Hiroto; Kaspers, Gertjan J L; Liang, Der-Cherng; Locatelli, Franco; Masetti, Riccardo; Perot, Christine; Raimondi, Susana C; Reinhardt, Katarina; Tomizawa, Daisuke; von Neuhoff, Nils; Zecca, Marco; Zwaan, C Michel; van den Heuvel-Eibrink, Marry M; Hasle, Henrik

2014-05-01

251

Mgat2 ablation in the myeloid lineage leads to defective glycoantigen T cell responses.  

PubMed

N-linked glycosylation is a central regulatory factor that influences the immune system in varied and profound ways, including leukocyte homing, T cell receptor signaling and others. Moreover, N-glycan branching has been demonstrated to change as a function of infection and inflammation. Our previous findings suggest that complex-type N-glycans on the class II major histocompatibility complex play an important role in antigen selection within antigen presenting cells (APCs) such that highly branched N-glycans promote polysaccharide (glycoantigen, GlyAg) presentation following Toll-like receptor 2 (TLR2)-dependent antigen processing. In order to explore the impact of N-glycan branching on the myeloid-derived APC population without the confounding problems of altering the branching of lymphocytes and non-hematopoietic cells, we created a novel myeloid-specific knockout of the ?-1,2-N-acetylglucosaminyltransferase II (Mgat2) enzyme. Using this novel mouse, we found that the reduction in multi-antennary N-glycans characteristic of Mgat2 ablation had no impact on GlyAg-mediated TLR2 signaling. Likewise, no deficits in antigen uptake or cellular homing to lymph nodes were found. However, we discovered that Mgat2 ablation prevented GlyAg presentation and T cell activation in vitro and in vivo without apparent alterations in protein antigen response or myeloid-mediated protection from infection. These findings demonstrate that GlyAg presentation can be regulated by the N-glycan branching pattern of APCs, thereby establishing an in vivo model where the T cell-dependent activity of GlyAgs can be experimentally distinguished from GlyAg-mediated stimulation of the innate response through TLR2. PMID:24310166

Ryan, Sean O; Leal, Sixto M; Abbott, Derek W; Pearlman, Eric; Cobb, Brian A

2014-03-01

252

Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia  

ClinicalTrials.gov

Acute Myeloid Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following; Myelodysplastic Syndrome; 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

2013-11-15

253

AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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

2014-09-20

254

Differential Expression of Novel Potential Regulators in Hematopoietic Stem Cells  

Microsoft Academic Search

The hematopoietic system is an invaluable model both for understanding basic developmental biology and for developing clinically relevant cell therapies. Using highly purified cells and rigorous microarray analysis we have compared the expression pattern of three of the most primitive hematopoietic subpopulations in adult mouse bone marrow: long-term hematopoietic stem cells (HSC), short-term HSC, and multipotent progenitors. All three populations

E. Camilla Forsberg; Susan S Prohaska; Sol Katzman; Garrett C Heffner; Josh M Stuart; Irving L Weissman

2005-01-01

255

Canine hematopoietic tumors: diagnosis, treatment and complications  

SciTech Connect

Canine hematopoietic tumors constitute a group of neoplasms that are frequently encountered in veterinary practice. Although common, they are also a diagnostically confusing group of tumors due to continued revision of their definition and classification. The confusion that arises from these changes presents the clinician with a perpetual challenge of diagnosis and therapy. Therapy of canine hematopoietic tumors has traditionally evolved from treatment of human patients with similar diseases, and in turn, these neoplasms have served as models for evaluating newer therapies for possible application in human patients. Methods of treatment have included chemotherapy, immunotherapy, radiation therapy, surgery, and hyperthermia. 9 tabs.

Weller, R.E.

1986-02-01

256

Signal, Transduction, and the Hematopoietic Stem Cell  

PubMed Central

The hematopoietic stem cell (HSC) is a unique cell positioned highest in the hematopoietic hierarchical system. The HSC has the ability to stay in quiescence, to self-renew, or to differentiate and generate all lineages of blood cells. The path to be actualized is influenced by signals that derive from the cell’s microenvironment, which activate molecular pathways inside the cell. Signaling pathways are commonly organized through inducible protein–protein interactions, mediated by adaptor proteins that link activated receptors to cytoplasmic effectors. This review will focus on the signaling molecules and how they work in concert to determine the HSC’s fate. PMID:25386349

Louria-Hayon, Igal

2014-01-01

257

Combination of vaccine-strain measles and mumps virus synergistically kills a wide range of human hematological cancer cells: Special focus on acute myeloid leukemia.  

PubMed

Through combining vaccine-derived measles and mumps viruses (MM), we efficiently targeted a wide range of hematopoietic cancer cell lines. MM synergistically killed many cell lines including acute myeloid leukemia (AML) cell lines. Further investigation suggested that enhanced oncolytic effect of MM was due to increased apoptosis induction. In an U937 xenograft AML mouse model, MM displayed greater tumor suppression and prolonged survival. Furthermore, MM efficiently killed blasts from 16 out of 20 AML patients and elicited more efficient killing effect on 11 patients when co-administered with Ara-C. Our results demonstrate that MM is a promising therapeutic candidate for hematological malignancies. PMID:25193462

Zhang, Li Feng; Tan, Darren Qian Cheng; Jeyasekharan, Anand D; Hsieh, Wen Son; Ho, Anh Son; Ichiyama, Koji; Ye, Min; Pang, Brendan; Ohba, Kenji; Liu, Xin; de Mel, Sanjay; Cuong, Bui Khac; Chng, Wee Joo; Ryo, Akihide; Suzuki, Youichi; Yeoh, Khay Guan; Toan, Nguyen Linh; Yamamoto, Naoki

2014-11-28

258

Testicular myeloid sarcoma: a rare manifestation of acute myeloid leukemia in an infant.  

PubMed

Myeloid sarcoma manifesting in the testis is rare and may occur concomitantly with bone marrow disease or as a separate entity. We describe our experience with a 6-month-old boy who presented with painless scrotal swelling and was found to have bilateral testicular masses on ultrasonography. The patient underwent unilateral radical inguinal orchiectomy. Surgical pathology revealed myeloid sarcoma of the testicle. He developed peripheral blood involvement 1 week postoperatively. Bone marrow biopsy showed acute myeloid leukemia. He is in remission after 2 cycles of induction chemotherapy, local radiation therapy, and allogeneic bone marrow transplantation. PMID:25260454

Tran, Christine N; Collie, Angela M B; Flagg, Aron; Rhee, Audrey

2014-10-01

259

Myelopoiesis and Myeloid Leukaemogenesis in the Zebrafish  

PubMed Central

Over the past ten years, studies using the zebrafish model have contributed to our understanding of vertebrate haematopoiesis, myelopoiesis, and myeloid leukaemogenesis. Novel insights into the conservation of haematopoietic lineages and improvements in our capacity to identify, isolate, and culture such haematopoietic cells continue to enhance our ability to use this simple organism to address disease biology. Coupled with the strengths of the zebrafish embryo to dissect developmental myelopoiesis and the continually expanding repertoire of models of myeloid malignancies, this versatile organism has established its niche as a valuable tool to address key questions in the field of myelopoiesis and myeloid leukaemogenesis. In this paper, we address the recent advances and future directions in the field of myelopoiesis and leukaemogenesis using the zebrafish system. PMID:22851971

Forrester, A. Michael; Berman, Jason N.; Payne, Elspeth M.

2012-01-01

260

Romidepsin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia  

ClinicalTrials.gov

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

2013-04-11

261

Genotoxicity of Retroviral Integration In Hematopoietic Cells  

Microsoft Academic Search

The experience of the past 3 years, since the first case of leukemia was reported in a child cured of X- linked severe combined immunodeficiency (X-SCID) by gene therapy, indicates that the potential genotoxicity of retroviral integration in hematopoietic cells will remain a consideration in evaluating the relative risks versus benefits of gene therapy for specific blood disorders. Although many

Arthur W. Nienhuis; Cynthia E. Dunbar; Brian P. Sorrentino

2006-01-01

262

Hematopoietic Stem Cell Donation in Children  

Microsoft Academic Search

Hematopoietic Stem Cell Transplant (HSCT) represents the second most frequent major organ transplant in the United States. Compared with other family members, siblings are more likely to be immunologically matched with the recipient and therefore are often the most suitable donors. Due to a dearth of information on the positive and adverse effects of HSCT on pediatric sibling donors, we

Lori S. Wiener; Emilie Steffen-Smith; Terry Fry; Alan S. Wayne

2007-01-01

263

MFR PAPER 1213 Gonadal and Hematopoietic  

E-print Network

, there was an oil spill in 1971 of #2 fuel oil and the jet fuel, JP-5 (Mayo, et al.'; 1972). There has been in which normal tissue Figure 1.-Soft shell clam. Mya arenaria, collected from the oil spill site arenaria, collected from oil spill site, Harpswell, Maine. Hematopoietic tumor. Neoplastic cells occupy con

264

CYTOMEGALOVIRUS PNEUMONIA IN HEMATOPOIETIC STEM CELL RECIPIENTS  

PubMed Central

Cytomegalovirus (CMV) is a frequently encountered infection following hematopoietic cell transplantation, and tissue invasive pneumonia is a dreaded complication of the virus in this population. In this review of CMV pneumonia, we address epidemiology, pathogenesis, diagnostics, current therapy and strategies to prevent the development of CMV disease. We also review emerging treatment and prevention options for this challenging disease. PMID:23753231

Travi, Giovanna; Pergam, Steven A

2013-01-01

265

Children as hematopoietic stem cell donors.  

PubMed

In the past half-century, hematopoietic stem cell transplantation has become standard treatment for a variety of diseases in children and adults, including selected hematologic malignancies, immunodeficiencies, hemoglobinopathies, bone marrow failure syndromes, and congenital metabolic disorders. There are 3 sources of allogeneic hematopoietic stem cells: bone marrow, peripheral blood, and umbilical cord blood; each has its own benefits and risks. Children often serve as hematopoietic stem cell donors, most commonly for their siblings. HLA-matched biological siblings are generally preferred as donors because of reduced risks of transplant-related complications as compared with unrelated donors. This statement includes a discussion of the ethical considerations regarding minors serving as stem cell donors, using the traditional benefit/burden calculation from the perspectives of both the donor and the recipient. The statement also includes an examination of the circumstances under which a minor may ethically participate as a hematopoietic stem cell donor, how the risks can be minimized, what the informed-consent process should entail, the role for a donor advocate (or some similar mechanism), and other ethical concerns. The American Academy of Pediatrics holds that minors can ethically serve as stem cell donors when specific criteria are fulfilled. PMID:20100753

2010-02-01

266

Chronic variable stress activates hematopoietic stem cells.  

PubMed

Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the ?3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans. PMID:24952646

Heidt, Timo; Sager, Hendrik B; Courties, Gabriel; Dutta, Partha; Iwamoto, Yoshiko; Zaltsman, Alex; von Zur Muhlen, Constantin; Bode, Christoph; Fricchione, Gregory L; Denninger, John; Lin, Charles P; Vinegoni, Claudio; Libby, Peter; Swirski, Filip K; Weissleder, Ralph; Nahrendorf, Matthias

2014-07-01

267

Proteoglycan synthesis by hematopoietic progenitor cells  

SciTech Connect

The synthesis of proteoglycans (PG) by hematopoietic stromal cells has been reported. But PG synthesis by hematopoietic progenitor cells has not been explored. We have studied synthesis, cellular distribution, and molecular characteristics of PG by a cloned interleukin-3 (IL-3)-dependent hematopoietic progenitor cell line, FDCP-1, which is cloned from murine long-term marrow cultures. Under appropriate conditions the cell can differentiate into granulocytes and macrophages, and therefore, can be considered CFU-GM equivalent. The pattern of PG synthesis was studied by 35SO4 labeling. FDCP-1 cells actively synthesize PG, which are distributed in the intracellular, membrane-associated (MP), and extracellular pools. After purification of the 35S-labeled material by ion-exchange and gel filtration techniques, a single chondroitin sulfate-PG (CIS-PG) was observed to be present in the three studied pools. By Sepharose CL-4B chromatography, this PG has a Kav of 0.47, which after alkaline treatment is shifted to a Kav of 0.67. This indicates the proteoglycan nature of the 35SO4-labeled material. The MP CIS-PG is not stable. It is released to the culture medium where it is subsequently processed. However, in the presence of hematopoietic stromal cells D2X, the stability of MP proteoglycan of FDCP-1 cells is enhanced, suggesting that the synthesis of PG by progenitor cells and its accumulation in the membrane may have a role in the interaction between progenitor and stromal cells.

Minguell, J.J.; Tavassoli, M. (Veterans Administration Medical Center, Jackson, MS (USA))

1989-05-15

268

Precursors to Lymphoproliferative Malignancies  

PubMed Central

We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. While these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy. PMID:23549397

Goldin, Lynn R.; McMaster, Mary L.; Caporaso, Neil E.

2013-01-01

269

Lenalidomide in Treating Older Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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

2014-07-25

270

Chronic intake of high fish oil diet induces myeloid-derived suppressor cells to promote tumor growth  

PubMed Central

Omega-3 polyunsaturated fatty acids enriched fish oil exerts beneficial anti-inflammatory effects in animal models with acute and chronic inflammatory diseases. Myeloid-derived suppressor cells (MDSCs), comprised of myeloid progenitors and precursors of myeloid cells, play vital roles in cancer. How fish oil affects the generation of MDSCs and the tumor development remains largely unexplored. Here, we show that dietary intake of high fish oil diet suppresses CD8+ T cells activation and proliferation in vivo via elevated levels of MDSCs. Mechanistically, high fish oil diet induces the expression of immunosuppressive cytokine IL-10 and promotes myelopoiesis in the spleen as well as other peripheral tissues. The immature myeloid cells in the spleen exhibit morphological and functional characteristics of MDSCs with the capability to downregulate CD8+ T cells activation. Depletion of MDSCs using anti-Gr-1 antibody decreases the growth of subcutaneously transferred B16 melanoma in mice on high fish oil diet. Interestingly, diet-induced production of MDSCs is not solely dependent of the spleen, as splenectomy has no effect on the tumor progress. Our data show that the liver functions as an alternative extramedullary hematopoiesis organ to support MDSCs differentiation and maintain tumor growth. Taken together, our study provides a novel insight into the physiological effects of fish oil and points to MDSCs as a possible mediator linking dietary fish oil intake and immunosuppression in cancer immunosurveillance. PMID:24691944

Li, Xiaoping; Cheng, Lu; Han, Mutian; Zhang, Miaomiao; Liu, Xia; Xu, Huaxi; Zhang, Minghui; Shao, Qixiang; Qi, Ling

2014-01-01

271

Earthquakes: Hydrogeochemical precursors  

NASA Astrophysics Data System (ADS)

Earthquake prediction is a long-sought goal. Changes in groundwater chemistry before earthquakes in Iceland highlight a potential hydrogeochemical precursor, but such signals must be evaluated in the context of long-term, multiparametric data sets.

Ingebritsen, S. E.; Manga, M.

2014-10-01

272

Pregancy complicated by acute myeloid leukaemia.  

PubMed

Combination cytotoxic chemotherapy was used to treat a case of acute myeloid leukaemia presenting in the 25th week of pregnancy with a sustained complete remission of the leukaemia and the successful delivery of a normal infant. The management of leukaemia presenting in pregnancy is discussed. PMID:286907

Hamer, J W; Beard, M E; Duff, G B

1979-03-28

273

Decitabine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia  

ClinicalTrials.gov

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; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

2013-09-27

274

Sorafenib Tosylate and Chemotherapy in Treating Older Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2014-10-09

275

Mutation of All Runx (AML1/Core) Sites in the Enhancer of T-Lymphomagenic SL3-3 Murine Leukemia Virus Unmasks a Significant Potential for Myeloid Leukemia Induction and Favors Enhancer Evolution toward Induction of Other Disease Patterns  

PubMed Central

SL3-3 murine leukemia virus is a potent inducer of T-lymphomas in mice. Using inbred NMRI mice, it was previously reported that a mutant of SL3-3 with all enhancer Runx (AML1/core) sites disrupted by 3-bp mutations (SL3-3dm) induces predominantly non-T-cell tumors with severely extended latency (S. Ethelberg, J. Lovmand, J. Schmidt, A. Luz, and F. S. Pedersen, J. Virol. 71:7273-7280, 1997). By use of three-color flow cytometry and molecular and histopathological analyses, we have now performed a detailed phenotypic characterization of SL3-3- and SL3-3dm-induced tumors in this mouse strain. All wild-type induced tumors had clonal T-cell receptor ? rearrangements, and the vast majority were CD3+ CD4+ CD8? T-lymphomas. Such a consistent phenotypic pattern is unusual for murine leukemia virus-induced T-lymphomas. The mutant virus induced malignancies of four distinct hematopoietic lineages: myeloid, T lymphoid, B lymphoid, and erythroid. The most common disease was myeloid leukemia with maturation. Thus, mutation of all Runx motifs in the enhancer of SL3-3 severely impedes viral T-lymphomagenicity and thereby discloses a considerable and formerly unappreciated potential of this virus for myeloid leukemia induction. Proviral enhancers with complex structural alterations (deletions, insertions, and/or duplications) were found in most SL3-3dm-induced T-lymphoid tumors and immature myeloid leukemias but not in any cases of myeloid leukemia with maturation, mature B-lymphoma, or erythroleukemia. Altogether, our results indicate that the SL3-3dm enhancer in itself promotes induction of myeloid leukemia with maturation but that structural changes may arise in vivo and redirect viral disease specificity to induction of T-lymphoid or immature myeloid leukemias, which typically develop with moderately shorter latencies. PMID:15542674

S?rensen, Karina Dalsgaard; Quintanilla-Martinez, Leticia; Kunder, Sandra; Schmidt, Jorg; Pedersen, Finn Skou

2004-01-01

276

Identification of Desirable Precursor Properties for Solution Precursor Plasma Spray  

NASA Astrophysics Data System (ADS)

In solution precursor plasma spray chemical precursor solutions are injected into a standard plasma torch and the final material is formed and deposited in a single step. This process has several attractive features, including the ability to rapidly explore new compositions and to form amorphous and metastable phases from molecularly mixed precursors. Challenges include: (a) moderate deposition rates due to the need to evaporate the precursor solvent, (b) dealing on a case by case basis with precursor characteristics that influence the spray process (viscosity, endothermic and exothermic reactions, the sequence of physical states through which the precursor passes before attaining the final state, etc.). Desirable precursor properties were identified by comparing an effective precursor for yttria-stabilized zirconia with four less effective candidate precursors for MgO:Y2O3. The critical parameters identified were a lack of major endothermic events during precursor decomposition and highly dense resultant particles.

Muoto, Chigozie K.; Jordan, Eric H.; Gell, Maurice; Aindow, Mark

2011-06-01

277

Modification of Hematopoietic Stem/Progenitor Cells with CD19-Specific Chimeric Antigen Receptors as a Novel Approach for Cancer Immunotherapy  

PubMed Central

Abstract Chimeric antigen receptors (CARs) against CD19 have been shown to direct T-cells to specifically target B-lineage malignant cells in animal models and clinical trials, with efficient tumor cell lysis. However, in some cases, there has been insufficient persistence of effector cells, limiting clinical efficacy. We propose gene transfer to hematopoietic stem/progenitor cells (HSPC) as a novel approach to deliver the CD19-specific CAR, with potential for ensuring persistent production of effector cells of multiple lineages targeting B-lineage malignant cells. Assessments were performed using in vitro myeloid or natural killer (NK) cell differentiation of human HSPCs transduced with lentiviral vectors carrying first and second generations of CD19-specific CAR. Gene transfer did not impair hematopoietic differentiation and cell proliferation when transduced at 1–2 copies/cell. CAR-bearing myeloid and NK cells specifically lysed CD19-positive cells, with second-generation CAR including CD28 domains being more efficient in NK cells. Our results provide evidence for the feasibility and efficacy of the modification of HSPC with CAR as a strategy for generating multiple lineages of effector cells for immunotherapy against B-lineage malignancies to augment graft-versus-leukemia activity. PMID:23978226

Ryan, Christine; Giannoni, Francesca; Hardee, Cinnamon L.; Tremcinska, Irena; Katebian, Behrod; Wherley, Jennifer; Sahaghian, Arineh; Tu, Andy; Grogan, Tristan; Elashoff, David; Cooper, Laurence J.N.; Hollis, Roger P.; Kohn, Donald B.

2013-01-01

278

Retention but significant reduction of BCR-ABL transcript in hematopoietic stem cells in chronic myelogenous leukemia after imatinib therapy  

PubMed Central

Chronic myelogenous leukemia (CML) is effectively treated with imatinib mesylate (IM), a small molecule inhibitor of the BCR-ABL tyrosine kinase that is expressed in the entire hematopoietic compartment including stem cells (HSC) and progenitors in CML patients. While IM induces disease remission, it does not appear to eradicate BCR-ABL-positive stem cells. We investigated the residual CML cells in HSC and myeloid progenitors isolated using fluorescence-activated cell sorting after IM-therapy. Quantitative real-time polymerase chain reaction detecting BCR-ABL transcripts showed that CML progenitors were eradicated within 12 months while the BCR-ABL-positive HSC remained. However, IM-therapy continuation could significantly decrease the ratio of BCR-ABL to BCR also in the HSC population. Our results implicate that the sorted and purified stem cells are useful for more sensitive quantification of BCR-ABL-positive minimal residual disease. PMID:19039626

Minami, Yosuke; Hayakawa, Fumihiko; Kitamura, Kunio; Nomura, Yuka; Murata, Makoto; Katsumi, Akira; Kiyoi, Hitoshi; Jamieson, Catriona H. M.; Wang, Jean Y. J.; Naoe, Tomoki

2009-01-01

279

DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells  

PubMed Central

The gene encoding DNA methyltransferase 3A (DNMT3A) is mutated in ?20% of acute myeloid leukemia cases, with Arg882 (R882) as the hotspot. Here, we addressed the transformation ability of the DNMT3A-Arg882His (R882H) mutant by using a retroviral transduction and bone marrow transplantation (BMT) approach and found that the mutant gene can induce aberrant proliferation of hematopoietic stem/progenitor cells. At 12 mo post-BMT, all mice developed chronic myelomonocytic leukemia with thrombocytosis. RNA microarray analysis revealed abnormal expressions of some hematopoiesis-related genes, and the DNA methylation assay identified corresponding changes in methylation patterns in gene body regions. Moreover, DNMT3A-R882H increased the CDK1 protein level and enhanced cell-cycle activity, thereby contributing to leukemogenesis. PMID:24497509

Xu, Jie; Wang, Yue-Ying; Dai, Yu-Jun; Zhang, Wu; Zhang, Wei-Na; Xiong, Shu-Min; Gu, Zhao-Hui; Wang, Kan-Kan; Zeng, Rong; Chen, Zhu; Chen, Sai-Juan

2014-01-01

280

The endoplasmic reticulum chaperone protein GRP94 is required for maintaining hematopoietic stem cell interactions with the adult bone marrow niche.  

PubMed

Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin ?4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology. PMID:21647226

Luo, Biquan; Lam, Ben S; Lee, Sung Hyung; Wey, Shiuan; Zhou, Hui; Wang, Miao; Chen, Si-Yi; Adams, Gregor B; Lee, Amy S

2011-01-01

281

The Endoplasmic Reticulum Chaperone Protein GRP94 Is Required for Maintaining Hematopoietic Stem Cell Interactions with the Adult Bone Marrow Niche  

PubMed Central

Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin ?4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology. PMID:21647226

Luo, Biquan; Lam, Ben S.; Lee, Sung Hyung; Wey, Shiuan; Zhou, Hui; Wang, Miao; Chen, Si-Yi; Adams, Gregor B.; Lee, Amy S.

2011-01-01

282

CX3CR1 delineates temporally and functionally distinct subsets of myeloid-derived suppressor cells in a mouse model of ovarian cancer.  

PubMed

Expression of the chemokine receptor CX3CR1 has been used to identify distinct populations within the monocyte, macrophage and dendritic cell lineages. Recent evidence indicates that CX3CR1-positive subsets of myeloid cells play distinct and important roles in a wide range of immunological maladies, and thus the use of CX3CR1 expression has leveraged our understanding of the myeloid contribution to a multitude of diseases. Here we use CX3CR1 expression as a means to identify a novel nongranulocytic CX3CR1-negative myeloid population that is functionally distinct from the previously described CX3CR1-positive cellular subsets within the CD11b-positive cellular compartment of ascites from ovarian tumor-bearing mice. We functionally identify CX3CR1-negative cells as myeloid suppressor cells and as a cellular subset with pathological specificity. Importantly, the CX3CR1-negative cells exhibit early IL-10 production in the ovarian tumor microenvironment, which we have shown to be critically tied to suppression and additional myeloid-derived suppressor cell accumulation, and we now show that this cellular population actively contributes to tumor progression. Furthermore, we demonstrate that the CX3CR1-negative population is derived from the recently described CX3CR1-positive macrophage/dendritic cell precursor cell. These studies provide a greater understanding of the generation and maintenance of regulatory myeloid subsets and have broad implications for the elucidation of myeloid function and contributions within the tumor microenvironment. PMID:24613975

Hart, Kevin M; Usherwood, Edward J; Berwin, Brent L

2014-07-01

283

A feeder-free differentiation system identifies autonomously proliferating B cell precursors in human bone marrow.  

PubMed

The peripheral B cell compartment is maintained by homeostatic proliferation and through replenishment by bone marrow precursors. Because hematopoietic stem cells cycle at a slow rate, replenishment must involve replication of precursor B cells. To study proliferation of early human B cell progenitors, we established a feeder cell-free in vitro system allowing the development of B cells from CD34(+) hematopoietic stem cells up to the stage of immature IgM(+) B cells. We found that pro-B and pre-B cells generated in vitro can proliferate autonomously and persist up to 7 wk in culture in the absence of signals induced by exogenously added cytokines. Nevertheless, addition of IL-7 enhanced pre-B cell expansion and inhibited maturation into IgM(+) B cells. The B cell precursor subsets replicating in vitro were highly similar to the bone marrow B cell precursors cycling in vivo. The autonomous proliferation of B cell precursor subsets in vitro and their long-term persistence implies that proliferation during pro-B and pre-B cell stages plays an important role in the homeostasis of the peripheral B cell compartment. Our in vitro culture can be used to study defects in B cell development or in reconstitution of the B cell pool after depletion and chemotherapy. PMID:24379121

Kraus, Helene; Kaiser, Sandra; Aumann, Konrad; Bönelt, Peter; Salzer, Ulrich; Vestweber, Dietmar; Erlacher, Miriam; Kunze, Mirjam; Burger, Meike; Pieper, Kathrin; Sic, Heiko; Rolink, Antonius; Eibel, Hermann; Rizzi, Marta

2014-02-01

284

HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia  

PubMed Central

Deregulated expression of Hox genes such as HoxA9 is associated with development of myeloproliferative disorders and leukemia and indicates a poor prognosis. To investigate the molecular mechanisms by which HoxA9 promotes immortalization of hematopoietic cells, we generated growth factor dependent myeloid cells in which HoxA9 expression is regulated by administration of 4-hydroxy-tamoxifen. Maintenance of HoxA9 overexpression is required for continued cell survival and proliferation, even in the presence of growth factors. We show for the first time that maintenance of Bcl-2 expression is critical for HoxA9-dependent immortalization and influences the latency of HoxA9-dependent leukemia. Hematopoietic cells lacking Bcl-2 were not immortalized by HoxA9 in vitro. Furthermore, deletion of Bcl-2 delayed the onset and reduced the severity of HoxA9/Meis1 and MLL-AF9 leukemias. This is the first description of a molecular link between HoxA9 and the regulation of Bcl-2 family members in acute myeloid leukemia. PMID:24177192

Brumatti, Gabriela; Salmanidis, Marika; Kok, Chung H; Bilardi, Rebecca A; Sandow, Jarrod J; Silke, Natasha; Mason, Kylie; Visser, Jolanda; Jabbour, Anissa M; Glaser, Stefan P; Okamoto, Toru; Bouillet, Philippe; D'Andrea, Richard J; Ekert, Paul G

2013-01-01

285

Embryonic Regulation of the Mouse Hematopoietic Niche  

PubMed Central

Hematopoietic stem cells (HSCs) can differentiate into several types of hematopoietic cells (HCs) (such as erythrocytes, megakaryocytes, lymphocytes, neutrophils, or macrophages) and also undergo self-renewal to sustain hematopoiesis throughout an organism's lifetime. HSCs are currently used clinically as transplantation therapy in regenerative medicine and are typically obtained from healthy donors or cord blood. However, problems remain in HSC transplantation, such as shortage of cells, donor risks, rejection, and graft-versus-host disease (GVHD). Thus, increased understanding of HSC regulation should enable us to improve HSC therapy and develop novel regenerative medicine techniques. HSC regulation is governed by two types of activity: intrinsic regulation, programmed primarily by cell autonomous gene expression, and extrinsic factors, which originate from so-called “niche cells” surrounding HSCs. Here, we focus on the latter and discuss HSC regulation with special emphasis on the role played by niche cells. PMID:22125435

Sugiyama, Daisuke; Inoue-Yokoo, Tomoko; Fraser, Stuart T.; Kulkeaw, Kasem; Mizuochi, Chiyo; Horio, Yuka

2011-01-01

286

Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration.  

PubMed

Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury. PMID:23644514

Lucas, Daniel; Scheiermann, Christoph; Chow, Andrew; Kunisaki, Yuya; Bruns, Ingmar; Barrick, Colleen; Tessarollo, Lino; Frenette, Paul S

2013-06-01

287

Blastic Plasmacytoid Dendritic Cell Leukemia Successfully Treated by Autologous Hematopoietic Stem Cell Transplantation to a Remission of 48-Month Duration  

PubMed Central

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare subtype of AML characterized by the clonal proliferation of precursors of plasmacytoid dendritic cells. It presents with an aggressive behavior. The clinical findings include cytopenia, particularly thrombocytopenia. Although it responds well to chemotherapy initially, the relapse is a rule and prognosis is very poor. There is limited data published in the literature, making it very problematic to define the biological and clinical features, hence, the appropriate therapeutic approach. There are various treatment methods such as multiagent chemotherapy based on ALL or AML and/or hematopoietic stem cell transplantation. However, none of them is approved as a standard therapy. From this point of view, we herein report a 20-year-old case at onset of a leukemic form of BPDCN who survived 48 months after autologous hematopoietic stem cell transplantation. PMID:24396617

Akay, Olga Meltem; Uskudar Teke, Hava; And?c, Neslihan; Gunduz, Eren; Gulbas, Zafer

2013-01-01

288

Complex Variant of Philadelphia Translocation Involving Chromosomes 9, 12, and 22 in a Case with Chronic Myeloid Leukaemia  

PubMed Central

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder included in the broader diagnostic category of myeloproliferative neoplasms, associated with fusion by BCR gene at chromosome 22q11 to ABL1 gene at chromosome 9q34 with the formation of the Philadelphia (Ph) chromosome. In 2–10% of CML cases, the fusion gene arises in connection with a variant translocation, involving chromosomes 9, 22, and one or more different chromosomes; consequently, the Ph chromosome could be masked within a complex chromosome rearrangement. In cases with variant Ph translocation a deletion on der(9) may be more frequently observed than in cases with the classical one. Herein we describe a novel case of CML with complex variant Ph translocation involving chromosomes 9, 12, and 22. We present the hematologic response and cytogenetic response after Imatinib treatment. We also speculated the mechanism which had originated the chromosome rearrangement. PMID:25045550

Malvestiti, F.; Agrati, C.; Chinetti, S.; Di Meco, A.; Cirrincione, S.; Oggionni, M.; Grimi, B.; Maggi, F.; Simoni, G.; Grati, F. R.

2014-01-01

289

MicroRNAs in hematopoietic development  

PubMed Central

Background MicroRNAs (miRNAs) are short non-coding RNAs involved in the posttranscriptional regulation of a wide range of biological processes. By binding to complementary sequences on target messenger RNAs, they trigger translational repression and degradation of the target, eventually resulting in reduced protein output. MiRNA-dependent regulation of protein translation is a very widespread and evolutionarily conserved mechanism of posttranscriptional control of gene expression. Accordingly, a high proportion of mammalian genes are likely to be regulated by miRNAs. In the hematopoietic system, both transcriptional and posttranscriptional regulation of gene expression ensure proper differentiation and function of stem cells, committed progenitors as well as mature cells. Results In recent years, miRNA expression profiling of various cell types in the hematopoietic system, as well as gene-targeting approaches to assess the function of individual miRNAs, revealed the importance of this type of regulation in the development of both innate and acquired immunity. Conclusions We discuss the general role of miRNA biogenesis in the development of hematopoietic cells, as well as specific functions of individual miRNAs in stem cells as well as in mature immune cells. PMID:24678908

2014-01-01

290

Emergent Complications in the Pediatric Hematopoietic Stem Cell Transplant Patient  

PubMed Central

Hematopoietic cell transplantation is the only potentially curative option for a variety of pediatric malignant and nonmalignant disorders. Despite advances in transplantation biology and immunology as well as in posttransplant management that have contributed to improved survival and decreased transplant-related mortality, hematopoietic cell transplantation does not come without significant risk of complications. When patients who have undergone hematopoietic cell transplantation present to the emergency department, it is important to consider a variety of therapy-related complications to optimize management and outcome. In this article, we use clinical cases to highlight some of the more common emergent complications after hematopoietic cell transplantation.

Munchel, Ashley; Chen, Allen; Symons, Heather

2014-01-01

291

Cytotoxic activity of an anti-transferrin receptor immunotoxin on normal and leukemic human hematopoietic progenitors.  

PubMed

The process of cellular iron uptake involves a specific receptor for the plasma carrier transferrin and a pathway of receptor-mediated endocytosis. Transferrin receptor expression is closely related to the rate of cell proliferation, and conjugates between anti-transferrin receptor monoclonal antibodies and toxins have been shown to have potent cytotoxic activity. We have constructed an anti-transferrin receptor immunotoxin by conjugating the anti-transferrin receptor monoclonal antibody B3/25 to a ribosome-inactivating protein, the saporin-6 (SO6), which is derived from the seeds of the plant Saponaria officinalis. The immunotoxin B3/25-SO6 was tested for in vitro cytotoxic activity against the human cell lines K-562 and HL-60 and against normal human bone marrow hematopoietic progenitors and acute myeloid leukemia clonogenic cells. The immunotoxin proved to be an effective inhibitor of K-562 and HL-60 clonogenic cell growth, in vitro colony formation being completely inhibited at immunotoxin concentrations ranging from 10(-7) to 10(-10) M. B3/25-SO6 markedly reduced the recloning efficiency of HL-60 clonogenic cells at 10(-12) M. Exposure of HL-60 cells in suspension culture to 10(-9) M B3/25-SO6 for 48-72 h completely abolished their clonogenic potential. The immunotoxin was also found to be cytotoxic against normal human bone marrow progenitor cells (burst-forming unit-erythroid and colony-forming unit-granulocyte, macrophage) in a dose-dependent manner. However, exposure of normal colony-forming unit-granulocyte, macrophage in suspension culture to 10(-9) M B3/25-SO6 for 72 h resulted in only 50% suppression of their clonogenic potential. Finally, B3/25-SO6 was found to be a potent inhibitor of in vitro growth of acute myeloid leukemia clonogenic cells. The cytotoxic effects of B3/25-SO6 were shown to be specific, since both saporin alone and irrelevant immunotoxins did not have any effect in the cellular systems examined. We conclude that the immunotoxin B3/25-SO6 has dose-related cytotoxic effects on both normal and leukemic human hematopoietic progenitors. Since there are substantial differences between normal and leukemic progenitors with respect to the proportion of cycling cells and the expression of transferrin receptors, B3/25-SO6 or similar immunotoxins may have clinical application in bone marrow-purging procedures. PMID:1985771

Cazzola, M; Bergamaschi, G; Dezza, L; D'Uva, R; Ponchio, L; Rosti, V; Ascari, E

1991-01-15

292

Acute myeloid leukemia among petrol station attendants  

Microsoft Academic Search

The risk of acute myeloid leukemia (AML) within different occupations was studied, using occupational information obtained from the Swedish 1970 census. Follow-up in the Swedish Cancer Register was carried out from 1971 to 1984. Among male petrol station attendants, 10 cases were observed versus 2.8 expected (observed\\/expected = 3.6, 95% confidence interval 1.7--6.6). For several decades, Swedish petrol has contained

R. Jakobsson; T. Bellander; I. Lundberg; A. Ahlbom

2009-01-01

293

Acute Myeloid Leukemia among Petrol Station Attendants  

Microsoft Academic Search

The risk of acute myeloid leukemia (AML) within different occupations was studied, using occupational information obtained from the Swedish 1970 census. Follow-up in the Swedish Cancer Register was carried out from 1971 to 1984. Among male petrol station attendants, 10 cases were observed versus 2.8 expected (observed\\/expected = 3.6, 95% confidence interval 1.7–6.6). For several decades, Swedish petrol has contained

Robert Jakobsson; Anders Ahlbom; Tom Bellander; Ingvar Lundberg

1993-01-01

294

Targeting Chronic Myeloid Leukemia Stem Cells  

Microsoft Academic Search

Chronic myeloid leukemia (CML) arises as a consequence of a chromosomal translocation giving rise to the Philadelphia chromosome\\u000a and Bcr-Abl oncogene. CML is a clonal disease of stem cell origin and an excellent example of a malignancy in which tumor-initiating\\u000a cells may hold the key to disease eradication. The known molecular basis of CML has enabled the development of Abl-specific

G. Vignir Helgason; Graham A. R. Young; Tessa L. Holyoake

2010-01-01

295

Targeted therapy of chronic myeloid leukemia  

Microsoft Academic Search

Inhibition of BCR-ABL with kinase inhibitors has become a well-accepted strategy for targeted therapy of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) and has been shown to be highly effective in controlling the disease. However, BCR-ABL kinase inhibitors do not efficiently kill leukemic stem cells (LSCs), indicating that this therapeutic strategy does not lead to a cure of CML. Development of

Con Sullivan; Cong Peng; Yaoyu Chen; Dongguang Li; Shaoguang Li

2010-01-01

296

Chronic Myeloid Leukemia: Biology of Advanced Phase  

Microsoft Academic Search

Chronic myeloid leukemia (CML) usually starts with an indolent chronic phase characterized by the overproduction of mature\\u000a granulocytes, but inevitably evolves to a terminal blastic phase in which excessive numbers of undifferentiated blasts are\\u000a produced. The molecular mechanisms underlying disease progression are still very poorly understood. Whereas the BCR-ABL oncogene has a central role in disease etiology, it is not

Junia V. Melo; David J. Barnes

297

Isolated myeloid sarcoma presenting in all four eyelids.  

PubMed

Myeloid sarcoma is an unusual manifestation of acute leukemia. These leukemic tumors have been described in multiple organ systems. Leukemia is almost always present, but may be undiagnosed when the myeloid sarcoma comes to medical attention. We present a clinicopathologic report of a previously healthy young woman with conjunctival myeloid sarcomas of all 4 eyelids without evidence of an underlying hematologic disorder over 15 months' follow-up, despite refusal of consolidation chemotherapy. Isolated, multifocal myeloid sarcoma of the periorbital region is a very rare manifestation of acute leukemia. PMID:17667120

Thomas, Scott A; Durairaj, Vikram D

2007-01-01

298

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

ClinicalTrials.gov

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

2014-08-18

299

In vitro inhibitory effects of imatinib mesylate on stromal cells and hematopoietic progenitors from bone marrow  

PubMed Central

Imatinib mesylate (IM) is used to treat chronic myeloid leukemia (CML) because it selectively inhibits tyrosine kinase, which is a hallmark of CML oncogenesis. Recent studies have shown that IM inhibits the growth of several non-malignant hematopoietic and fibroblast cells from bone marrow (BM). The aim of the present study was to evaluate the effects of IM on stromal and hematopoietic progenitor cells, specifically in the colony-forming units of granulocyte/macrophage (CFU-GM), using BM cultures from 108 1.5- to 2-month-old healthy Swiss mice. The results showed that low concentrations of IM (1.25?µM) reduced the growth of CFU-GM in clonogenic assays. In culture assays with stromal cells, fibroblast proliferation and ?-SMA expression by immunocytochemistry analysis were also reduced in a concentration-dependent manner, with a survival rate of approximately 50% with a dose of 2.5?µM. Cell viability and morphology were analyzed using MTT and staining with acrydine orange/ethidium bromide. Most cells were found to be viable after treatment with 5?µM IM, although there was gradual growth inhibition of fibroblastic cells while the number of round cells (macrophage-like cells) increased. At higher concentrations (15?µM), the majority of cells were apoptotic and cell growth ceased completely. Oil red staining revealed the presence of adipocytes only in untreated cells (control). Cell cycle analysis of stromal cells by flow cytometry showed a blockade at the G0/G1 phases in groups treated with 5-15?µM. These results suggest that IM differentially inhibits the survival of different types of BM cells since toxic effects were achieved. PMID:23011404

Soares, P.B.; Jeremias, T.S.; Alvarez-Silva, M.; Licinio, M.A.; Santos-Silva, M.C.; Vituri, C.L.

2012-01-01

300

Role of membrane-type 1 matrix metalloproteinase in hematopoietic stem/progenitor cell trafficking.  

E-print Network

??Hematopoietic stem/progenitor cells (HSPC) are routinely used for transplantation to restore hematopoietic function; however, the molecular mechanisms governing their trafficking are not completely understood. Soluble… (more)

Shirvaikar, Neeta Chandan

2010-01-01

301

OXIDANT-PRECURSOR RELATIONSHIPS  

EPA Science Inventory

New methods of ambient air analysis were used to define more clearly the relationships between oxidants and their precursors. Non-methane hydrocarbons, NOx, O2, and oxidants were measured at the same time and location (Riverside, California). The ambient air data presented in thi...

302

Murine Models of Human Acute Myeloid Leukemia  

Microsoft Academic Search

\\u000a Primary human AML cells can be isolated and studied in vitro, but many experimental questions can only be addressed using\\u000a in vivo models. In particular, tractable animal models are needed to test novel therapies. The genetic complexity of human\\u000a AML poses significant challenges for the generation of reliable animal models.\\u000a \\u000a \\u000a The hematopoietic systems of both zebrafish (Danio rerio) and Drosophila

Julie M. Fortier; Timothy A. Graubert

303

Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers.  

PubMed

Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival. PMID:24850867

Xu, Lan; Gu, Zhao-Hui; Li, Yang; Zhang, Jin-Li; Chang, Chun-Kang; Pan, Chun-Ming; Shi, Jing-Yi; Shen, Yang; Chen, Bing; Wang, Yue-Ying; Jiang, Lu; Lu, Jing; Xu, Xin; Tan, Jue-Ling; Chen, Yu; Wang, Sheng-Yue; Li, Xiao; Chen, Zhu; Chen, Sai-Juan

2014-06-10

304

HACS1 encodes a novel SH3-SAM adaptor protein differentially expressed in normal and malignant hematopoietic cells.  

PubMed

SH3 and SAM domains are protein interaction motifs that are predominantly seen in signaling molecules, adaptors, and scaffold proteins. We have identified a novel family of putative adaptor genes that includes HACS1. HACS1 encodes a 441 amino acid protein that is differentially expressed in hematopoietic cells and has restricted expression in human tissues. Its SH3 domain is most similar to the same motif in Crk and its SAM domain shares homology with a family of uncharacterized putative scaffold and adaptor proteins. HACS1 maps to human chromosome 21q11.2 in a region that is frequently disrupted by translocation events in hematopoietic malignancies. Polyclonal antibodies against HACS1 recognized a 49.5 kDa protein whose mRNA is expressed in human immune tissues, bone marrow, heart, lung, placenta and brain. Cell lines and primary cells from acute myeloid leukemias and multiple myeloma patients express HACS1. Immunostaining and cellular fractionation studies localized the HACS1 protein predominantly to the cytoplasm. PMID:11536050

Claudio, J O; Zhu, Y X; Benn, S J; Shukla, A H; McGlade, C J; Falcioni, N; Stewart, A K

2001-08-30

305

LSK derived LSK- cells have a high apoptotic rate related to survival regulation of hematopoietic and leukemic stem cells.  

PubMed

A balanced pool of hematopoietic stem cells (HSCs) in bone marrow is tightly regulated, and this regulation is disturbed in hematopoietic malignancies such as chronic myeloid leukemia (CML). The underlying mechanisms are largely unknown. Here we show that the Lin(-)Sca-1(+)c-Kit(-) (LSK(-)) cell population derived from HSC-containing Lin(-)Sca-1(+)c-Kit(+) (LSK) cells has significantly higher numbers of apoptotic cells. Depletion of LSK cells by radiation or the cytotoxic chemical 5-fluorouracil results in an expansion of the LSK(-) population. In contrast, the LSK(-) population is reduced in CML mice, and depletion of leukemia stem cells (LSCs; BCR-ABL-expressing HSCs) by deleting Alox5 or by inhibiting heat shock protein 90 causes an increase in this LSK(-) population. The transition of LSK to LSK(-) cells is controlled by the Icsbp gene and its downstream gene Lyn, and regulation of this cellular transition is critical for the survival of normal LSK cells and LSCs. These results indicate a potential function of the LSK(-) cells in the regulation of LSK cells and LSCs. PMID:22675576

Peng, Cong; Chen, Yaoyu; Shan, Yi; Zhang, Haojian; Guo, Zhiru; Li, Dongguang; Li, Shaoguang

2012-01-01

306

An intragenic long noncoding RNA interacts epigenetically with the RUNX1 promoter and enhancer chromatin DNA in hematopoietic malignancies.  

PubMed

RUNX1, a master regulator of hematopoiesis, is the most commonly perturbed target of chromosomal abnormalities in hematopoietic malignancies. The t(8;21) translocation is found in 30-40% of cases of acute myeloid leukemia (AML). Recent whole-exome sequencing also reveals mutations and deletions of RUNX1 in some solid tumors. We describe a RUNX1-intragenic long noncoding RNA RUNXOR that is transcribed as unspliced transcript from an upstream overlapping promoter. RUNXOR was upregulated in AML samples and in response to Ara-C treatment in vitro. RUNXOR utilizes its 3'-terminal fragment to directly interact with the RUNX1 promoter and enhancers and participates in the orchestration of an intrachromosomal loop. The 3' region of RUNXOR also participates in long-range interchromosomal interactions with chromatin regions that are involved in multiple RUNX1 translocations. These data suggest that RUNXOR noncoding RNA may function as a previously unidentified candidate component that is involved in chromosomal translocation in hematopoietic malignancies. PMID:24752773

Wang, Hong; Li, Wei; Guo, Rui; Sun, Jingnan; Cui, Jiuwei; Wang, Guanjun; Hoffman, Andrew R; Hu, Ji-Fan

2014-12-15

307

Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia  

PubMed Central

Background Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. Methods We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca-1+ cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors. Results We identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML. Conclusions Our study identified early aberrantly methylated genes as potential contributors to onset and progression of AML. PMID:24944583

2014-01-01

308

Fak Depletion in Both Hematopoietic and Non-hematopoietic Niche cells Leads to Hematopoietic Stem Cell Expansion  

PubMed Central

Hematopoietic stem cells (HSCs) reside in complex bone marrow (BM) microenvironments where niche-induced signals regulate hematopoiesis. Focal adhesion kinase (Fak) is a non-receptor protein tyrosine kinase, which plays an essential role in many cell types, where its activation controls adhesion, motility and survival. Fak expression is relatively increased in HSCs compared to progenitors and mature blood cells. Therefore we explored its role in HSC homeostasis. We have used the Mx1-Cre inducible conditional knockout mouse model to investigate the effects of Fak deletion in bone marrow compartments. Results. The total number as well as the fraction of cycling Lin-Sca-1+c-kit+ (LSK) cells is increased in Fak?/? mice, compared to controls, while hematopoietic progenitors and mature blood cells are unaffected. BM cells from Fak?/? mice exhibit enhanced, long-term (i.e. 20 week duration) engraftment in competitive transplantation assays. Intrinsic Fak function was assessed in serial transplantation assays, which showed that HSCs (Lin-Sca-1+c-kit +CD34-Flk-2-cells) sorted from Fak?/? mice have similar self-renewal and engraftment ability on a per cell basis as wild type HSCs. When Fak deletion is induced following engraftment of Fakfl/flMx1-Cre+ BM cells into wild type recipient mice, the number of LSKs is unchanged. In conclusion, Fak inactivation does not intrinsically regulate HSC behavior and is not essential for steady-state hematopoiesis. However, widespread Fak inactivation in the hematopoietic system induces an increased and activated HSC pool size, potentially as a result of altered reciprocal interactions between HSCs and their microenvironment. PMID:22155722

Lu, Jiayun; Sun, Yan; Nombela-Arrieta, Cesar; Du, Karrie P.; Park, Shin-Young; Chai, Li; Walkley, Carl; Luo, Hongbo R.; Silberstein, Leslie E.

2012-01-01

309

Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity.  

PubMed

Potent graft-versus-leukemia (GVL) effects can be mediated by donor-derived T cells recognizing minor histocompatibility antigens (mHags) in patients treated with donor lymphocyte infusion (DLI) for relapsed hematologic malignancies after HLA-matched allogeneic stem cell transplantation (alloSCT). Donor-derived T cells, however, may not only induce GVL, but also mediate detrimental graft-versus-host disease (GVHD). Because HLA-class II is under noninflammatory conditions predominantly expressed on hematopoietic cells, CD4+ T cells administered late after alloSCT may selectively confer GVL without GVHD. Although a broad range of different HLA-class I-restricted mHags have been identified, the first 2 autosomal HLA-class II-restricted mHags have only recently been characterized. By screening a recombinant bacteria cDNA expression library, we identified 4 new HLA-class II-restricted mHags recognized by CD4+ T cells induced in a patient with relapsed chronic myeloid leukemia who achieved long-term complete remission and experienced only mild GVHD of the skin after DLI. All CD4+ T cells were capable of recognizing the mHags presented by HLA-DR surface molecules on primary hematopoietic cells, but not on skin-derived (cytokine-treated) fibroblasts. The selective recognition of hematopoietic cells as well as the balanced population frequencies and common HLA-DR restriction elements make the novel mHags possible targets for development of immunotherapeutic strategies. PMID:19706888

Stumpf, Anita N; van der Meijden, Edith D; van Bergen, Cornelis A M; Willemze, Roel; Falkenburg, J H Frederik; Griffioen, Marieke

2009-10-22

310

Slug deficiency enhances self-renewal of hematopoietic stem cells during hematopoietic regeneration  

PubMed Central

Both extrinsic and intrinsic mechanisms tightly govern hematopoietic stem cell (HSC) decisions of self-renewal and differentiation. However, transcription factors that can selectively regulate HSC self-renewal division after stress remain to be identified. Slug is an evolutionarily conserved zinc-finger transcription factor that is highly expressed in primitive hematopoietic cells and is critical for the radioprotection of these key cells. We studied the effect of Slug in the regulation of HSCs in Slug-deficient mice under normal and stress conditions using serial functional assays. Here, we show that Slug deficiency does not disturb hematopoiesis or alter HSC homeostasis and differentiation in bone marrow but increases the numbers of primitive hematopoietic cells in the extramedullary spleen site. Deletion of Slug enhances HSC repopulating potential but not its homing and differentiation ability. Furthermore, Slug deficiency increases HSC proliferation and repopulating potential in vivo after myelosuppression and accelerates HSC expansion during in vitro culture. Therefore, we propose that Slug is essential for controlling the transition of HSCs from relative quiescence under steady-state condition to rapid proliferation under stress conditions. Our data suggest that inhibition of Slug in HSCs may present a novel strategy for accelerating hematopoietic recovery, thus providing therapeutic benefits for patients after clinical myelosuppressive treatment. PMID:20032500

Sun, Yan; Shao, Lijian; Bai, Hao; Wang, Zack Z.

2010-01-01

311

Slug deficiency enhances self-renewal of hematopoietic stem cells during hematopoietic regeneration.  

PubMed

Both extrinsic and intrinsic mechanisms tightly govern hematopoietic stem cell (HSC) decisions of self-renewal and differentiation. However, transcription factors that can selectively regulate HSC self-renewal division after stress remain to be identified. Slug is an evolutionarily conserved zinc-finger transcription factor that is highly expressed in primitive hematopoietic cells and is critical for the radioprotection of these key cells. We studied the effect of Slug in the regulation of HSCs in Slug-deficient mice under normal and stress conditions using serial functional assays. Here, we show that Slug deficiency does not disturb hematopoiesis or alter HSC homeostasis and differentiation in bone marrow but increases the numbers of primitive hematopoietic cells in the extramedullary spleen site. Deletion of Slug enhances HSC repopulating potential but not its homing and differentiation ability. Furthermore, Slug deficiency increases HSC proliferation and repopulating potential in vivo after myelosuppression and accelerates HSC expansion during in vitro culture. Therefore, we propose that Slug is essential for controlling the transition of HSCs from relative quiescence under steady-state condition to rapid proliferation under stress conditions. Our data suggest that inhibition of Slug in HSCs may present a novel strategy for accelerating hematopoietic recovery, thus providing therapeutic benefits for patients after clinical myelosuppressive treatment. PMID:20032500

Sun, Yan; Shao, Lijian; Bai, Hao; Wang, Zack Z; Wu, Wen-Shu

2010-03-01

312

The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia.  

PubMed

Abnormal proliferation, apoptosis repression and differentiation blockage of hematopoietic stem/progenitor cells have been characterized to be the main reasons leading to acute myeloid leukemia (AML). Previous studies showed that miR-29a and miR-29b could function as tumor suppressors in leukemogenesis. However, a comprehensive investigation of the function and mechanism of miR-29 family in AML development and their potentiality in AML therapy still need to be elucidated. Herein, we reported that the family members, miR-29a, -29b and -29c, were commonly downregulated in peripheral blood mononuclear cells and bone marrow (BM) CD34+ cells derived from AML patients as compared with the healthy donors. Overexpression of each miR-29 member in THP1 and NB4 cells markedly inhibited cell proliferation and promoted cell apoptosis. AKT2 and CCND2 mRNAs were demonstrated to be targets of the miR-29 members, and the role of miR-29 family was attributed to the decrease of Akt2 and CCND2, two key signaling molecules. Significantly increased Akt2, CCND2 and c-Myc levels in the AML cases were detected, which were correlated with the decreased miR-29 expression in AML blasts. Furthermore, a feed-back loop comprising of c-Myc, miR-29 family and Akt2 were found in myeloid leukemogenesis. Reintroduction of each miR-29 member partially corrected abnormal cell proliferation and apoptosis repression and myeloid differentiation arrest in AML BM blasts. An intravenous injection of miR-29a, -29b and -29c in the AML model mice relieved leukemic symptoms significantly. Taken together, our finding revealed a pivotal role of miR-29 family in AML development and rescue of miR-29 family expression in AML patients could provide a new therapeutic strategy. PMID:24076586

Gong, J-N; Yu, J; Lin, H-S; Zhang, X-H; Yin, X-L; Xiao, Z; Wang, F; Wang, X-S; Su, R; Shen, C; Zhao, H-L; Ma, Y-N; Zhang, J-W

2014-01-01

313

Two distinct types of murine blast colony-forming cells are multipotential hematopoietic precursors  

PubMed Central

Two types of blast colonies can be stimulated to develop in semisolid agar cultures of murine bone marrow cells. Typically, these are either multicentric colonies stimulated by stem cell factor (SCF) plus interleukin-6 (IL-6) or dispersed colonies stimulated by Flt3 ligand (FL) plus IL-6. Both types of blast colony-forming cells (BL-CFCs) can generate large numbers of lineage-committed granulocyte-macrophage progenitor cells and exhibit some capacity for self-generation and the formation of eosinophil and megakaryocyte progenitor cells. However, the two populations of BL-CFCs are largely distinct and partially separable by fluorescence-activated cell sorting and are distinguished by differing capacity to form granulocyte-committed progeny. Both types of BL-CFCs can generate dendritic cells and small numbers of lymphocytes but the FL-responsive BL-CFCs have a greater capacity to form both B and T lymphocytes. Both types of blast colonies offer remarkable opportunities to analyze multilineage commitment at a clonal level in vitro. PMID:19011094

Metcalf, D.; Greig, K. T.; de Graaf, C. A.; Loughran, S. J.; Alexander, W. S.; Kauppi, M.; Hyland, C. D.; Di Rago, L.; Mifsud, S.

2008-01-01

314

Repair of 06-Alkylguanine during DNA Synthesis in Murine Bone Marrow Hematopoietic Precursors1  

Microsoft Academic Search

O'-AIkylguanine, a DNA adduci formed by nitrosoureas, becomes the site of a point mutation during DNA synthesis by preferentially base mispairing with thymine rather than correctly base pairing with cytosine. To repair this adduct, cells contain a limited amount of 06-alkylguanine- DNA alkyltransferase (alkyltransferase), a protein which removes the alkyl group in a stoichiometric reaction. To prevent mutations, repair must

Stanton L. Gerson; Joan E. Trey; Kathleen Miller; Evan Benjamin

315

Retrovirus-mediated gene transfer into human hematopoietic stem cells.  

PubMed

Human hematopoietic stem cells genetically modified by retroviral-mediated gene transfer may offer new treatment options for patients with genetic disease. The potential of gene-modified hematopoietic stem cells as vehicles for gene delivery was first illustrated by the demonstration that hematopoietic systems of lethally irradiated mice can be reconstituted with retroviral vector transduced syngeneic bone marrow, and that these cells can in turn provide genetically marked progeny which persist in blood and marrow over extended time periods. In contrast, hematopoietic stem cells from large animals prove difficult to transduce with retroviral vectors and are consequently less likely to function as vehicles for long-term gene therapy. Indeed, clinically relevant levels of gene transfer into large animal and human hematopoietic stem cells has not been widely achieved. The need for improved retroviral vector systems and for understanding the biology of hematopoietic stem cell gene transfer continue to fuel intense research activity. Preliminary results from human stem cell gene marking and gene therapy trials currently underway are encouraging. This contribution reviews the underlying concepts relevant to retroviral-mediated gene transfer into hematopoietic stem cells. We survey the evolution of approaches for gene transfer into hematopoietic stem cells, from murine and large animal models to the first human clinical trials. Finally, we discuss new strategies which are currently being pursued. PMID:9535551

Chu, P; Lutzko, C; Stewart, A K; Dubé, I D

1998-03-01

316

Hematopoietic stem cell gene therapy: progress toward therapeutic targets  

Microsoft Academic Search

The concept of hematopoietic stem cell gene therapy is as exciting as that of stem cell transplantation itself. The past 20 years of research have led to improved techniques for transferring and expressing genes in hematopoietic stem cells and preclinical models now routinely indicate the ease with which new genes can be expressed in repopulating stem cells of multiple species.

J L Vollweiler; S P Zielske; J S Reese; S L Gerson

2003-01-01

317

Family History of Hematopoietic Malignancy and Risk of Lymphoma  

Microsoft Academic Search

Background: A family history of hematopoietic malignancy is associated with an increased risk of non-Hodgkin lym- phoma (NHL) and Hodgkin lymphoma (HL), although the magnitude of the relative risk is unclear. We estimated the association between familial hematopoietic cancer and risk of lymphoma using validated, registry-based family data, and we also investigated whether associations between some environmental exposures and risk

Ellen T. Chang; Karin Ekström Smedby; Henrik Hjalgrim; Anna Porwit-MacDonald; Göran Roos; Bengt Glimelius; Hans-Olov Adami

2005-01-01

318

Regeneration-associated WNT Signaling Is Activated in Long-term Reconstituting AC133bright Acute Myeloid Leukemia Cells12  

PubMed Central

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/?-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133+ cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133bright AML cells and shows a diffuse expression and release of WNT10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133+ AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated ?-catenin in vivo. We tested the LSC functional activity in AC133+ cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2-/-?c-/- mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133bright LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration. PMID:23308055

Beghini, Alessandro; Corlazzoli, Francesca; Del Giacco, Luca; Re, Matteo; Lazzaroni, Francesca; Brioschi, Matteo; Valentini, Giorgio; Ferrazzi, Fulvia; Ghilardi, Anna; Righi, Marco; Turrini, Mauro; Mignardi, Marco; Cesana, Clara; Bronte, Vincenzo; Nilsson, Mats; Morra, Enrica; Cairoli, Roberto

2012-01-01

319

Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.  

PubMed

Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells. PMID:24747972

Sato, T; Goyama, S; Kataoka, K; Nasu, R; Tsuruta-Kishino, T; Kagoya, Y; Nukina, A; Kumagai, K; Kubota, N; Nakagawa, M; Arai, S; Yoshimi, A; Honda, H; Kadowaki, T; Kurokawa, M

2014-10-16

320

Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia  

PubMed Central

Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR–ABL and by crossing BCR–ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR–ABL and NUP98–HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR–ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38–CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells. PMID:24747972

Sato, T; Goyama, S; Kataoka, K; Nasu, R; Tsuruta-Kishino, T; Kagoya, Y; Nukina, A; Kumagai, K; Kubota, N; Nakagawa, M; Arai, S; Yoshimi, A; Honda, H; Kadowaki, T; Kurokawa, M

2014-01-01

321

Myeloid hyperplasia in the SENCAR mouse: differentiation from granulocytic leukemia  

SciTech Connect

The term myeloid hyperplasia has been used interchangeably with many other terms to describe an increased production of granulocytes, megakaryocytes, and erythrocytes in the spleen and other organs in the mouse. This process is occasionally misdiagnosed as granulocytic leukemia. This paper reviews some of the terms used interchangeably with myeloid hyperplasia and describes criteria that can be used to differentiate myeloid hyperplasia from granulocytic leukemia. Additionally, the results of a study in which myeloid hyperplasia was induced following the formation of skin tumors in SENCAR mice is discussed. In this study, positive correlations were found between skin lesions, the spleen weight, and histologic appearance of the spleen. The liver rarely showed microscopic changes of myeloid hyperplasia unless the spleen weighed at least 1.0% of the body weight.

Long, R.E.; Knutsen, G.; Robinson, M.

1986-09-01

322

Stromal cell-derived factor-1 and hematopoietic cell homing in an adult zebrafish model of hematopoietic cell transplantation  

PubMed Central

In mammals, stromal cell–derived factor-1 (SDF-1) promotes hematopoietic cell mobilization and migration. Although the zebrafish, Danio rerio, is an emerging model for studying hematopoietic cell transplantation (HCT), the role of SDF-1 in the adult zebrafish has yet to be determined. We sought to characterize sdf-1 expression and function in the adult zebrafish in the context of HCT. In situ hybridization of adult zebrafish organs shows sdf-1 expression in kidney tubules, gills, and skin. Radiation up-regulates sdf-1 expression in kidney to nearly 4-fold after 40 Gy. Assays indicate that zebrafish hematopoietic cells migrate toward sdf-1, with a migration ratio approaching 1.5 in vitro. A sdf-1a:DsRed2 transgenic zebrafish allows in vivo detection of sdf-1a expression in the adult zebrafish. Matings with transgenic reporters localized sdf-1a expression to the putative hematopoietic cell niche in proximal and distal renal tubules and collecting ducts. Importantly, transplant of hematopoietic cells into myelosuppressed recipients indicated migration of hematopoietic cells to sdf-1a–expressing sites in the kidney and skin. We conclude that sdf-1 expression and function in the adult zebrafish have important similarities to mammals, and this sdf-1 transgenic vertebrate will be useful in characterizing the hematopoietic cell niche and its interactions with hematopoietic cells. PMID:21622651

Glass, Tiffany J.; Patrinostro, Xiaobai; Tolar, Jakub; Bowman, Teresa V.; Zon, Leonard I.; Blazar, Bruce R.

2011-01-01

323

The EM Earthquake Precursor  

NASA Astrophysics Data System (ADS)

Many attempts have been made to determine a sound forecasting method regarding earthquakes and warn the public in turn. Presently, the animal kingdom leads the precursor list alluding to a transmission related source. By applying the animal-based model to an electromagnetic (EM) wave model, various hypotheses were formed, but the most interesting one required the use of a magnetometer with a differing design and geometry. To date, numerous, high-end magnetometers have been in use in close proximity to fault zones for potential earthquake forecasting; however, something is still amiss. The problem still resides with what exactly is forecastable and the investigating direction of EM. After the 1989 Loma Prieta Earthquake, American earthquake investigators predetermined magnetometer use and a minimum earthquake magnitude necessary for EM detection. This action was set in motion, due to the extensive damage incurred and public outrage concerning earthquake forecasting; however, the magnetometers employed, grounded or buried, are completely subject to static and electric fields and have yet to correlate to an identifiable precursor. Secondly, there is neither a networked array for finding any epicentral locations, nor have there been any attempts to find even one. This methodology needs dismissal, because it is overly complicated, subject to continuous change, and provides no response time. As for the minimum magnitude threshold, which was set at M5, this is simply higher than what modern technological advances have gained. Detection can now be achieved at approximately M1, which greatly improves forecasting chances. A propagating precursor has now been detected in both the field and laboratory. Field antenna testing conducted outside the NE Texas town of Timpson in February, 2013, detected three strong EM sources along with numerous weaker signals. The antenna had mobility, and observations were noted for recurrence, duration, and frequency response. Next, two directional techniques were employed, resulting in three mapped, potential epicenters. The remaining, weaker signals presented similar directionality results to more epicentral locations. In addition, the directional results of the Timpson field tests lead to the design and construction of a third prototype antenna. In a laboratory setting, experiments were created to fail igneous rock types within a custom-designed Faraday Cage. An antenna emplaced within the cage detected EM emissions, which were both reproducible and distinct, and the laboratory results paralleled field results. With a viable system and continuous monitoring, a fracture cycle could be established and observed in real-time. Sequentially, field data would be reviewed quickly for assessment; thus, leading to a much improved earthquake forecasting capability. The EM precursor determined by this method may surpass all prior precursor claims, and the general public will finally receive long overdue forecasting.

Jones, K. B., II; Saxton, P. T.

2013-12-01

324

Inhibiting the palmitoylation/depalmitoylation cycle selectively reduces the growth of hematopoietic cells expressing oncogenic Nras  

PubMed Central

The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-RasG12D formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations. PMID:22144181

Xu, Jin; Hedberg, Christian; Dekker, Frank J.; Li, Qing; Haigis, Kevin M.; Hwang, Eugene; Waldmann, Herbert

2012-01-01

325

Directional DNA Methylation Changes and Complex Intermediate States Accompany Lineage Specificity in the Adult Hematopoietic Compartment  

PubMed Central

SUMMARY DNA methylation has been implicated as an epigenetic component of mechanisms that stabilize cell-fate decisions. Here, we have characterized the methylomes of human female hematopoietic stem/progenitor cells (HSPCs) and mature cells from the myeloid and lymphoid lineages. Hypomethylated regions (HMRs) associated with lineage-specific genes were often methylated in the opposing lineage. In HSPCs, these sites tended to show intermediate, complex patterns that resolve to uniformity upon differentiation, by increased or decreased methylation. Promoter HMRs shared across diverse cell types typically display a constitutive core that expands and contracts in a lineage-specific manner to fine-tune the expression of associated genes. Many newly identified intergenic HMRs, both constitutive and lineage specific, were enriched for factor binding sites with an implied role in genome organization and regulation of gene expression, respectively. Overall, our studies represent an important reference data set and provide insights into directional changes in DNA methylation as cells adopt terminal fates. PMID:21924933

Hodges, Emily; Molaro, Antoine; Dos Santos, Camila O.; Thekkat, Pramod; Song, Qiang; Uren, Philip J.; Park, Jin; Butler, Jason; Rafii, Shahin; McCombie, W. Richard; Smith, Andrew D.; Hannon, Gregory J.

2012-01-01

326

Probing altered hematopoietic progenitors of preleukemic dogs with JANUS fission neutrons  

SciTech Connect

Toward the goal of developing basic insights to mechanisms of radiation leukemogenesis, the authors have developed a canine model that responds to protracted courses of low-daily-dose gamma irradiation with high incidences of myeloproliferative disease (MPD), principally myeloid leukemia. Using this model system, the authors have identified and partially characterized a four-phase preclinical sequence in the induction of MPD, including (1) suppression, (2) recovery, (3) accommodation, and (4) preleukemic transition. Further, they have identified within this sequence, a critical early hematopoietic target cell event that appears to promote progression of the initial preclinical phase to the second preclinical phase. This key target cell event is characterized by the acquisition of increased radioresistance to low-LET gamma rays by granulocyte/monocyte-committed progenitors (CFU-GM). In order to gain further insight into the basis of this critical event, the acquired survival responses of preleukemic progenitors have been probed in vitro with high-LET fission neutrons. 23 refs., 4 figs., 1 tab.

Seed, T.M.; Kaspar, L.V.

1990-01-01

327

Tgif1 Regulates Quiescence and Self-Renewal of Hematopoietic Stem Cells  

PubMed Central

TG-interacting factor 1 (TGIF1) is a transcriptional repressor that can modulate retinoic acid and transforming growth factor ? signaling pathways. It is required for myeloid progenitor cell differentiation and survival, and mutations in the TGIF1 gene cause holoprosencephaly. Furthermore, we have previously observed that acute myelogenous leukemia (AML) patients with low TGIF1 levels had worse prognoses. Here, we explored the role of Tgif1 in murine hematopoietic stem cell (HSC) function. CFU assays showed that Tgif1?/? bone marrow cells produced more total colonies and had higher serial CFU potential. These effects were also observed in vivo, where Tgif1?/? bone marrow cells had higher repopulation potential in short- and long-term competitive repopulation assays than wild-type cells. Serial transplantation and replating studies showed that Tgif1?/? HSCs exhibited greater self-renewal and were less proliferative and more quiescent than wild-type cells, suggesting that Tgif1 is required for stem cells to enter the cell cycle. Furthermore, HSCs from Tgif1+/? mice had a phenotype similar to that of HSCs from Tgif1?/? mice, while bone marrow cells with overexpressing Tgif1 showed increased proliferation and lower survival in long-term transplant studies. Taken together, our data suggest that Tgif1 suppresses stem cell self-renewal and provide clues as to how reduced expression of TGIF1 may contribute to poor long-term survival in patients with AML. PMID:24100014

Yan, Ling; Womack, Bethany; Wotton, David; Guo, Yan; Shyr, Yu; Dave, Utpal; Li, Chun; Hiebert, Scott

2013-01-01

328

The Quality of Life of Adult Survivors of Childhood Hematopoietic Cell Transplant  

PubMed Central

Survival rates following myeloablative hematopoietic cell transplantation (HCT) in childhood have improved. We conducted a cross-sectional study evaluating the quality of life (QOL) of 214 adult survivors of a childhood HCT compared to controls using standardized self report measures with strong psychometric properties to evaluate physical function, psychological function, and cognitive symptoms. From these results we conducted a multivariate analysis of risk factors. This analysis for physical functioning showed poorer function among myeloid disease survivors compared to patients with all other diagnoses (p=0.02), males functioned better than females (p=0.05) and those >18 years after transplant functioned more poorly than those <18 years after transplant (p=0.05). Psychological functioning showed those who received more therapy and females were more likely to be depressed (p=0.03) and (p=0.005). Perceived cognitive symptoms demonstrated that female survivors had more symptoms than male survivors (p=0.01), and those receiving more preceding therapy compared to those with less preceding therapy (p=0.001) or cranial irradiation compared to those without cranial irradiation (p=0.002) had more perceived cognitive symptoms. Overall, these data indicate the majority of adult survivors of a childhood transplant are functioning well, but some have problems which need to be addressed. PMID:19718073

Sanders, Jean E.; Hoffmeister, Paul A.; Storer, Barry E.; Appelbaum, Frederick R.; Storb, Rainer F.; Syrjala, Karen L.

2009-01-01

329

Clonal-level responses of functionally distinct hematopoietic stem cells to trophic factors.  

PubMed

Recent findings from several groups have identified distinct classes of hematopoietic stem cells (HSCs) in the bone marrow, each with inherent functional biases in terms of their differentiation, self-renewal, proliferation, and lifespan. It has previously been demonstrated that myeloid- and lymphoid-biased HSCs can be prospectively enriched based on their degree of Hoechst dye efflux. In the present study, we used differential Hoechst efflux to enrich lineage-biased HSC subtypes and analyzed their functional potentials. Despite similar outputs in vitro, bone marrow transplantation assays revealed contrasting lineage differentiation in vivo. To stratify the molecular differences underlying these contrasting functional potentials at the clonal level, single-cell gene expression analysis was performed using the Fluidigm BioMark system and revealed dynamic expression of genes including Meis1, CEBP/?, Sfpi1, and Dnmt3a. Finally, single-cell gene expression analysis was used to unravel the opposing proliferative responses of lineage-biased HSCs to the growth factor TGF-?1, revealing a potential role for the cell cycle inhibitor Cdkn1c as molecular mediator. This work lends further credence to the concept of HSC heterogeneity, and it presents unprecedented molecular resolution of the HSC response to trophic factors using single-cell gene expression analysis. PMID:24373928

Mallaney, Cates; Kothari, Alok; Martens, Andrew; Challen, Grant A

2014-04-01

330

Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation  

PubMed Central

Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow–derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45+HLA-DR+ cells: CD1a+CD14? DC, CD1a?CD14+ DC, and CD1a?CD14+FXIIIa+ macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a+ and CD14+ DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4+ T cells, macrophages induce cytokine expression in memory CD4+ T cells and activation and proliferation of CD8+ T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells. PMID:19171766

Haniffa, Muzlifah; Ginhoux, Florent; Wang, Xiao-Nong; Bigley, Venetia; Abel, Michal; Dimmick, Ian; Bullock, Sarah; Grisotto, Marcos; Booth, Trevor; Taub, Peter; Hilkens, Catharien; Merad, Miriam

2009-01-01

331

Pathology Case Study: Chronic Myeloid Leukemia  

NSDL National Science Digital Library

This is a case study presented by the University of Pittsburgh Department of Pathology in which a woman was diagnosed with Chronic Myeloid Leukemia, and became a candidate for a bone marrow transplant. Visitors can view both PB Count Chart and Flow Cytometry, including images, and have the opportunity to diagnose the patient. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose disease. It is also a helpful site for educators to introduce or test students of hematopathology.

Persad, Rajendra

2009-04-23

332

Liver Involvement with Acute Myeloid Leukemia  

PubMed Central

Liver involvement with acute myeloid leukemia (AML) is rarely reported. The majority of published cases suggest a cholestatic picture and obstructive jaundice at presentation. On the contrary, our patient presented with transaminitis without cholestasis. Elevated liver function tests persisted in our patient despite cholecystectomy; however, they normalized with chemotherapy administration, suggesting that AML was the causative effect of the hepatitis-like picture. Our review of the literature revealed that most reported cases of AML with liver involvement had short-lived remissions and an overall ominous prognosis. In our opinion, patients who have liver involvement with AML should be offered alternative investigational therapies with a low hepatic toxicity profile. PMID:21490850

Mathews, Emily; Laurie, Timothy; O'Riordan, Kenneth; Nabhan, Chadi

2008-01-01

333

Ipilimumab in Treating Patients With Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia  

ClinicalTrials.gov

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); Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

2014-11-15

334

Hematopoietic stem cell mobilization: updated conceptual renditions  

PubMed Central

Despite its specific clinical relevance, the field of hematopoietic stem cell mobilization has received broad attention, owing mainly to the belief that pharmacologic stem cell mobilization might provide clues as to how stem cells are retained in their natural environment, the bone marrow ‘niche’. Inherent to this knowledge is also the desire to optimally engineer stem cells to interact with their target niche (such as after transplantation), or to lure malignant stem cells out of their protective niches (in order to kill them), and in general to decipher the niche’s structural components and its organization. Whereas, with the exception of the recent addition of CXCR4 antagonists to the armamentarium for mobilization of patients refractory to granulocyte colony-stimulating factor alone, clinical stem cell mobilization has not changed significantly over the last decade or so, much effort has been made trying to explain the complex mechanism(s) by which hematopoietic stem and progenitor cells leave the marrow. This brief review will report some of the more recent advances about mobilization, with an attempt to reconcile some of the seemingly inconsistent data in mobilization and to interject some commonalities among different mobilization regimes. PMID:22951944

Bonig, H; Papayannopoulou, T

2013-01-01

335

Genetic Therapy of Hematopoietic Stem Cells Using a ? C31 Integrase Based System  

Microsoft Academic Search

Gene therapy holds the potential promise to correct disease-causing mutations by delivering therapeutic genes into the genomes of hematopoietic stem cells. Hematopoietic stem cells have been identified as a target for gene therapy due to their unique bility to repopulate and maintain a functional hematopoietic system from the lifetime of an individual. Because hematopoietic stem cells give rise to many

Joshua R. Clevenger

2007-01-01

336

Radioprotection of mouse hematopoietic stem cells by leukotriene A4 and lipoxin B4  

SciTech Connect

The cytoprotective properties of eicosanoids were used for both cyclooxygenase products and, more recently, lipoxygenase products to induce radioprotection. This protection was shown with cells in culture, mouse hematopoietic stem cell in vivo, and with whole animal survival. DRF's of 1.7 or greater can be obtained with DiPGE2, a synthetic derivative of the naturally occurring prostaglandin E2, and with LTC4. These cytoprotective/radioprotective properties have significance in normal physiological processes and also in cancer biology where some tumors produce elevated levels of eicosanoids and may influence therapeutic efficacy. The potent cyto/radioprotective biological activity induced by leukotrienes prompted a search for other lipoxygenase products exhibiting similar properties. Pretreatment of mice with 1 to 20 microgram of leukotriene A(4) before sublethal irradiation induced an increase in the number of endogenous hematopoietic stem cells. Radioprotection was also provided by pretreatment with lipoxin B(4) but not with lipoxin A(4) or with potential lipoxin precursors: 5-HETE, 15-HPETE, 15-HETE, and arachidonic acid. The degree of protection induced by leukotriene A(4) or lipoxin B(4) is less than that previously reported for an equivalent dose of leukotriene C(4). Administration of the lipoxins did not result in any visibly detectable side effects such as diarrhea or ataxia.

Walden, T.L.

1988-01-01

337

Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion.  

PubMed

By restraining T-cell activation and promoting Treg-cell expansion, myeloid-derived suppressor cells (MDSCs) and tolerogenic DCs can control self-reactive and antigraft effector T cells in autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor-free donors. In the present study, we describe and characterize a novel population of human myeloid suppressor cells, named fibrocytic MDSC, which are differentiated from umbilical cord blood precursors by 4-day culture with FDA-approved cytokines (recombinant human-GM-CSF and recombinant human-G-CSF). This MDSC subset, characterized by the expression of MDSC-, DC-, and fibrocyte-associated markers, promotes Treg-cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes. In order to exert their protolerogenic function, fibrocytic MDSCs require direct contact with activated T cells, which leads to the production and secretion of IDO. This new myeloid subset may have an important role in the in vitro and in vivo production of Treg cells for the treatment of autoimmune diseases, and in either the prevention or control of allograft rejection. PMID:25113564

Zoso, Alessia; Mazza, Emilia M C; Bicciato, Silvio; Mandruzzato, Susanna; Bronte, Vincenzo; Serafini, Paolo; Inverardi, Luca

2014-11-01

338

The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity  

SciTech Connect

The widely expressed adaptor protein Shb has previously been reported to contribute to T cell function due to its association with the T cell receptor and furthermore, several of Shb's known interaction partners are established regulators of blood cell development and function. In addition, Shb deficient embryonic stem cells displayed reduced blood cell colony formation upon differentiation in vitro. The aim of the current study was therefore to explore hematopoietic stem and progenitor cell function in the Shb knockout mouse. Shb deficient bone marrow contained reduced relative numbers of long-term hematopoietic stem cells (LT-HSCs) that exhibited lower proliferation rates. Despite this, Shb knockout LT-HSCs responded promptly by entering the cell cycle in response to genotoxic stress by 5-fluorouracil treatment. In competitive LT-HSC transplantations, Shb null cells initially engrafted as well as the wild-type cells but provided less myeloid expansion over time. Moreover, Shb knockout bone marrow cells exhibited elevated basal activities of focal adhesion kinase/Rac1/p21-activated kinase signaling and reduced responsiveness to Stem Cell Factor stimulation. Consequently, treatment with a focal adhesion kinase inhibitor increased Shb knockout LT-HSC proliferation. The altered signaling characteristics thus provide a plausible mechanistic explanation for the changes in LT-HSC proliferation since these signaling intermediates have all been shown to participate in LT-HSC cell cycle control. In summary, the loss of Shb dependent signaling in bone marrow cells, resulting in elevated focal adhesion kinase activity and reduced proliferative responses in LT-HSCs under steady state hematopoiesis, confers a disadvantage to the maintenance of LT-HSCs over time. -- Highlights: • Shb is an adaptor protein operating downstream of tyrosine kinase receptors. • Shb deficiency reduces hematopoietic stem cell proliferation. • The proliferative effect of Shb occurs via increased focal adhesion kinase activity. • Shb is critical for the long-term maintenance of the hematopoietic stem cell pool.

Gustafsson, Karin [Department of Medical Cell Biology, Uppsala University, Uppsala 751 23 (Sweden); Heffner, Garrett; Wenzel, Pamela L.; Curran, Matthew [HHMI, Children's Hospital Boston, Harvard Medical School, Boston, 02115 MA (United States); Grawé, Jan [Department of Genetics and Pathology, Uppsala University, Uppsala 75185 (Sweden); McKinney-Freeman, Shannon L. [Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105 (United States); Daley, George Q. [HHMI, Children's Hospital Boston, Harvard Medical School, Boston, 02115 MA (United States); Welsh, Michael, E-mail: michael.welsh@mcb.uu.se [Department of Medical Cell Biology, Uppsala University, Uppsala 751 23 (Sweden)

2013-07-15

339

MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells.  

PubMed

Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34(+)/lineage(-)/CD38(-) cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34(+) populations as similar results were obtained with leukemic cells from patients with CD34(-) disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1(high)) led to development of leukemia in NOD-SCID IL2Rgamma(null) (NSG) immunodeficient mice. In contrast, MUC1(low) cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication. PMID:23867470

Stroopinsky, Dina; Rosenblatt, Jacalyn; Ito, Keisuke; Mills, Heidi; Yin, Li; Rajabi, Hasan; Vasir, Baldev; Kufe, Turner; Luptakova, Katarina; Arnason, Jon; Nardella, Caterina; Levine, James D; Joyce, Robin M; Galinsky, Ilene; Reiter, Yoram; Stone, Richard M; Pandolfi, Pier Paolo; Kufe, Donald; Avigan, David

2013-09-01

340

MUC1 IS A POTENTIAL TARGET FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA STEM CELLS  

PubMed Central

Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here we report that MUC1 is highly expressed on AML CD34+/lineage?/CD38? cells as compared to their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34+ populations as similar results were obtained with leukemic cells from patients with CD34? disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1high) led to development of leukemia in NSG immunodeficient mice. In contrast, MUC1low cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication. PMID:23867470

Stroopinsky, Dina; Rosenblatt, Jacalyn; Ito, Keisuke; Mills, Heidi; Yin, Li; Rajabi, Hasan; Vasir, Baldev; Kufe, Turner; Luptakova, Katarina; Arnason, Jon; Nardella, Caterina; Levine, James D.; Joyce, Robin; Galinsky, Ilene; Reiter, Yoram; Stone, Richard; Pandolfi, Pier Paolo; Kufe, Donald; Avigan, David

2014-01-01

341

DNMT3A Mutations in Patients with Acute Myeloid Leukemia in South Brazil  

PubMed Central

Acute myeloid leukemia (AML) is a complex and heterogeneous hematopoietic tissue neoplasm. Several molecular markers have been described that help to classify AML patients into risk groups. DNA methyltransferase 3A (DNMT3A) gene mutations have been recently identified in about 22% of AML patients and associated with poor prognosis as an independent risk factor. Our aims were to determine the frequency of somatic mutations in the gene DNMT3A and major chromosomal translocations in a sample of patients with AML. We investigated in 82 samples of bone marrow from patients with AML for somatic mutations in DNMT3A gene by sequencing and sought major fusion transcripts by RT-PCR. We found mutations in the DNMT3A gene in 6 patients (8%); 3 were type R882H. We found fusion transcripts in 19 patients, namely, AML1/ETO (n = 5; 6.1%), PML/RAR? (n = 12; 14.6%), MLL/AF9 (0; 0%), and CBF?/MYH11 (n = 2; 2.4%). The identification of recurrent mutations in the DNMT3A gene and their possible prognostic implications can be a valuable tool for making treatment decisions. This is the first study on the presence of somatic mutations of the DNMT3A gene in patients with AML in Brazil. The frequency of these mutations suggests a possible ethnogeographic variation. PMID:23193409

Pezzi, Annelise; Moraes, Lauro; Valim, Vanessa; Amorin, Bruna; Melchiades, Gabriela; Oliveira, Fernanda; da Silva, Maria Aparecida; Matte, Ursula; Pombo-de-Oliveira, Maria S.; Bittencourt, Rosane; Daudt, Liane; Silla, Lucia

2012-01-01

342

The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond  

PubMed Central

Acute myeloid leukemia remains associated with poor outcomes despite advances in our understanding of the complicated molecular events driving leukemogenesis and malignant progression. Those patients harboring mutations in the FLT3 receptor tyrosine kinase have a particularly poor prognosis; however, significant excitement has been generated by the emergence of a variety of targeted inhibitors capable of suppressing FLT3 signaling in vivo. Here we will review results from preclinical studies and early clinical trials evaluating both first- and second-generation FLT3 inhibitors. Early FLT3 inhibitors (including sunitinib, midostaurin, and lestaurtinib) demonstrated significant promise in preclinical models of FLT3 mutant AML. Unfortunately, many of these compounds failed to achieve robust and sustained FLT3 inhibition in early clinical trials, at best resulting in only transient decreases in peripheral blast counts. These results have prompted the development of second-generation FLT3 inhibitors, epitomized by the novel agent quizartinib. These second-generation inhibitors have demonstrated enhanced FLT3 specificity and have been generally well tolerated in early clinical trials. Several FLT3 inhibitors have reached phase III clinical trials, and a variety of phase I/II trials exploring a role for these novel compounds in conjunction with conventional chemotherapy or hematopoietic stem cell transplantation are ongoing. Finally, molecular insights provided by FLT3 inhibitors have shed light upon the variety of mechanisms underlying the acquisition of resistance and have provided a rationale supporting the use of combinatorial regimens with other emerging targeted therapies. PMID:24883179

Wander, Seth A.; Levis, Mark J.

2014-01-01

343

Isolation of myeloid dendritic cells and epithelial cells from human thymus.  

PubMed

In this protocol we provide a method to isolate dendritic cells (DC) and epithelial cells (TEC) from the human thymus. DC and TEC are the major antigen presenting cell (APC) types found in a normal thymus and it is well established that they play distinct roles during thymic selection. These cells are localized in distinct microenvironments in the thymus and each APC type makes up only a minor population of cells. To further understand the biology of these cell types, characterization of these cell populations is highly desirable but due to their low frequency, isolation of any of these cell types requires an efficient and reproducible procedure. This protocol details a method to obtain cells suitable for characterization of diverse cellular properties. Thymic tissue is mechanically disrupted and after different steps of enzymatic digestion, the resulting cell suspension is enriched using a Percoll density centrifugation step. For isolation of myeloid DC (CD11c(+)), cells from the low-density fraction (LDF) are immunoselected by magnetic cell sorting. Enrichment of TEC populations (mTEC, cTEC) is achieved by depletion of hematopoietic (CD45(hi)) cells from the low-density Percoll cell fraction allowing their subsequent isolation via fluorescence activated cell sorting (FACS) using specific cell markers. The isolated cells can be used for different downstream applications. PMID:24084687

Stoeckle, Christina; Rota, Ioanna A; Tolosa, Eva; Haller, Christoph; Melms, Arthur; Adamopoulou, Eleni

2013-01-01

344

Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia  

PubMed Central

Acute myeloid leukemia (AML) is a hematopoietic disorder in which there are too many immature blood-forming cells accumulating in the bone marrow and interfering with the production of normal blood cells. It has long been recognized that AML is a clinically heterogeneous disease characterized by a multitude of chromosomal abnormalities and gene mutations, which translate to marked differences in responses and survival following chemotherapy. The cytogenetic and molecular genetic aberrations associated with AML are not mutually exclusive and often coexist in the leukemic cells. AML is a disease of the elderly, with a mean age of diagnosis of 70 years. Adverse cytogenetic abnormalities increase with age, and within each cytogenetic group, prognosis with standard treatment worsens with age. In the past 20 years, there has been little improvement in chemotherapeutic regimens and hence the overall survival for patients with AML. A huge unmet need exists for efficacious targeted therapies for elderly patients that are less toxic than available chemotherapy regimens. The multitude of chromosomal and genetic abnormalities makes the treatment of AML a challenging prospect. A detailed understanding of the molecular changes associated with the chromosomal and genetic abnormalities in AML is likely to provide a rationale for therapy design and biomarker development. This review summarizes the variety of cytogenetic and genetic changes observed in AML and gives an overview of the clinical status of new drugs in development. PMID:21779483

Kumar, C. Chandra

2011-01-01

345

The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond.  

PubMed

Acute myeloid leukemia remains associated with poor outcomes despite advances in our understanding of the complicated molecular events driving leukemogenesis and malignant progression. Those patients harboring mutations in the FLT3 receptor tyrosine kinase have a particularly poor prognosis; however, significant excitement has been generated by the emergence of a variety of targeted inhibitors capable of suppressing FLT3 signaling in vivo. Here we will review results from preclinical studies and early clinical trials evaluating both first- and second-generation FLT3 inhibitors. Early FLT3 inhibitors (including sunitinib, midostaurin, and lestaurtinib) demonstrated significant promise in preclinical models of FLT3 mutant AML. Unfortunately, many of these compounds failed to achieve robust and sustained FLT3 inhibition in early clinical trials, at best resulting in only transient decreases in peripheral blast counts. These results have prompted the development of second-generation FLT3 inhibitors, epitomized by the novel agent quizartinib. These second-generation inhibitors have demonstrated enhanced FLT3 specificity and have been generally well tolerated in early clinical trials. Several FLT3 inhibitors have reached phase III clinical trials, and a variety of phase I/II trials exploring a role for these novel compounds in conjunction with conventional chemotherapy or hematopoietic stem cell transplantation are ongoing. Finally, molecular insights provided by FLT3 inhibitors have shed light upon the variety of mechanisms underlying the acquisition of resistance and have provided a rationale supporting the use of combinatorial regimens with other emerging targeted therapies. PMID:24883179

Wander, Seth A; Levis, Mark J; Fathi, Amir T

2014-06-01

346

The Thoc1 Encoded Ribonucleoprotein Is Required for Myeloid Progenitor Cell Homeostasis in the Adult Mouse  

PubMed Central

Co-transcriptionally assembled ribonucleoprotein (RNP) complexes are critical for RNA processing and nuclear export. RNPs have been hypothesized to contribute to the regulation of coordinated gene expression, and defects in RNP biogenesis contribute to genome instability and disease. Despite the large number of RNPs and the importance of the molecular processes they mediate, the requirements for individual RNP complexes in mammalian development and tissue homeostasis are not well characterized. THO is an evolutionarily conserved, nuclear RNP complex that physically links nascent transcripts with the nuclear export apparatus. THO is essential for early mouse embryonic development, limiting characterization of the requirements for THO in adult tissues. To address this shortcoming, a mouse strain has been generated allowing inducible deletion of the Thoc1 gene which encodes an essential protein subunit of THO. Bone marrow reconstitution was used to generate mice in which Thoc1 deletion could be induced specifically in the hematopoietic system. We find that granulocyte macrophage progenitors have a cell autonomous requirement for Thoc1 to maintain cell growth and viability. Lymphoid lineages are not detectably affected by Thoc1 loss under the homeostatic conditions tested. Myeloid lineages may be more sensitive to Thoc1 loss due to their relatively high rate of proliferation and turnover. PMID:24830368

Chinnam, Meenalakshmi; Povinelli, Benjamin J.; Fisher, Daniel T.; Golding, Michelle; Appenheimer, Michelle M.; Nemeth, Michael J.; Evans, Sharon; Goodrich, David W.

2014-01-01

347

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

PubMed

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

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

348

[The methods used to collect hematopoietic stem cells].  

PubMed

The methods used to collect hematopoietic stem cells in their natural environment (bone marrow or cord blood) or in the peripheral blood after stimulation are well-defined and ruled both to ensure the donor security and perform a quality hematopoietic transplantation. Safety of the familial or non-familial donor must be ensured not only during the collection but also on a medium- or a long-term basis. The stem cells amount in a graft and its characterisation depend on the collection site of hematopoietic stem cells and on the technique used. The knowledge of conditions influencing these amounts allows optimising the hematopoietic stem cells collection while preventing conditions in which the donor safety could be decreased. The collection site also influences the collection of significant amounts of other blood cells. This knowledge conditions the preparation procedures of the graft in cell therapy units or the management of per- or post-transplantations complications in haematology units. Thus, hematopoietic transplantations concern not only hematological units but also the teams involved in various stages of donor selection, hematopoietic stem cells collection and graft preparation. In order to allow an appropriate care of both donor and recipient, a concomitant knowledge of all the stages involved in hematopoietic collection conditions, characterisation of collected cells, hematological diseases and conditioning must be brought to hematological, collection and cell therapy teams. PMID:21397542

Hequet, O

2011-04-01

349

Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis.  

PubMed

Klotho deficiency is a characteristic feature of chronic kidney disease in which anemia and cardiovascular complications are prevalent. Disruption of the Klotho gene in mice results in hypervitaminosis D and a syndrome resembling accelerated aging that includes osteopenia and vascular calcifications. Given that the bone microenvironment and its cellular components considerably influence hematopoiesis, in the present study, we addressed the in vivo role of klotho in blood cell formation and differentiation. Herein, we report that genetic ablation of Klotho in mice results in a significant increase in erythropoiesis and a decrease in the hematopoietic stem cell pool size in the bone marrow, leading to impaired hematopoietic stem cell homing in vivo. Our data also suggest that high vitamin D levels are only partially responsible for these hematopoietic changes in Klotho(-/-) mice. Importantly, we found similar hematopoietic abnormalities in Klotho(-/-) fetal liver cells, suggesting that the effects of klotho in hematopoietic stem cell development are independent of the bone microenvironment. Finally, injection of klotho protein results in hematopoietic changes opposite to the ones observed in Klotho(-/-) mice. These observations unveil a novel role for the antiaging hormone klotho in the regulation of prenatal and postnatal hematopoiesis and provide new insights for the development of therapeutic strategies targeting klotho to treat hematopoietic disorders associated with aging. PMID:24412515

Vadakke Madathil, Sangeetha; Coe, Lindsay M; Casu, Carla; Sitara, Despina

2014-03-01

350

Pleiotrophin mediates hematopoietic regeneration via activation of RAS.  

PubMed

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner. PMID:25250571

Himburg, Heather A; Yan, Xiao; Doan, Phuong L; Quarmyne, Mamle; Micewicz, Eva; McBride, William; Chao, Nelson J; Slamon, Dennis J; Chute, John P

2014-11-01

351

An in vivo propagated human acute myeloid leukemia expressing ABCA3.  

PubMed

Analyzing the regenerative compartment in the blast cell population of patients with acute myeloid leukemia (AML) may yield important insights into the mechanisms of disease progression. Here we present findings with a human AML cell line (AML-SP1), initiated from leukemic precursor cells and consecutively propagated by serial xenotransplantation in vivo. AML-SP1 maintained the characteristics of a human AML, consistently exhibiting a small leukemic side population (SP) of blast cells with high Hoechst 33342 exclusion. In the AML-SP1 line, an increased expression of the ABC transporters MDR1, MRP, ABCG2 and ABCA3 was found in the SP cells. The detection of ABCA3 in leukemic progenitor cells merits further investigation with regard to intracellular drug transport in AML blast cells. In vivo propagation of leukemias, such as AML-SP1 is a model system of maintaining the populational heterogeneity of AML disease, especially the unique characteristics of leukemic SP cells. PMID:14687625

Norwood, Kevin; Wang, Rui-Yu; Hirschmann-Jax, Charlotte; Andreeff, Michael; Brenner, Malcolm K; Goodell, Margaret A; Wulf, Gerald G

2004-03-01

352

Mechanisms of resistance to targeted therapies in acute myeloid leukemia and chronic myeloid leukemia.  

PubMed

Small molecule kinase inhibitors of BCR-ABL in chronic myeloid leukemia (CML) and of FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in acute myeloid leukemia (AML) have been successful at achieving remissions in these diseases as monotherapy, but these leukemias do not initially respond in a subset of patients (primary resistance) and they progress in an additional group of patients after an initial response (secondary resistance). Resistance to these agents can be divided into mechanisms that allow reactivation kinase activity and those that bypass reliance on oncogenic signaling mediated by the target kinase. Elucidation of clinical resistance mechanisms to targeted therapies for patients can provide important insights into disease pathogenesis and signaling. PMID:24451819

Smith, Catherine C; Shah, Neil P

2012-01-01

353

JC Virus Multiplication in Human Hematopoietic Progenitor Cells Requires the NF-1 Class D Transcription Factor  

PubMed Central

JCV, a small DNA virus of the polyomavirus family, has been shown to infect glial cells of the central nervous system, hematopoietic progenitor cells, and immune system lymphocytes. A family of DNA binding proteins called nuclear factor-1 (NF-1) has been linked with site-coding specific transcription of cellular and viral genes and replication of some viruses, including JC virus (JCV). It is unclear which NF-1 gene product must be expressed by cells to promote JCV multiplication. Previously, it was shown that elevated levels of NF-1 class D mRNA were expressed by human brain cells that are highly susceptible to JCV infection but not by JCV nonpermissive HeLa cells. Recently, we reported that CD34+ precursor cells of the KG-1 line, when treated with the phorbol ester phorbol 12-myristate 13-acetate (PMA), differentiated to cells with macrophage-like characteristics and lost susceptibility to JCV infection. These studies have now been extended by asking whether loss of JCV susceptibility by PMA-treated KG-1 cells is linked with alterations in levels of NF-1 class D expression. Using reverse transcription-PCR, we have found that PMA-treated KG-1 cells express mRNA that codes for all four classes of NF-1 proteins, although different levels of RNA expression were observed in the hematopoietic cells differentiated into macrophages. Northern hybridization confirms that the expression of NF-1 class D gene is lower in JCV nonpermissive PMA-treated KG-1 cells compared with non-PMA-treated cells. Further, using gel mobility shift assays, we were able to show the induction of specific NF-1–DNA complexes in KG-1 cells undergoing PMA treatment. The binding increases in direct relation to the duration of PMA treatment. These results suggest that the binding pattern of NF-1 class members may change in hematopoietic precursor cells, such as KG-1, as they undergo differentiation to macrophage-like cells. Transfection of PMA-treated KG-1 cells with an NF-1 class D expression vector restored the susceptibility of these cells to JCV infection, while the transfection of PMA-treated KG-1 cells with NF-1 class A, B, and C vectors was not able to restore JCV susceptibility. These data collectively suggest that selective expression of NF-1 class D has a regulatory role in JCV multiplication. PMID:11559801

Monaco, Maria Chiara G.; Sabath, Bruce F.; Durham, Linda C.; Major, Eugene O.

2001-01-01

354

Adult neurogenesis in the crayfish brain: the hematopoietic anterior proliferation center has direct access to the brain and stem cell niche.  

PubMed

Neuronal stem cells residing in a niche on the surface of the adult crayfish (Procambarus clarkii) brain are not self-renewing. However, the neuronal precursors in the niche are not depleted despite continued neurogenesis and the exit of precursor cells from the niche throughout the organism's life. The neurogenic niche is therefore not a closed system, and we have previously proposed that the stem cell pool is replenished from the hematopoietic system. Noonin et al. (2012) demonstrated that the hematopoietic system in the crayfish Pacifastacus leniusculus includes an anterior proliferation center (APC) lying near the brain; they suggest that multipotent stem cells are concentrated in this region, and that the APC may provide neuronal stem cells for adult neurogenesis. The present study extends this work by describing the location and cellular organization of hematopoietic tissues in P. clarkii. We find that the APC lies within the cor frontale, or auxiliary heart, which pumps hemolymph to the brain and eyes through the cerebral and ophthalmic arteries, respectively. Vascular extensions of the cerebral artery converge on the neurogenic niche. APC cells lie in layered sheets within the cor frontale and form rosette-like structures reminiscent of stem cells in other developing tissues. We confirm here that APC cells in P. clarkii have characteristics of multipotent stem cells, and that their location within the cor frontale allows direct access to regions in the central nervous system in which adult neurogenesis occurs. PMID:23181901

Chaves da Silva, Paula Grazielle; Benton, Jeanne L; Sandeman, David C; Beltz, Barbara S

2013-04-01

355

Identified EM Earthquake Precursors  

NASA Astrophysics Data System (ADS)

Many attempts have been made to determine a sound forecasting method regarding earthquakes and warn the public in turn. Presently, the animal kingdom leads the precursor list alluding to a transmission related source. By applying the animal-based model to an electromagnetic (EM) wave model, various hypotheses were formed, but the most interesting one required the use of a magnetometer with a differing design and geometry. To date, numerous, high-end magnetometers have been in use in close proximity to fault zones for potential earthquake forecasting; however, something is still amiss. The problem still resides with what exactly is forecastable and the investigating direction of EM. After a number of custom rock experiments, two hypotheses were formed which could answer the EM wave model. The first hypothesis concerned a sufficient and continuous electron movement either by surface or penetrative flow, and the second regarded a novel approach to radio transmission. Electron flow along fracture surfaces was determined to be inadequate in creating strong EM fields, because rock has a very high electrical resistance making it a high quality insulator. Penetrative flow could not be corroborated as well, because it was discovered that rock was absorbing and confining electrons to a very thin skin depth. Radio wave transmission and detection worked with every single test administered. This hypothesis was reviewed for propagating, long-wave generation with sufficient amplitude, and the capability of penetrating solid rock. Additionally, fracture spaces, either air or ion-filled, can facilitate this concept from great depths and allow for surficial detection. A few propagating precursor signals have been detected in the field occurring with associated phases using custom-built loop antennae. Field testing was conducted in Southern California from 2006-2011, and outside the NE Texas town of Timpson in February, 2013. The antennae have mobility and observations were noted for recurrence, duration, and frequency response. At the Southern California field sites, one loop antenna was positioned for omni-directional reception and also detected a strong First Schumann Resonance; however, additional Schumann Resonances were absent. At the Timpson, TX field sites, loop antennae were positioned for directional reception, due to earthquake-induced, hydraulic fracturing activity currently conducted by the oil and gas industry. Two strong signals, one moderately strong signal, and approximately 6-8 weaker signals were detected in the immediate vicinity. The three stronger signals were mapped by a biangulation technique, followed by a triangulation technique for confirmation. This was the first antenna mapping technique ever performed for determining possible earthquake epicenters. Six and a half months later, Timpson experienced two M4 (M4.1 and M4.3) earthquakes on September 2, 2013 followed by a M2.4 earthquake three days later, all occurring at a depth of five kilometers. The Timpson earthquake activity now has a cyclical rate and a forecast was given to the proper authorities. As a result, the Southern California and Timpson, TX field results led to an improved design and construction of a third prototype antenna. With a loop antenna array, a viable communication system, and continuous monitoring, a full fracture cycle can be established and observed in real-time. In addition, field data could be reviewed quickly for assessment and lead to a much more improved earthquake forecasting capability. The EM precursors determined by this method appear to surpass all prior precursor claims, and the general public will finally receive long overdue forecasting.

Jones, Kenneth, II; Saxton, Patrick

2014-05-01

356

Hematopoietic Stem and Progenitor Cells in Inflammation and Allergy  

PubMed Central

Hematopoietic stem and progenitor cells contribute to allergic inflammation. Pro-inflammatory cytokines that are generated following allergen challenge can impact the differentiation of hematopoietic progenitor cells leading to increased production of effector cells such as eosinophils and basophils, which are key cells involved in the pathogenesis of allergic airway inflammation. Homing of stem cells to the lungs is associated with inflammatory and remodeling changes in asthmatics. Factors that modulate the differentiation and increased migration of stem cells to the site of inflammation in asthma remain to be defined. Stem cells can mature at the site of inflammation in response to inflammatory mediators and other components in the milieu. While the available data suggest that hematopoietic cells traffic to target tissues, the molecular factors underlying in situ differentiation have yet to be specified. Here, we critically evaluate the potential role of hematopoietic progenitors in contributing to the increased immune cell infiltrate in allergic asthma and the factors that drive their differentiation. PMID:24363657

Fischer, Kimberly D.; Agrawal, Devendra K.

2013-01-01

357

Transcriptome Analysis Identifies Regulators of Hematopoietic Stem and Progenitor Cells  

E-print Network

Hematopoietic stem cells (HSCs) maintain blood homeostasis and are the functional units of bone marrow transplantation. To improve the molecular understanding of HSCs and their proximal progenitors, we performed transcriptome ...

Gazit, Roi

358

The Hematopoietic Stem Cell Therapy for Exploration of Space  

Microsoft Academic Search

Departments of Biochemistry &Molecular Biology, Genetics &Human Genetics, Pediatrics &Child Long-duration space missions require countermeasures against severe\\/invasive disorders in astronauts that are caused by space environments, such as hematological\\/cardiac abnormalities, bone\\/muscle losses, immunodeficiency, neurological disorders, and cancer. Some, if not all, of these disorders may be amenable to hematopoietic stem cell therapy and gene therapy. Growing evidence indicates that hematopoietic

S. Ohi

2002-01-01

359

Parathyroid Hormone Mediates Hematopoietic Cell Expansion through Interleukin6  

Microsoft Academic Search

Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control.

Flavia Q. Pirih; Megan N. Michalski; Sun W. Cho; Amy J. Koh; Janice E. Berry; Eduardo Ghaname; Pachiyappan Kamarajan; Edith Bonnelye; Charles W. Ross; Yvonne L. Kapila; Pierre Jurdic; Laurie K. McCauley; Derya Unutmaz

2010-01-01

360

Hospital infection control in hematopoietic stem cell transplant recipients.  

PubMed Central

Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients contains a section on hospital infection control including evidence-based recommendations regarding ventilation, construction, equipment, plants, play areas and toys, health-care workers, visitors, patient skin and oral care, catheter-related infections, drug-resistant organisms, and specific nosocomial infections. These guidelines are intended to reduce the number and severity of hospital infections in hematopoietic stem cell transplant recipients. PMID:11294720

Dykewicz, C. A.

2001-01-01

361

Acute Myeloid Leukemia Presenting with Pulmonary Tuberculosis  

PubMed Central

We report the case of a 58-year-old immunocompetent man presenting with fever, cough, anorexia, weight loss, and cervical lymphadenopathy. Blood investigations revealed severe neutropenia with monocytosis. Chest imaging showed bilateral reticular infiltrates with mediastinal widening. Bronchoalveolar lavage culture and molecular test were positive for Mycobacterium tuberculosis and treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol was started. Although pulmonary tuberculosis could explain this clinical presentation we suspected associated blood dyscrasias in view of significant monocytosis and mild splenomegaly. Bone marrow aspiration revealed acute myeloid leukemia. Thereafter the patient received induction chemotherapy and continued antituberculous treatment. After first induction of chemotherapy patient was in remission and successfully completed 6 months antituberculosis therapy without any complications. To our knowledge there has been no such case reported from the State of Qatar to date. PMID:24987539

Thomas, Merlin; AlGherbawe, Mushtak

2014-01-01

362

[FLT3 inhibitors for acute myeloid leukemia].  

PubMed

FLT3 is a class III receptor tyrosine kinase. FLT3 mutation is the most frequent genetic alteration in acute myeloid leukemia (AML), and involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells. Since FLT3 mutation is strongly associated with leukocytosis and a poor prognosis, it is expected that development of FLT3 kinase inhibitors will make more efficacious therapeutic strategy for leukemia therapy. Although many FLT3 inhibitors have been subjected to clinical trials, their clinical efficacies for AML seem unimpressive, and several problems regarding adverse effects and resistant mechanism are apparent. Here, I would like to summarize recent advances of FLT3 inhibitors in development. PMID:25016800

Kiyoi, Hitoshi

2014-06-01

363

Comparative proteomics in acute myeloid leukemia  

PubMed Central

The term proteomics was used for the first time in 1995 to describe large-scale protein analyses. At the same time proteomics was distinguished as a new domain of the life sciences. The major object of proteomic studies is the proteome, i.e. the set of all proteins accumulating in a given cell, tissue or organ. During the last years several new methods and techniques have been developed to increase the fidelity and efficacy of proteomic analyses. The most widely used are two-dimensional electrophoresis (2DE) and mass spectrometry (MS). In the past decade proteomic analyses have also been successfully applied in biomedical research. They allow one to determine how various diseases affect the pattern of protein accumulation. In this paper, we attempt to summarize the results of the proteomic analyses of acute myeloid leukemia (AML) cells. They have increased our knowledge on the mechanisms underlying AML development and contributed to progress in AML diagnostics and treatment. PMID:23788862

Luczak, Magdalena; Kazmierczak, Maciej; Hadschuh, Luiza; Lewandowski, Krzysztof; Komarnicki, Mieczyslaw

2012-01-01

364

EVI1 expression in acute myeloid leukaemia.  

PubMed

Acute myeloid leukaemia (AML) with 3q26 cytogenetic abnormalities is associated with overexpression of EVI1, dysmegakaryopoiesis and poor prognosis. Screening for EVI1 transcripts was performed in 336 cases of AML, including 139 patients with acute promyelocytic leukaemia (APL). Expression was detected in 7 out of 10 cases with and 23 out of 326 without 3q26 abnormalities including one APL case. Among cases lacking 3q abnormalities, detection of EVI1 transcripts was neither associated with characteristic dysmegakaryopoietic features, nor predictive of a poor outcome, indicating that screening will probably not assist in treatment stratification. This study nevertheless demonstrates that deregulation of EVI1, although rare in APL, is a relatively frequent event in AML. PMID:11167805

Langabeer, S E; Rogers, J R; Harrison, G; Wheatley, K; Walker, H; Bain, B J; Burnett, A K; Goldstone, A H; Linch, D C; Grimwade, D

2001-01-01

365

Total body irradiation in chronic myeloid leukemia  

SciTech Connect

Total body irradiation (TBI), given as 10 rad daily for five days a week for a total dose of 150 rad has been used in an attempt to control the chronic phase of chronic myeloid leukemia (CML). Thirteen patients with CML received fractionated TBI leading to rapid and good control of WBC count without any adverse reaction. The chronic phase of CML could also be controlled with TBI, even in three patients who were resistant to busulfan. Following TBI, WBC count remained under control for a period of 32 weeks as compared to 40 weeks following vusulfan alone. Repeat TBI was also well tolerated with good response. It appears that TBI is an effective and safe therapy for controlling the chronic phase of CML.

Advani, S.H.; Dinshaw, K.A.; Nair, C.N.; Ramakrishnan, G.

1983-04-01

366

Cytogenetic analysis in acute myeloid leukaemia.  

PubMed

Cytogenetic analysis is an integral part of the diagnostic work-up of the patient with acute myeloid leukaemia. Conventional cytogenetic analysis relies on obtaining a good quality bone marrow specimen in a timely fashion and setting up at least two short-term cultures. A 15-24-h culture and a 48-h synchronised culture are routinely set up but as the cytogenetics result is often required urgently to determine the type of therapy to be administered, analysis is undertaken using the overnight culture in the first instance. Rapid and accurate analysis relies on obtaining high-quality G-banding. Knowledge of the conditions affecting banding is therefore essential. PMID:21431634

Campbell, Lynda J; White, Joanne S

2011-01-01

367

Genetics Home Reference: Core binding factor acute myeloid leukemia  

MedlinePLUS

Core binding factor acute myeloid leukemia Related Chromosome(s) Related Gene(s) References Quick links to this topic MedlinePlus Health information Additional NIH Resources National Institutes of Health Educational resources Information pages Patient ...

368

Chronic Myeloid Leukemia (CML) in Adults (Beyond the Basics)  

MedlinePLUS

... fusion gene Chronic myeloid leukemia Dasatinib Donor lymphocyte infusion Imatinib Leukemia Myeloblasts Nilotinib Patient information Tyrosine kinase ... can be treated with a TKI or with infusions of leukocytes from the original donor, with the ...

369

Pan myeloid antigen-negative pediatric acute megakaryoblastic leukemia.  

PubMed

Acute megakaryoblastic leukemia (AMKL) is a relatively common type of acute myeloid leukemia in children. We describe two unusual cases of AMKL that by flow cytometry (FC) lacked expression of any commonly evaluated myeloid antigens. One case presented as a periorbital myeloid sarcoma and clinically was thought to be a solid tumor. In both cases, the leukemic blasts were variably positive for the megakaryocytic marker CD61. Cytogenetics confirmed the presence of the t(1;22) in one case. Cytogenetics and inclusion of megakaryocytic markers in FC panels when evaluating pediatric specimens is critical for appropriate diagnosis for myeloid antigen negative AMKL. Pediatr Blood Cancer 2014;61:2089-2091. © 2014 Wiley Periodicals, Inc. PMID:24962432

Cetin, Neslihan; Lorsbach, Robert B

2014-11-01

370

Omacetaxine mepesuccinate in the treatment of intractable chronic myeloid leukemia  

PubMed Central

In a significant proportion of patients with chronic myeloid leukemia, resistance to BCR-ABL tyrosine kinase inhibitors develops due to acquisition of BCR-ABL kinase domain mutations and insensitivity of leukemia stem cells to tyrosine kinase inhibitors. Omacetaxine mepesuccinate (formerly called homoharringtonine) is a natural alkaloid that inhibits protein synthesis and induces cell death. Omacetaxine mepesuccinate has been recently approved by the US Food and Drug Administration to treat patients with chronic myeloid leukemia who failed to respond to multiple tyrosine kinase inhibitors and/or acquired the BCR-ABL-T315I mutation. In this review, we discuss the use and effectiveness of omacetaxine mepesuccinate in the treatment of chronic myeloid leukemia, with coverage of its pharmacology, mode of action, and pharmacokinetics. We believe that omacetaxine mepesuccinate will be beneficial to many patients with chronic myeloid leukemia who do not respond well to tyrosine kinase inhibitors. PMID:24516334

Chen, Yaoyu; Li, Shaoguang

2014-01-01

371

Researchers discover key mutation in acute myeloid leukemia;  

Cancer.gov

Researchers have discovered mutations in a particular gene that affects the treatment prognosis for some patients with acute myeloid leukemia (AML), an aggressive blood cancer that kills 9,000 Americans annually.

372

Eltrombopag Olamine in Improving Platelet Recovery in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy  

ClinicalTrials.gov

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; 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 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

2014-04-29

373

Lenalidomide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

2014-11-21

374

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

ClinicalTrials.gov

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); Recurrent Adult Acute Myeloid Leukemia

2014-07-02

375

Choline Magnesium Trisalicylate and Combination Chemotherapy in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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

2014-05-20

376

Azacitidine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With High-Risk Acute Myeloid Leukemia  

ClinicalTrials.gov

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

2014-10-14

377

S0432 Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

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

2013-01-14

378

Zebrafish Stromal Cells have Endothelial Properties and Support Hematopoietic Cells  

PubMed Central

Objective The goal of this study was to determine if we could establish a mesenchymal stromal line from zebrafish that would support hematopoietic cells. Such a co-culture system would be a great benefit to study the hematopoietic cell-stromal cell interaction in both the in vitro and in vivo environments. Methods Zebrafish stromal cells, ZStrC, were isolated from the “mesenchymal” tissue of the caudal tail and expanded in a specialized growth media. ZStrC were evaluated for phenotype, gene expression, and the ability to maintain zebrafish marrow cells in co-culture experiments. Results ZStrC showed mesenchymal and endothelial gene expression. Although ZStrC lacked the ability to differentiate into classic MSC lineages (osteocytes, adipocytes, chondrocytes), they did have the capacity for endotube formation on matrigel and LDL-uptake. ZStrC supported marrow cells for greater than 2 weeks in vitro. Importantly, the marrow cells were shown to retain homing ability in adoptive transfer experiments. ZStrC also were shown to improve hematopoietic recovery after sub-lethal irradiation after adoptive transfer. Conclusion As the zebrafish model grows in popularity and importance in the study of hematopoiesis, new tools to aid in our understanding of the hematopoietic cell-stromal cell interaction are required. ZStrC represent an additional tool in the study of hematopoiesis and will be useful to understand the factors that mediate the stromal cell-hematopoietic cell interaction that are important in hematopoietic maintenance. PMID:21920471

Lund, Troy C.; Glass, Tiffany J.; Somani, Arif; Nair, Sethu; Tolar, Jakub; Nyquist, Mick; Patrinostro, Xiaobai; Blazar, Bruce R.

2014-01-01

379

Parathyroid Hormone Mediates Hematopoietic Cell Expansion through Interleukin-6  

PubMed Central

Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45+ and CD11b+ cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls) but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin- Sca-1+c-Kit+ (LSK) hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion. PMID:21048959

Pirih, Flavia Q.; Michalski, Megan N.; Cho, Sun W.; Koh, Amy J.; Berry, Janice E.; Ghaname, Eduardo; Kamarajan, Pachiyappan; Bonnelye, Edith; Ross, Charles W.; Kapila, Yvonne L.; Jurdic, Pierre; McCauley, Laurie K.

2010-01-01

380

Targeting myeloid regulatory cells in cancer by chemotherapeutic agents  

Microsoft Academic Search

Recent findings in humans and numerous experimental models provide evidence of the important role of immune regulatory cells\\u000a in cancer and various diseases. “Myeloid regulatory cells” (MRC) include myeloid-derived suppressor cells, regulatory dendritic\\u000a cells, regulatory macrophages, and subsets of granulocytes that expand during pathologic conditions and that have the ability\\u000a to suppress cellular immunity. A decrease in MRC population and\\/or

Hiam Naiditch; Michael R. Shurin; Galina V. Shurin

2011-01-01

381

Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia  

Microsoft Academic Search

A b s t r ac t Background Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT\\/enhancer binding protein ? gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these

Richard F. Schlenk; Konstanze Döhner; Jürgen Krauter; Stefan Fröhling; Andrea Corbacioglu; Lars Bullinger; Marianne Habdank; Daniela Späth; Michael Morgan; Axel Benner; Brigitte Schlegelberger; Gerhard Heil; Arnold Ganser; Hartmut Döhner

2009-01-01

382

Constitutional Hypomorphic Telomerase Mutations in Patients with Acute Myeloid Leukemia  

Microsoft Academic Search

Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone

Rodrigo T. Calado; Joshua A. Regal; Mark Hills; William T. Yewdell; Leandro F. Dalmazzo; Marco A. Zago; Peter M. Lansdorp; Donna Hogge; Stephen J. Chanock; Elihu H. Estey; Roberto P. Falcão; Neal S. Young; Ira Pastan

2009-01-01

383

Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia  

Microsoft Academic Search

Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone

Rodrigo T. Calado; Joshua A. Regal; Mark Hills; William T. Yewdell; Leandro F. Dalmazzo; Marco A. Zago; Peter M. Lansdorp; Donna Hogge; Stephen J. Chanock; Elihu H. Estey; Roberto P. Falcão; Neal S. Young

2009-01-01

384

The role of natural killer cells in chronic myeloid leukemia  

PubMed Central

Chronic myeloid leukemia is a neoplasia resulting from a translocation between chromosomes 9 and 22 producing the BCR-ABL hybrid known as the Philadelphia chromosome (Ph). In chronic myeloid leukemia a proliferation of malignant myeloid cells occurs in the bone marrow due to excessive tyrosine kinase activity. In order to maintain homeostasis, natural killer cells, by means of receptors, identify the major histocompatibility complex on the surface of tumor cells and subsequently induce apoptosis. The NKG2D receptor in the natural killer cells recognizes the transmembrane proteins related to major histocompatibility complex class I chain-related genes A and B (MICA and MICB), and it is by the interaction between NKG2D and MICA that natural killer cells exert cytotoxic activity against chronic myeloid leukemia tumor cells. However, in the case of chronic exposure of the NKG2D receptor, the MICA ligand releases soluble proteins called sMICA from the tumor cell surface, which negatively modulate NKG2D and enable the tumor cells to avoid lysis mediated by the natural killer cells. Blocking the formation of sMICA may be an important antitumor strategy. Treatment using tyrosine kinase inhibitors induces modulation of NKG2DL expression, which could favor the activity of the natural killer cells. However this mechanism has not been fully described in chronic myeloid leukemia. In the present study, we analyze the role of natural killer cells to reduce proliferation and in the cellular death of tumor cells in chronic myeloid leukemia. PMID:23049299

Danier, Anna Carolyna Araujo; de Melo, Ricardo Pereira; Napimoga, Marcelo Henrique; Laguna-Abreu, Maria Theresa Ceravolo

2011-01-01

385

MS-275 and Azacitidine in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia  

ClinicalTrials.gov

Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

2014-10-14

386

Vaccine Therapy Plus Immune Adjuvant in Treating Patients With Chronic Myeloid Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome  

ClinicalTrials.gov

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

2013-01-04

387

Interleukin 3 perfusion in W/Wv mice allows the development of macroscopic hematopoietic spleen colonies and restores cutaneous mast cell number  

SciTech Connect

The genetically anemic W/Wv mice are characterized by the inability of their bone marrow cells to form macroscopic pluripotent hematopoietic colonies in the spleen of irradiated recipients upon transfer (colony-forming units). Furthermore, they almost totally lack mast cells, notably in the skin. In the present study, we have tested the effect of recombinant murine interleukin 3 (rmIL-3) on W/Wv mice hematopoiesis. Transfer of W/Wv bone marrow cells into lethally irradiated recipients perfused with rmIL-3 is followed by the appearance of macroscopic spleen colonies. Moreover, perfusion of rmIL-3 in W/Wv mice: (a) restores almost normal total numbers of hematopoietic precursors (colony-forming cells), but without modification of anemia; and (b) leads to the appearance of a normal number of mastocytes in the skin.

Ody, C.; Kindler, V.; Vassalli, P. (Univ. of Geneva (Switzerland))

1990-07-01

388

Isolated Gastric Myeloid Sarcoma: A Case Report and Review of the Literature  

PubMed Central

Myeloid sarcoma represents the proliferation of myeloblasts of acute myeloid leukemia (AML) at extramedullary sites. While extramedullary involvement in AML is uncommon in itself, isolated myeloi