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Sample records for hematopoietic myeloid precursors

  1. CD34(+) Liver Cancer Stem Cells Were Formed by Fusion of Hepatobiliary Stem/Progenitor Cells with Hematopoietic Precursor-Derived Myeloid Intermediates.

    PubMed

    Zeng, Changjun; Zhang, Yanling; Park, Su Cheol; Eun, Jong Ryeol; Nguyen, Ngoc Tue; Tschudy-Seney, Benjamin; Jung, Yong Jin; Theise, Neil D; Zern, Mark A; Duan, Yuyou

    2015-11-01

    A large number of cancer stem cells (CSCs) were identified and characterized; however, the origins and formation of CSCs remain elusive. In this study, we examined the origination of the newly identified CD34(+) liver CSC (LCSC). We found that CD34(+) LCSC coexpressed liver stem cell and myelomonocytic cell markers, showing a mixed phenotype, a combination of hepatobiliary stem/progenitor cells (HSPCs) and myelomonocytic cells. Moreover, human xenografts produced by CD34(+) LCSCs and the parental cells, which CD34(+) LCSC was isolated from, coexpressed liver cancer and myelomonocytic markers, also demonstrating mixed phenotypes. The xenografts and the parental cells secreted albumin demonstrating their hepatocyte origin and also expressed cytokines [interleukin (IL)-1b, IL-6, IL-12A, IL-18, tumor necrosis factor-alpha (TNF-α), and CSF1] and chemokines (IL-8, CCL2, and CCL5). Expression of these cytokines and chemokines responded to the stimuli [interferon-γ (INF-γ), IL-4, and lipopolysaccharide (LPS)]. Furthermore, human xenografts and the parental cells phagocytized Escherichia coli. CD34(+) LCSC coexpressed CD45, demonstrating that its origin appears to be from a hematopoietic precursor. The percentage of cells positive for OV6, CD34, and CD31, presenting the markers of HSPC, hematopoietic, and myelomonocytic cells, increased under treatment of CD34(+) LCSC with a drug. Cytogenetic analysis showed that CD34(+) LCSC contained a greater number of chromosomes. HBV DNA integrations and mutations in CD34(+) LCSC and the parental cells were identical to those in the literature or the database. Thus, these results demonstrated that CD34(+) LCSCs were formed by fusion of HSPC with CD34(+) hematopoietic precursor-derived myeloid intermediates; it appears that this is the first report that human CSCs have been formed by the fusion. Therefore, it represents a significant step toward better understanding of the formation of human CSC and the diverse origins of liver

  2. Proteomic Cornerstones of Hematopoietic Stem Cell Differentiation: Distinct Signatures of Multipotent Progenitors and Myeloid Committed Cells*

    PubMed Central

    Klimmeck, Daniel; Hansson, Jenny; Raffel, Simon; Vakhrushev, Sergey Y.; Trumpp, Andreas; Krijgsveld, Jeroen

    2012-01-01

    Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem/progenitor cells (HSPCs, LinnegSca-1+c-Kit+) or myeloid committed precursors (LinnegSca-1−c-Kit+). By employing stable isotope dimethyl labeling and high-resolution mass spectrometry, more than 5000 proteins were quantified. From biological triplicate experiments subjected to rigorous statistical evaluation, 893 proteins were found differentially expressed between multipotent and myeloid committed cells. The differential protein content in these cell populations points to a distinct structural organization of the cytoskeleton including remodeling activity. In addition, we found a marked difference in the expression of metabolic enzymes, including a clear shift of specific protein isoforms of the glycolytic pathway. Proteins involved in translation showed a collective higher expression in myeloid progenitors, indicating an increased translational activity. Strikingly, the data uncover a unique signature related to immune defense mechanisms, centering on the RIG-I and type-1 interferon response systems, which are installed in multipotent progenitors but not evident in myeloid committed cells. This suggests that specific, and so far unrecognized, mechanisms protect these immature cells before they mature. In conclusion, this study indicates that the transition of hematopoietic stem/progenitors toward myeloid commitment is accompanied by a profound change in processing of

  3. The Hematopoietic Differentiation and Production of Mature Myeloid Cells from Human Pluripotent Stem Cells

    PubMed Central

    Choi, Kyung-Dal; Vodyanik, Maxim; Slukvin, Igor I.

    2011-01-01

    Here we describe a protocol for hematopoietic differentiation of human pluripotent stem cells (hPSCs) and generation of mature myeloid cells from hPSCs through expansion and differentiation of hPSC-derived lin-CD34+CD43+CD45+ multipotent progenitors. The protocol is comprised of three major steps: (i) induction of hematopoietic differentiation by coculture of hPSCs with OP9 bone marrow stromal cells, (ii) short-term expansion of multipotent myeloid progenitors with a high dose of GM-CSF, and (iii) directed differentiation of myeloid progenitors into neutrophils, eosinophils, dendritic cells (DCs), Langerhans cells (LCs), macrophages, and osteoclasts. The generation of multipotent hematopoietic progenitors from hPSCs requires 9 days of culture, and an additional 2 days are needed to expand myeloid progenitors. Differentiation of myeloid progenitors into mature myeloid cells requires an additional 5–19 days of culture with cytokines, depending on the cell type. PMID:21372811

  4. Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies.

    PubMed

    Pasquini, Marcelo C; Zhang, Mei-Jie; Medeiros, Bruno C; Armand, Philippe; Hu, Zhen-Huan; Nishihori, Taiga; Aljurf, Mahmoud D; Akpek, Görgün; Cahn, Jean-Yves; Cairo, Mitchell S; Cerny, Jan; Copelan, Edward A; Deol, Abhinav; Freytes, César O; Gale, Robert Peter; Ganguly, Siddhartha; George, Biju; Gupta, Vikas; Hale, Gregory A; Kamble, Rammurti T; Klumpp, Thomas R; Lazarus, Hillard M; Luger, Selina M; Liesveld, Jane L; Litzow, Mark R; Marks, David I; Martino, Rodrigo; Norkin, Maxim; Olsson, Richard F; Oran, Betul; Pawarode, Attaphol; Pulsipher, Michael A; Ramanathan, Muthalagu; Reshef, Ran; Saad, Ayman A; Saber, Wael; Savani, Bipin N; Schouten, Harry C; Ringdén, Olle; Tallman, Martin S; Uy, Geoffrey L; Wood, William A; Wirk, Baldeep; Pérez, Waleska S; Batiwalla, Minoo; Weisdorf, Daniel J

    2016-02-01

    The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed.

  5. Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies.

    PubMed

    Pasquini, Marcelo C; Zhang, Mei-Jie; Medeiros, Bruno C; Armand, Philippe; Hu, Zhen-Huan; Nishihori, Taiga; Aljurf, Mahmoud D; Akpek, Görgün; Cahn, Jean-Yves; Cairo, Mitchell S; Cerny, Jan; Copelan, Edward A; Deol, Abhinav; Freytes, César O; Gale, Robert Peter; Ganguly, Siddhartha; George, Biju; Gupta, Vikas; Hale, Gregory A; Kamble, Rammurti T; Klumpp, Thomas R; Lazarus, Hillard M; Luger, Selina M; Liesveld, Jane L; Litzow, Mark R; Marks, David I; Martino, Rodrigo; Norkin, Maxim; Olsson, Richard F; Oran, Betul; Pawarode, Attaphol; Pulsipher, Michael A; Ramanathan, Muthalagu; Reshef, Ran; Saad, Ayman A; Saber, Wael; Savani, Bipin N; Schouten, Harry C; Ringdén, Olle; Tallman, Martin S; Uy, Geoffrey L; Wood, William A; Wirk, Baldeep; Pérez, Waleska S; Batiwalla, Minoo; Weisdorf, Daniel J

    2016-02-01

    The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed. PMID:26327629

  6. Effects of mycobacterial infection on proliferation of hematopoietic precursor cells.

    PubMed

    Choi, Hong-Hee; Kim, Kwang-Kyu; Kim, Kwang Dong; Kim, Hwa-Jung; Jo, Eun-Kyeong; Song, Chang-Hwa

    2011-12-01

    Bacterial infection can affect hematopoietic precursor cells in bone marrow, because the infected tissues produce various cytokines and chemokines. Little is known about hematopoietic precursor cells, including hematopoietic stem cells and their progenitors, during mycobacterial infection. Here, we showed that mycobacterial infections result in the expansion of not only the lin-c-kit+sca-1+ (LKS+) cell population, but also granulocyte-monocyte progenitor cells in a chronic murine tuberculosis model. Interestingly, stimulation of LKS+ cells with attenuated Mycobacterium tuberculosis H37Ra culture filtrate (RaCF) was significantly stronger than that by virulent H37Rv culture filtrate (RvCF). Lower TNF-α and IL-6 levels were observed in RvCF-stimulated bone marrow cells. Neutralization of TNF-α or IL-6 in RaCF-stimulated bone marrow cells markedly suppressed LKS+ cell clonal expansion. Additionally, numbers of LKS+ cells were lower in TLR2(-/-) and MyD88(-/-) mice after mycobacterial infection. Taken together, LKS+ cell proliferation related to mycobacterial virulence may be related to the secretion of TNF-α and IL-6 associated with TLR signaling. Expansion of hematopoietic progenitor cells may, therefore, play an important role during mycobacterial infection.

  7. Vav promotes differentiation of human tumoral myeloid precursors

    SciTech Connect

    Bertagnolo, Valeria; Brugnoli, Federica; Mischiati, Carlo; Sereni, Alessia; Bavelloni, Alberto; Carini, Cinzia; Capitani, Silvano . E-mail: cps@unife.it

    2005-05-15

    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.

  8. Characterization of the Murine Myeloid Precursor Cell Line MuMac-E8

    PubMed Central

    Fricke, Stephan; Riemschneider, Sina; Kohlschmidt, Janine; Hilger, Nadja; Fueldner, Christiane; Knauer, Jens; Sack, Ulrich; Emmrich, Frank; Lehmann, Jörg

    2014-01-01

    Starting point for the present work was the assumption that the cell line MuMac-E8 represents a murine cell population with stem cell properties. Preliminary studies already pointed to the expression of stem-cell associated markers and a self-regenerative potential of the cells. The cell line MuMac-E8 should be examined for their differential stage within stem cell hierarchy. MuMac-E8 cells were derived from a chimeric mouse model of arthritis. It could be shown that MuMac-E8 cells express mRNA of some genes associated with pluripotent stem cells (Nanog, Nucleostemin), of genes for hematopoietic markers (EPCR, Sca-1, CD11b, CD45), for the mesenchymal marker CD105 and of genes for the neural markers Pax-6 and Ezrin. In methylcellulose and May-Grünwald-Giemsa staining, hematopoietic colonies were obtained but the hematopoietic system of lethally irradiated mice could not be rescued. Osteogenic differentiation was not detectable. Thus, it became evident that MuMac-E8 represents not a stem cell line. However, MuMac-E8 cells expressed several myeloid surface markers (i.e. CD11b, F4/80, CD14, CD64), showed phagocytosis and is capable of producing nitric oxide. Thus, this cell line seems to be arrested an advanced stage of myeloid differentiation. Adherence data measured by impedance-based real-time cell analysis together with cell morphology data suggested that MuMac-E8 represents a new macrophage precursor cell line exhibiting weak adherence. This cell line is suitable as an in-vitro model for testing of macrophage functions. Moreover, it might be also useful for differentiation or reprogramming studies. PMID:25546418

  9. Characterization of the murine myeloid precursor cell line MuMac-E8.

    PubMed

    Fricke, Stephan; Pfefferkorn, Cathleen; Wolf, Doris; Riemschneider, Sina; Kohlschmidt, Janine; Hilger, Nadja; Fueldner, Christiane; Knauer, Jens; Sack, Ulrich; Emmrich, Frank; Lehmann, Jörg

    2014-01-01

    Starting point for the present work was the assumption that the cell line MuMac-E8 represents a murine cell population with stem cell properties. Preliminary studies already pointed to the expression of stem-cell associated markers and a self-regenerative potential of the cells. The cell line MuMac-E8 should be examined for their differential stage within stem cell hierarchy. MuMac-E8 cells were derived from a chimeric mouse model of arthritis. It could be shown that MuMac-E8 cells express mRNA of some genes associated with pluripotent stem cells (Nanog, Nucleostemin), of genes for hematopoietic markers (EPCR, Sca-1, CD11b, CD45), for the mesenchymal marker CD105 and of genes for the neural markers Pax-6 and Ezrin. In methylcellulose and May-Grünwald-Giemsa staining, hematopoietic colonies were obtained but the hematopoietic system of lethally irradiated mice could not be rescued. Osteogenic differentiation was not detectable. Thus, it became evident that MuMac-E8 represents not a stem cell line. However, MuMac-E8 cells expressed several myeloid surface markers (i.e. CD11b, F4/80, CD14, CD64), showed phagocytosis and is capable of producing nitric oxide. Thus, this cell line seems to be arrested an advanced stage of myeloid differentiation. Adherence data measured by impedance-based real-time cell analysis together with cell morphology data suggested that MuMac-E8 represents a new macrophage precursor cell line exhibiting weak adherence. This cell line is suitable as an in-vitro model for testing of macrophage functions. Moreover, it might be also useful for differentiation or reprogramming studies.

  10. BET bromodomain inhibition suppresses the functional output of hematopoietic transcription factors in acute myeloid leukemia

    PubMed Central

    Roe, Jae-Seok; Mercan, Fatih; Rivera, Keith; Pappin, Darryl J.; Vakoc, Christopher R.

    2015-01-01

    Summary The bromodomain and extraterminal (BET) protein BRD4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that BRD4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) PU.1, FLI1, ERG, C/EBPα, C/EBPβ, and MYB at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate BRD4 recruitment to their occupied sites to promote transcriptional activation. Chemical inhibition of BET bromodomains was found to suppress the functional output each hematopoietic TF, thereby interfering with essential lineage-specific transcriptional circuits in this disease. These findings reveal a chromatin-based signaling cascade comprised of hematopoietic TFs, p300/CBP, and BRD4 that supports leukemia maintenance and is suppressed by BET bromodomain inhibition. PMID:25982114

  11. Current status of hematopoietic stem cell transplant in chronic myeloid leukemia

    PubMed Central

    Gupta, Alok; Khattry, Navin

    2014-01-01

    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. PMID:25336791

  12. Twist-1, a novel regulator of hematopoietic stem cell self-renewal and myeloid lineage development.

    PubMed

    Dong, Cheng-Ya; Liu, Xiao-Yan; Wang, Nan; Wang, Li-Na; Yang, Bin-Xia; Ren, Qian; Liang, Hao-Yue; Ma, Xiao-Tong

    2014-12-01

    Transcription factor Twist-1 plays essential roles in specification and differentiation of mesoderm-derived tissues. Growing evidences now link Twist-1 to the acquisition of stem-cell-like properties. However, the role of Twist-1 in hematopoietic stem cell (HSC) remains largely uncharacterized. We report that Twist-1 is more highly expressed in murine HSC and its expression declines with differentiation. To investigate Twist-1 gene function, retroviral-mediated overexpression or removal experiments are performed. Competitive repopulation studies demonstrate that enforced expression of Twist-1 in HSC-enriched Lin(-) c-Kit(+) Sca-1(+) (LKS) cells results in an increase in the size of the G(0) population, and in their reconstitution ability after the first and a second transplantation. Conversely, removal of Twist-1 in LKS cells impairs their ability to repopulate. In addition, increased Twist-1 expression causes a shift toward production of myeloid cells. Twist-1 transduction in LKS cells activates myeloid lineage-determining factors PU.1 and GATA-1 and downregulates lymphoid factor GATA-3 in vitro, suggesting that Twist-1-mediated myeloid skewing occurs in hematopoietic stem and progenitor cells (HSPCs). These findings indicate that Twist-1 is not only involved in the maintenance of HSC dormancy and self-renewal capacity but also implicated in the myeloid lineage fate choice of HSPCs. Exploration of the underlying mechanisms reveals that Runx1/c-Mpl/Tie2 regulatory pathway could possibly account for the observed effects caused by Twist-1 overexpression. Our study provides the first evidence supporting a role for Twist-1 in hematopoiesis.

  13. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via re-specification of lineage-restricted precursors

    PubMed Central

    Doulatov, Sergei; Vo, Linda T.; Chou, Stephanie S.; Kim, Peter G.; Arora, Natasha; Li, Hu; Hadland, Brandon K.; Bernstein, Irwin D.; Collins, James J.; Zon, Leonard I.; Daley, George Q.

    2013-01-01

    Summary Human pluripotent stem cells (hPSCs) represent a promising source of patient-specific cells for disease modeling, drug screens, and cellular therapies. However, the inability to derive engraftable human hematopoietic stem and progenitor (HSPCs) has limited their characterization to in vitro assays. We report a strategy to re-specify lineage-restricted CD34+CD45+ myeloid precursors derived from hPSCs into multilineage progenitors that can be expanded in vitro and engraft in vivo. HOXA9, ERG, and RORA conferred self-renewal and multilineage potential in vitro and maintained primitive CD34+CD38− cells. Screening cells via transplantation revealed that two additional factors, SOX4 and MYB, were required for engraftment. Progenitors specified with all five factors gave rise to reproducible short-term engraftment with myeloid and erythroid lineages. Erythroid precursors underwent hemoglobin switching in vivo, silencing embryonic and activating adult globin expression. Our combinatorial screening approach establishes a strategy for obtaining transcription factor-mediated engraftment of blood progenitors from human pluripotent cells. PMID:24094326

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

    PubMed

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

    2015-12-01

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

  15. Generation of hematopoietic progenitor cell lines with myeloid and lymphoid potential

    PubMed Central

    Redecke, Vanessa; Wu, Ruiqiong; Zhou, Jingran; Finkelstein, David; Chaturvedi, Vandana; High, Anthony A.; Häcker, Hans

    2013-01-01

    Investigation of immune cell differentiation and function is limited by shortcomings of suitable and scalable experimental systems. Here we show that an estrogen–regulated form of HOXB8 that is retrovirally delivered into mouse bone marrow cells can be used along with FLT3 ligand to conditionally immortalize early hematopoietic progenitor cells (Hoxb8–FL). Hoxb8–FL cells have lost self–renewal capacity and megakaryocyte/ erythroid lineage potential, but sustain myeloid and lymphoid potential. Hoxb8–FL cells differentiate in vitro and in vivo into different myeloid and lymphoid cell types, including macrophages, granulocytes, dendritic cells and B– and T–lymphocytes, which are phenotypically and functionally indistinguishable from their primary counterparts. Quantitative in vitro cell lineage potential assays implicate that myeloid and B–cell potential of Hoxb8–FL cells is comparable to primary lymphoid–primed multipotent progenitors, while T–cell potential is comparatively reduced. Given the simplicity and unlimited proliferative capacity of Hoxb8–FL cells, this system provides unique opportunities to investigate cell differentiation and immune cell functions. PMID:23749299

  16. (Lymph)angiogenic influences on hematopoietic cells in acute myeloid leukemia

    PubMed Central

    Lee, Ji Yoon; Kim, Hee-Je

    2014-01-01

    The purpose of this review is to provide an overview of the effect of (lymph)angiogenic cytokines on hematopoietic cells involved in acute myeloid leukemia (AML). Like angiogenesis, lymphangiogenesis occurs in pathophysiological conditions but not in healthy adults. AML is closely associated with the vasculature system, and the interplay between lymphangiogenic cytokines maintains leukemic blast survival in the bone marrow (BM). Once AML is induced, proangiogenic cytokines function as angiogenic or lymphangiogenic factors and affect hematopoietic cells, including BM-derived immune cells. Simultaneously, the representative cytokines, VEGFs and their receptors are expressed on AML blasts in vascular and osteoblast niches in both the BM and the peripheral circulation. After exposure to (lymph)angiogenic cytokines in leukemogenesis and infiltration, immune cell phenotypes and functions are affected. These dynamic behaviors in the BM reflect the clinical features of AML. In this review, we note the importance of lymphangiogenic factors and their receptors in hematopoietic cells in AML. Understanding the functional characterization of (lymph)angiogenic factors in the BM niche in AML will also be helpful in interrupting the engraftment of leukemic stem cells and for enhancing immune cell function by modulating the tumor microenvironment. PMID:25412683

  17. Enhanced generation of myeloid lineages in hematopoietic differentiation from embryonic stem cells by silencing transcriptional repressor Twist-2.

    PubMed

    Sharabi, Andrew B; Lee, Sung-Hyung; Goodell, Margaret A; Huang, Xue F; Chen, Si-Yi

    2009-12-01

    The self-renewal and multilineage differentiation of embryonic stem cells (ESC) is largely governed by transcription factors or repressors. Extensive efforts have focused on elucidating critical factors that control the differentiation of specific cell lineages, for instance, myeloid lineages in hematopoietic development. In this study, we found that Twist-2, a basic helix-loop-helix (bHLH) transcription factor, plays a critical role in inhibiting the differentiation of ESC. Murine ES cells, in which Twist-2 expression is silenced by lentivirally delivered shRNA, exhibit an enhanced formation of primary embryoid bodies (EB) and enhanced differentiation into mesodermally derived hematopoietic colonies. Furthermore, Twist-2 silenced (LV-siTwist-2) ESC display significantly increased generation of myeloid lineages (Gr-1(+) and F4/80(+) cells) during in vitro hematopoietic differentiation. Treatment with the Toll-like receptor (TLR) 4 ligand synergistically stimulates the generation of primary EB formation as well as of hematopoietic progenitors differentiated from LV-siTwist-2 ES cells. Thus, this study reveals the critical role of the transcriptional repressor Twist-2 in regulating the development of myeloid lineage in hematopoietic differentiation from ESC. This study also suggests a potential strategy for directional differentiation of ESC by inhibiting a transcriptional repressor.

  18. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J.; Llanos-Gómez, Juan M.; Cabello-Rodríguez, Ana I.; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called “sanctuaries,” are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass.

  19. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J.; Llanos-Gómez, Juan M.; Cabello-Rodríguez, Ana I.; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called “sanctuaries,” are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass. PMID:27642531

  20. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Facenda-Lorenzo, María; Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J; Llanos-Gómez, Juan M; Cabello-Rodríguez, Ana I; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called "sanctuaries," are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass. PMID:27642531

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

    SciTech Connect

    Seed, T.M.

    1990-01-01

    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.

  2. High-level expression of the ER-MP58 antigen on mouse bone marrow hematopoietic progenitor cells marks commitment to the myeloid lineage.

    PubMed

    de Bruijn, M F; Ploemacher, R E; Mayen, A E; Voerman, J S; Slieker, W A; van Ewijk, W; Leenen, P J

    1996-12-01

    Studies on the early events in the differentiation of the nonspecific immune system require the identification and isolation of myeloid-committed progenitor cells. Using the monoclonal antibodies (mAb) ER-MP12 and ER-MP20, generated against immortalized macrophage precursors, we have shown previously that the earliest macrophage colony-stimulating factor (M-CSF)-responsive cells in the bone marrow have the ER-MP12hi 20- phenotype. In addition, we found that the ER-MP12hi 20- subset (comprising about 2 % of total nucleated marrow) contains progenitor cells of all hematopoietic lineages. Aiming at the identification and purification of the myeloid progenitor cells within the ER-MP12hi 20-subset, we used ER-MP58, a marker expressed at high level by all M-CSF-responsive bone marrow progenitors. With this marker the ER-MP12hi 20- cell population could be divided into three subfractions: one with absent or low level ER-MP58 expression, one with intermediate, and one with high ER-MP58 expression. These subfractions were isolated by fluorescence-activated cell sorting and tested in vitro and in vivo for their differentiation capacities. In addition, the expression of ER-MP58 on stem cell subsets was examined in the cobblestone area-forming cell (CAFC) assay. Our data indicate that in the ER-MP12hi 20- subpopulation myeloid-committed progenitors are characterized by high-level expression of the ER-MP58 antigen, whereas cells with other or broader differentiation capacities have an ER-MP58 negative/low or intermediate phenotype. These myeloid-committed progenitors have no significant repopulating ability in vivo, in contrast to the ER-MP58 intermediate cells. Primitive CAFC-28/35, corresponding to cells providing long-term hematopoietic engraftment in vivo, also did not express the ER-MP58 Ag at a high level. Thus, cells committed to the myeloid lineage can be separated from progenitor cells with other differentiation capacities by means of multiparameter cell sorting using

  3. Myeloid/Microglial Driven Autologous Hematopoietic Stem Cell Gene Therapy Corrects a Neuronopathic Lysosomal Disease

    PubMed Central

    Sergijenko, Ana; Langford-Smith, Alexander; Liao, Ai Y; Pickford, Claire E; McDermott, John; Nowinski, Gabriel; Langford-Smith, Kia J; Merry, Catherine LR; Jones, Simon A; Wraith, J Edmond; Wynn, Robert F; Wilkinson, Fiona L; Bigger, Brian W

    2013-01-01

    Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice. PMID:23748415

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

    PubMed Central

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

    2014-01-01

    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

  5. Risk Assessment before Allogeneic Hematopoietic Cell Transplantation for Older Adults with Acute Myeloid Leukemia

    PubMed Central

    Sorror, Mohamed L.; Appelbaum, Frederick R.

    2013-01-01

    SUMMARY Acute myeloid leukemia (AML) most commonly affects patients older than 60 years. Outcomes of treatment of older AML patients have been poor. The advent of reduced-intensity conditioning (RIC) regimens made allogeneic hematopoietic cell transplantation (HCT) an available treatment option with curative intent for older AML patients. Because older patients are often excluded from clinical trials, little is known about the stratification of their risks before allogeneic HCT. While recent studies of RIC and allogeneic HCT have shown little impact of age on outcomes, other variables such as the recipient health status and the AML disease status and chromosomal aberrations have proven to be of prognostic significance. Here, we review recent studies of allogeneic HCT for older patients with AML with detailed evaluation of risk factors for relapse as well as non-relapse mortality. We have integrated the currently available information on transplant risks into a five-category risk-benefit system that could aid in the decision-making in this patient population. PMID:24083472

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-06-01

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

  8. Testicular myeloid sarcoma: case report

    PubMed Central

    Zago, Luzia Beatriz Ribeiro; Ladeia, Antônio Alexandre Lisbôa; Etchebehere, Renata Margarida; de Oliveira, Leonardo Rodrigues

    2013-01-01

    Myeloid sarcomas are extramedullary solid tumors composed of immature granulocytic precursor cells. In association with acute myeloid leukemia and other myeloproliferative disorders, they may arise concurrently with compromised bone marrow related to acute myeloid leukemia, as a relapsed presentation, or occur as the first manifestation. The testicles are considered to be an uncommon site for myeloid sarcomas. No therapeutic strategy has been defined as best but may include chemotherapy, radiotherapy and/or hematopoietic stem cell transplantation. This study reports the evolution of a patient with testicular myeloid sarcoma as the first manifestation of acute myeloid leukemia. The patient initially refused medical treatment and died five months after the clinical condition started. PMID:23580888

  9. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in older adults.

    PubMed

    Sorror, Mohamed L; Estey, Elihu

    2014-12-01

    Acute myeloid leukemia (AML) is primarily a disease of the elderly and the numbers of these patients are increasing. Patients ≥60 years of age continue to have poor prognosis. Preliminary results suggest benefit from reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in selected patients 60-80 years of age. However, although patients in this age range comprise >50% of those with AML, they currently constitute only 17% of those offered HCT. In the absence of prospective randomized studies comparing HCT and chemotherapy, the decision to recommend HCT rests on retrospective analyses of the risks of relapse and nonrelapse mortality after each approach. There is strong evidence that pre-HCT comorbidities can predict HCT-related morbidity and mortality. Age alone does not appear predictive and, particularly if the risk of relapse with chemotherapy is high, should not be the sole basis for deciding against HCT. Use of geriatric assessment tools, inflammatory biomarkers, and genetic polymorphism data may further aid in predicting nonrelapse mortality after HCT. Disease status and pretreatment cytogenetics with FLT3-TID, NPM-1, and CEBP-α status are the main factors predicting relapse and these are likely to be supplemented by incorporation of other molecular markers and the level of minimal residual disease after chemotherapy. HLA-matched related and unrelated donor grafts seem preferable to those from other donor sources. Donor age is of no clear significance. Models combining comorbidities with AML risk factors are useful in risk assessment before HCT. In this chapter, we integrated information on AML-specific, HCT-specific, and patient-specific risk factors into a risk-adapted approach to guide decisions about HCT versus no HCT.

  10. Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia

    PubMed Central

    Gyurkocza, Boglarka; Storb, Rainer; Storer, Barry E.; Chauncey, Thomas R.; Lange, Thoralf; Shizuru, Judith A.; Langston, Amelia A.; Pulsipher, Michael A.; Bredeson, Christopher N.; Maziarz, Richard T.; Bruno, Benedetto; Petersen, Finn B.; Maris, Michael B.; Agura, Edward; Yeager, Andrew; Bethge, Wolfgang; Sahebi, Firoozeh; Appelbaum, Frederick R.; Maloney, David G.; Sandmaier, Brenda M.

    2010-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning regimens imposes prohibitively high risks of morbidity and mortality for patients with high-risk acute myeloid leukemia (AML) who are older or have comorbid conditions. Here, we examined outcomes after nonmyeloablative allogeneic HCT in such patients. Patients and Methods Two hundred seventy-four patients (median age, 60 years) with de novo or secondary AML underwent allogeneic HCT from related (n = 118) or unrelated donors (n = 156) after conditioning with 2 Gy of total-body irradiation (TBI) with or without fludarabine. A calcineurin inhibitor and mycophenolate mofetil were used for postgrafting immunosuppression. Results With a median follow-up of 38 months in surviving patients, the estimated overall survival at 5 years was 33%. The estimated 5-year relapse/progression and nonrelapse mortality rates were 42% and 26%, respectively. The cumulative incidences of grades 2, 3, and 4 acute graft-versus-host disease (GVHD) were 38%, 9%, and 5%, respectively. The cumulative incidence of chronic GVHD at 5 years was 44%. Patients in first and second complete remission had better survival rates than patients with more advanced disease (37% and 34% v 18%, respectively). Patients with HLA-matched related or unrelated donors had similar survivals. Unfavorable cytogenetic risk status was associated with increased relapse and subsequent mortality. Chronic GVHD was associated with lower relapse risk. Conclusion Allogeneic HCT from related or unrelated donors after conditioning with low-dose TBI and fludarabine, relying almost exclusively on graft-versus-leukemia effects, can result in long-term remissions in older or medically infirm patients with AML. PMID:20439626

  11. Extracellular vesicle miR-7977 is involved in hematopoietic dysfunction of mesenchymal stromal cells via poly(rC) binding protein 1 reduction in myeloid neoplasms

    PubMed Central

    Horiguchi, Hiroto; Kobune, Masayoshi; Kikuchi, Shohei; Yoshida, Masahiro; Murata, Masaki; Murase, Kazuyuki; Iyama, Satoshi; Takada, Kohichi; Sato, Tsutomu; Ono, Kaoru; Hashimoto, Akari; Tatekoshi, Ayumi; Kamihara, Yusuke; Kawano, Yutaka; Miyanishi, Koji; Sawada, Norimasa; Kato, Junji

    2016-01-01

    The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition. Importantly, the transfer of myeloid neoplasm-derived extracellular vesicles reduced the hematopoietic supportive capacity of mesenchymal stem cells. Analysis of extracellular vesicle microRNA indicated that several species, including miR-7977 from acute myeloid leukemia cells, were higher than those from normal CD34+ cells. Remarkably, the copy number of miR-7977 in bone marrow interstitial fluid was elevated not only in acute myeloid leukemia, but also in myelodysplastic syndrome, as compared with lymphoma without bone marrow localization. The transfection of the miR-7977 mimic reduced the expression of the posttranscriptional regulator, poly(rC) binding protein 1, in mesenchymal stem cells. Moreover, the miR-7977 mimic induced aberrant reduction of hematopoietic growth factors in mesenchymal stem cells, resulting in decreased hematopoietic-supporting capacity of bone marrow CD34+ cells. Furthermore, the reduction of hematopoietic growth factors including Jagged-1, stem cell factor and angiopoietin-1 were reverted by target protection of poly(rC) binding protein 1, suggesting that poly(rC) binding protein 1 could be involved in the stabilization of several growth factors. Thus, miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression. PMID:26802051

  12. [Effect of decitabine on immune regulation in patients with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

    PubMed

    Wang, Jing; Zhou, Jin; Zheng, Hui-Fei; Fu, Zheng-Zheng

    2014-10-01

    Based on the representative articles in recent years, the different mechanisms of decitabine on immune regulation in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) are summarized. Decitabine improves the expression of WT1 gene to stimulate specific cytotoxic T cells which can enhance graft versus leukemia effect (GVL) and improve the expression of FOXP3 gene to stimulate regulatory T cells so as to inhibit the acute graft versus host disease (GVHD). Through the above-mentimed mechanisms, decitabine can improve both therapeutic effect and quality of life in the patients with AML after allogeneic HSCT.

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

    PubMed Central

    2013-01-01

    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

  14. Changes of nucleolar organizer regions in granulopoietic precursors during the course of chronic myeloid leukemia.

    PubMed

    Gilberti, M F; Metze, K; Lorand-Metze, I

    1995-12-01

    The aim of the present study was to analyze the nucleolar organizer region (AgNOR) pattern of granulopoietic precursors in chronic myeloid leukemia (CML) at diagnosis and during the course of the disease. Clusters of AgNORs and isolated dots were counted separately in 24 cases of CML at diagnosis, in 19 cases during the relapse of the chronic phase after treatment, and in 16 cases of blast crisis. For comparison, 20 cases of normal bone marrow were studied. Each cell type had its own characteristic AgNOR pattern, as has been described for normal bone marrow. There was no significant difference in the number of AgNORs between cells in the peripheral blood and bone marrow. Compared with normal granulopoiesis, myeloblasts in CML at diagnosis had lower numbers of clusters, which decreased further during relapse of chronic phase and in blast crisis. Promyelocytes and myelocytes showed significantly fewer dots. The number of AgNOR clusters correlates inversely with the duration of the cell cycle. Therefore, these findings are consistent with the progressive loss in proliferative activity of immature precursors described during the course of CML. As the number of dots indicates cellular maturation, their lower number in promyelocytes and myelocytes in CML favors the concept of a discordant maturation process described in this disease. The separate counting of clusters and dots provides a useful, simple, and cheap method of describing cytokinetic changes during the course of this myeloproliferative disorder.

  15. Heterogeneity of clonal expansion and maturation-linked mutation acquisition in hematopoietic progenitors in human acute myeloid leukemia.

    PubMed

    Walter, R B; Laszlo, G S; Lionberger, J M; Pollard, J A; Harrington, K H; Gudgeon, C J; Othus, M; Rafii, S; Meshinchi, S; Appelbaum, F R; Bernstein, I D

    2014-10-01

    Recent technological advances led to an appreciation of the genetic complexity of human acute myeloid leukemia (AML), but underlying progenitor cells remain poorly understood because their rarity precludes direct study. We developed a co-culture method integrating hypoxia, aryl hydrocarbon receptor inhibition and micro-environmental support via human endothelial cells to isolate these cells. X-chromosome inactivation studies of the least mature precursors derived following prolonged culture of CD34(+)/CD33(-) cells revealed polyclonal growth in highly curable AMLs, suggesting that mutations necessary for clonal expansion were acquired in more mature progenitors. Consistently, in core-binding factor (CBF) leukemias with known complementing mutations, immature precursors derived following prolonged culture of CD34(+)/CD33(-) cells harbored neither mutation or the CBF mutation alone, whereas more mature precursors often carried both mutations. These results were in contrast to those with leukemias with poor prognosis that showed clonal dominance in the least mature precursors. These data indicate heterogeneity among progenitors in human AML that may have prognostic and therapeutic implications.

  16. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells.

    PubMed

    Ruud, Johan; Wilhelms, Daniel Björk; Nilsson, Anna; Eskilsson, Anna; Tang, Yan-Juan; Ströhle, Peter; Caesar, Robert; Schwaninger, Markus; Wunderlich, Thomas; Bäckhed, Fredrik; Engblom, David; Blomqvist, Anders

    2013-05-01

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

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

    PubMed Central

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

    2011-01-01

    Background Allogeneic hematopoietic stem cell transplantation with HLA-identical donors has been established for the treatment of acute myeloid leukemia patients for over 30 years with a cure rate of 50% to 60%. Objectives To analyze the overall survival of patients and identify factors that influence the outcomes of this type of transplant in patients in 1st complete remission who received a busulfan and melphalan combination as conditioning regimen. Methods Twenty-five consecutive patients with acute myeloid leukemia were enrolled between 2003 and 2008. The median age was 34 years old (Range: 16 - 57 years). All patients received cyclosporine and methotrexate for prophylaxis against graft-versus-host disease. Median neutrophil engraftment time was 16 days (Range: 7 - 22 days) and 17 days (Range: 7 - 46 days) for platelets. Sinusoidal obstructive syndrome was observed in three patients, seven had grade II acute graft-versus-host disease and one extensive chronic graft-versus-host disease. Results The overall survival by the Kaplan-Meier method was 48% after 36 months with a plateau at 36 months after transplantation. Intensive consolidation with high-dose arabinoside resulted in an improved survival (p-value = 0.0001), as did grade II acute graft-versus-host disease (p-value = 0.0377) and mild chronic graft-versus-host disease (p-value < 0.0001). Thirteen patients died, five due to infection within 100 days of transplant, two due to hemorrhages, one to infection and graftversus-host disease and three relapses followed by renal failure (one) and infection (two). The cause of death could not be determined for two patients. Conclusion The busulfan and melphalan conditioning regimen is as good as other conditioning regimens providing an excellent survival rate. PMID:23049292

  18. Allogeneic hematopoietic cell transplant outcomes in acute myeloid leukemia: Similar outcomes regardless of donor type

    PubMed Central

    Warlick, Erica D.; de Latour, Regis Peffault; Shanley, Ryan; Robin, Marie; Bejanyan, Nelli; Xhaard, Alienor; Brunstein, Claudio; de Fontbrune, Flore Sicre; Ustun, Celalettin; Weisdorf, Daniel J; Socie, Gerard

    2016-01-01

    The use of alternative donor transplants is increasing as the transplant eligible population ages and sibling donors are less available. We evaluated the impact of donor source on transplant outcomes for adults with acute myeloid leukemia undergoing myeloablative or reduced intensity conditioning transplant. Between January 2000 and December 2010, 414 consecutive adult patients with acute myeloid leukemia in remission received myeloablative or reduced intensity conditioning allogeneic transplant from either a matched related donor (n=187), unrelated donor (n=76), or umbilical cord blood donor (n=151) at the University of Minnesota or Hôpital St. Louis in Paris. We noted similar 6 year overall survival across donor types: matched related donor 47% (95% CI, 39–54%), umbilical cord blood 36% (95% CI, 28–44%), matched unrelated donor 54% (95% CI, 40–66%), mismatched unrelated donor 51% (95% CI, 28–70%) (p=0.11). Survival differed based on conditioning intensity and age with 6 year survival of 57% (95% CI 47–65%), 39% (95% CI, 28–49%), 23% (95% CI, 6–47%), 47% (95% CI, 36–57%) and 28% (95% CI, 17–41%) for myeloablative age 18–39, myeloablative age 40+, or reduced intensity conditioning ages 18–39, 40–56, and 57–74 respectively (p< 0.01). Relapse was increased with reduced intensity conditioning and lowest in younger patients receiving myeloablative conditioning (HR 1.0 versus 2.5 or above for all RIC age cohorts), p<0.01. Transplant related mortality was similar across donor types. In summary, our data support the use of alternative donors as a graft source with MA or RIC for patients with acute myeloid leukemia when a sibling donor is unavailable. PMID:25452032

  19. Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia

    PubMed Central

    Kayser, S; Benner, A; Thiede, C; Martens, U; Huber, J; Stadtherr, P; Janssen, J W G; Röllig, C; Uppenkamp, M J; Bochtler, T; Hegenbart, U; Ehninger, G; Ho, A D; Dreger, P; Krämer, A

    2016-01-01

    The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89% P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD. PMID:27471865

  20. Mobilization of CD34+CD38- hematopoietic stem cells after priming in acute myeloid leukemia

    PubMed Central

    Plesa, Adriana; Chelghoum, Youcef; Mattei, Eve; Labussière, Hélène; Elhamri, Mohamed; Cannas, Giovanna; Morisset, Stéphane; Tagoug, Inès; Michallet, Mauricette; Dumontet, Charles; Thomas, Xavier

    2013-01-01

    AIM: To evaluate quantitatively and qualitatively the different CD34+ cell subsets after priming by chemotherapy granulocyte colony-stimulating factor (± G-CSF) in patients with acute myeloid leukemia. METHODS: Peripheral blood and bone marrow samples were harvested in 8 acute myeloid leukemia patients during and after induction chemotherapy. The CD34/CD38 cell profile was analyzed by multi-parameter flow cytometry. Adhesion profile was made using CXC chemokine receptor 4 (CXCR4) (CD184), VLA-4 (CD49d/CD29) and CD47. RESULTS: Chemotherapy ± G-CSF mobilized immature cells (CD34+CD38− population), while the more mature cells (CD34+CD38low and CD34+CD38+ populations) decreased progressively after treatment. Circulating CD34+ cells tended to be more sensitive to chemotherapy after priming with G-CSF. CD34+ cell mobilization was correlated with a gradual increase in CXCR4 and CD47 expression, suggesting a role in cell protection and the capacity of homing back to the marrow. CONCLUSION: Chemotherapy ± G-CSF mobilizes into the circulation CD34+ bone marrow cells, of which, the immature CD34+CD38– cell population. Further manipulations of these interactions may be a means with which to control the trafficking of leukemia stem cells to improve patients’ outcomes. PMID:24179607

  1. Sorting for storage in myeloid cells of nonmyeloid proteins and chimeras with the propeptide of myeloperoxidase precursor.

    PubMed

    Bülow, E; Nauseef, W M; Goedken, M; McCormick, S; Calafat, J; Gullberg, U; Olsson, I

    2002-02-01

    During formation of polymorphonuclear neutrophils, proteins are synthesized for storage in granules. Whereas sorting of proteins into distinct subtypes of cytoplasmic granules may reflect the coordinated expression of the proteins contained in them, still the mechanism(s) for the retrieval of proteins from the constitutive secretion is unknown. To investigate the mechanisms of retrieval, nonmyeloid secretory proteins were expressed in myeloid cell lines, and their subcellular fate was assessed. The contribution of the propeptide (MPOpro) of the myeloperoxidase (MPO) precursor was investigated by determining the fate of chimeras containing MPOpro. The nonmyeloid protein alpha(1)-microglobulin (alpha(1)-m) was targeted to storage organelles in 32D cells and colocalized with the lysosomal marker LAMP-1, whereas soluble TNF receptor 1 (sTNFR1) was secreted without granule targeting. Fusion of MPOpro to alpha(1)-m delayed exit from endoplasmic reticulum (ER), but subsequent targeting to dense organelles was indistinguishable from that of alpha(1)-m alone. Fusion proteins between MPOpro and sTNFR1 or green fluorescent protein expressed in myeloid 32D, K562, or PLB-985 cells did not associate stably with calreticulin or calnexin, molecular chaperones that normally interact transiently with the MPO precursor, but were still efficiently retained in the ER followed by degradation. We conclude that normally secreted, nonmyeloid proteins can be targeted efficiently to storage organelles in myeloid cells, that myeloid cells selectively target some proteins for storage but not others, and that MPOpro may contribute to the prolonged ER retention of the MPO precursor independent of the ER-molecular chaperones calreticulin and calnexin.

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

    ClinicalTrials.gov

    2016-09-12

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

  3. Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity.

    PubMed

    Gibbs, Bernhard F; Gonçalves Silva, Isabel; Prokhorov, Alexandr; Abooali, Maryam; Yasinska, Inna M; Casely-Hayford, Maxwell A; Berger, Steffen M; Fasler-Kan, Elizaveta; Sumbayev, Vadim V

    2015-10-01

    Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells.

  4. [Effects of myeloid antigen expression on hematopoietic reconstitution and disease prognosis in acute lymphocytic leukemia patients after allogeneic stem cell transplantation].

    PubMed

    Wang, Xiao-Ning; Liu, Hua-Sheng; Zhang, Mei

    2014-08-01

    This study was aimed to investigate the effects of myeloid antigen expression on hematopoietic reconstitution and disease prognosis in acute lymphocytic leukemia patients post-allogeneic stem cell transplantation (allo-HSCT). Clinical data of 20 patients with acute lymphocytic leukemia in Department of Hematology of the First Affiliated Hospital of Xi'an Jiaotong University from 2008 January to 2014 April were retrospectively analyzed, in which 5 cases were with myeloid antigen (My(+) ALL), while 15 patients were without myeloid antigen expression (My(-) ALL). Differences in prognosis and hematopoietic reconstitution post-allo-HSCT were observed in My(+) ALL and My(-) ALL patients. The results showed that the poor platelet engraftment in patients with My(+) ALL was found more than that in My(-)ALL patients. Three My(+) ALL patients experienced skin chronic graft versus host disease (cGVHD) including local in 2 cases and extensive in one case, and 3 My(-) ALL patients developed grade I-II acute GVHD, while five patients of My(-) ALL experienced cGVHD including local in 3 cases, extensive in 2 cases. One and two year overall survival rate of My(+) ALL and My(-) ALL patients was 80% and 85.7%, 53% and 69.8% respectively, one and two year progress-free survival rate was 53.3% and 54.7%, 26% and 27.4%, respectively. And there was no significant statistical difference between two groups (P > 0.05). It is concluded that the myeloid antigen expression may impact the platelet engraftment post-transplantation. There is no significant difference between one and two year overall survival rate and progress-free survival rate of My(+) ALL and My(-) ALL patients after allogeneic stem cell transplantation.

  5. Consequences of irradiation on bone and marrow phenotypes, and its relation to disruption of hematopoietic precursors.

    PubMed

    Green, Danielle E; Rubin, Clinton T

    2014-06-01

    The rising levels of radiation exposure, specifically for medical treatments and accidental exposures, have added great concern for the long term risks of bone fractures. Both the bone marrow and bone architecture are devastated following radiation exposure. Even sub-lethal doses cause a deficit to the bone marrow microenvironment, including a decline in hematopoietic cells, and this deficit occurs in a dose dependent fashion. Certain cell phenotypes though are more susceptible to radiation damage, with mesenchymal stem cells being more resilient than the hematopoietic stem cells. The decline in total bone marrow hematopoietic cells is accompanied with elevated adipocytes into the marrow cavity, thereby inhibiting hematopoiesis and recovery of the bone marrow microenvironment. Poor bone marrow is also associated with a decline in bone architectural quality. Therefore, the ability to maintain the bone marrow microenvironment would hinder much of the trabecular bone loss caused by radiation exposure, ultimately decreasing some comorbidities in patients exposed to radiation. PMID:24607941

  6. CBFB and MYH11 in inv(16)(p13q22) of Acute Myeloid Leukemia Display Close Spatial Proximity in Interphase Nuclei of Human Hematopoietic Stem Cells

    PubMed Central

    Weckerle, Allison B.; Santra, Madhumita; Ng, Maggie C.Y.; Koty, Patrick P.; Wang, Yuh-Hwa

    2013-01-01

    To gain a better understanding of the mechanism of chromosomal translocations in cancer, we investigated the spatial proximity between CBFB and MYH11 genes involved in inv(16)(p13q22) found in acute myeloid leukemia patients. Previous studies have demonstrated a role for spatial genome organization in the formation of tumorigenic abnormalities. The non-random localization of chromosomes and, more specifically, of genes appears to play a role in the mechanism of chromosomal translocations. Here, two-color fluorescence in situ hybridization and confocal microscopy were used to measure the interphase distance between CBFB and MYH11 in hematopoietic stem cells, where inv(16)(p13q22) is believed to occur, leading to leukemia development. The measured distances in hematopoietic stem cells were compared to mesenchymal stem cells, peripheral blood lymphocytes and fibroblasts, as spatial genome organization is determined to be cell-type specific. Results indicate that CBFB and MYH11 are significantly closer in hematopoietic stem cells compared to all other cell types examined. Furthermore, the CBFB-MYH11 distance is significantly reduced compared to CBFB and a control locus in hematopoietic stem cells, although separation between CBFB and the control is ~70% of that between CBFB and MYH11 on metaphase chromosomes. Hematopoietic stem cells were also treated with fragile site-inducing chemicals since both genes contain translocation breakpoints within these regions. However, treatment with fragile site-inducing chemicals did not significantly affect the interphase distance. Consistent with previous studies, our results suggest that gene proximity may play a role in the formation of cancer-causing rearrangements, providing insight into the mechanism of chromosomal abnormalities in human tumors. PMID:21638519

  7. Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on SHP2 phosphatase function.

    PubMed

    Broxmeyer, Hal E; Etienne-Julan, Maryse; Gotoh, Akihiko; Braun, Stephen E; Lu, Li; Cooper, Scott; Feng, Gen-Sheng; Li, Xing Jun; Chan, Rebecca J

    2013-03-15

    The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity.

  8. Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation.

    PubMed

    Licciulli, S; Cambiaghi, V; Scafetta, G; Gruszka, A M; Alcalay, M

    2010-02-01

    Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight-twenty-one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML. PMID:20010624

  9. In Vivo Deletion of the Cebpa +37 kb Enhancer Markedly Reduces Cebpa mRNA in Myeloid Progenitors but Not in Non-Hematopoietic Tissues to Impair Granulopoiesis

    PubMed Central

    Guo, Hong; Cooper, Stacy; Friedman, Alan D.

    2016-01-01

    The murine Cebpa gene contains a +37 kb, evolutionarily conserved 440 bp enhancer that directs high-level expression to myeloid progenitors in transgenic mice. The enhancer is bound and activated by Runx1, Scl, GATA2, C/EBPα, c-Myb, Pu.1, and additional Ets factors in myeloid cells. CRISPR/Cas9-mediated replacement of the wild-type enhancer with a variant mutant in its seven Ets sites leads to 20-fold reduction of Cebpa mRNA in the 32Dcl3 myeloid cell line. To determine the effect of deleting the enhancer in vivo, we now characterize C57BL/6 mice in which loxP sites flank a 688 bp DNA segment containing the enhancer. CMV-Cre mediated germline deletion resulted in diminution of the expected number of viable Enh(f/f);CMV-Cre offspring, with 28-fold reduction in marrow Cebpa mRNA but normal levels in liver, lung, adipose, intestine, muscle, and kidney. Cre-transduction of lineage-negative marrow cells in vitro reduced Cebpa mRNA 12-fold, with impairment of granulocytic maturation, morphologic blast accumulation, and IL-3 dependent myeloid colony replating for >12 generations. Exposure of Enh(f/f);Mx1-Cre mice to pIpC led to 14-fold reduction of Cebpa mRNA in GMP or CMP, 30-fold reduction in LSK, and <2-fold reduction in the LSK/SLAM subset. FACS analysis of marrow from these mice revealed 10-fold reduced neutrophils, 3-fold decreased GMP, and 3-fold increased LSK cells. Progenitor cell cycle progression was mildly impaired. Granulocyte and B lymphoid colony forming units were reduced while monocytic and erythroid colonies were increased, with reduced Pu.1 and Gfi1 and increased Egr1 and Klf4 in GMP. Finally, competitive transplantation indicated preservation of functional long-term hematopoietic stem cells upon enhancer deletion and confirmed marrow-intrinsic impairment of granulopoiesis and B cell generation with LSK and monocyte lineage expansion. These findings demonstrate a critical role for the +37 kb Cebpa enhancer for hematopoietic-specific Cebpa expression

  10. Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment

    PubMed Central

    Meinders, Marjolein; Hoogenboezem, Mark; Scheenstra, Maaike R.; De Cuyper, Iris M.; Papadopoulos, Petros; Németh, Tamás; Mócsai, Attila; van den Berg, Timo K.; Kuijpers, Taco W.

    2016-01-01

    During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes. To specifically analyze the impact of Gata1 loss in mature committed megakaryocytes, we generated Gata1-Lox|Pf4-Cre mice (Gata1cKOMK). Consistent with previous findings, Gata1cKOMK mice are macrothrombocytopenic with platelet dysfunction. Supporting this notion we demonstrate that Gata1 regulates directly the transcription of Syk, a tyrosine kinase that functions downstream of Clec2 and GPVI receptors in megakaryocytes and platelets. Furthermore, we show that Gata1cKOMK mice display an additional aberrant megakaryocyte differentiation stage. Interestingly, these mice present a misbalance of the multipotent progenitor compartment and the erythroid lineage, which translates into compensatory stress erythropoiesis and splenomegaly. Despite the severe thrombocytopenia, Gata1cKOMK mice display a mild reduction of TPO plasma levels, and Gata1cKOMK megakaryocytes show a mild increase in Pf4 mRNA levels; such a misbalance might be behind the general hematopoietic defects observed, affecting locally normal TPO and Pf4 levels at hematopoietic stem cell niches. PMID:27152938

  11. Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment.

    PubMed

    Meinders, Marjolein; Hoogenboezem, Mark; Scheenstra, Maaike R; De Cuyper, Iris M; Papadopoulos, Petros; Németh, Tamás; Mócsai, Attila; van den Berg, Timo K; Kuijpers, Taco W; Gutiérrez, Laura

    2016-01-01

    During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes. To specifically analyze the impact of Gata1 loss in mature committed megakaryocytes, we generated Gata1-Lox|Pf4-Cre mice (Gata1cKOMK). Consistent with previous findings, Gata1cKOMK mice are macrothrombocytopenic with platelet dysfunction. Supporting this notion we demonstrate that Gata1 regulates directly the transcription of Syk, a tyrosine kinase that functions downstream of Clec2 and GPVI receptors in megakaryocytes and platelets. Furthermore, we show that Gata1cKOMK mice display an additional aberrant megakaryocyte differentiation stage. Interestingly, these mice present a misbalance of the multipotent progenitor compartment and the erythroid lineage, which translates into compensatory stress erythropoiesis and splenomegaly. Despite the severe thrombocytopenia, Gata1cKOMK mice display a mild reduction of TPO plasma levels, and Gata1cKOMK megakaryocytes show a mild increase in Pf4 mRNA levels; such a misbalance might be behind the general hematopoietic defects observed, affecting locally normal TPO and Pf4 levels at hematopoietic stem cell niches. PMID:27152938

  12. Expression Levels of Histone Deacetylases Determine the Cell Fate of Hematopoietic Progenitors*

    PubMed Central

    Wada, Taeko; Kikuchi, Jiro; Nishimura, Noriko; Shimizu, Rumi; Kitamura, Toshio; Furukawa, Yusuke

    2009-01-01

    Histone deacetylases (HDACs) are globally implicated in the growth and differentiation of mammalian cells; however, relatively little is known about their specific roles in hematopoiesis. In this study, we investigated the expression of HDACs in human hematopoietic cells and their functions during hematopoiesis. The expression of HDACs was very low in hematopoietic progenitor cells, which was accompanied by histone hyperacetylation. HDACs were detectable in more differentiated progenitors and erythroid precursors but down-regulated in mature myeloid cells especially granulocytes. In contrast, acute myeloid leukemias showed HDAC overexpression and histone hypoacetylation. Transcription of the HDAC1 gene was repressed by CCAAT/enhancer binding proteins during myeloid differentiation, and activated by GATA-1 during erythro-megakaryocytic differentiation. Small interfering RNA-mediated knockdown of HDAC1 enhanced myeloid differentiation in immature hematopoietic cell lines and perturbed erythroid differentiation in progenitor cells. Myeloid but not erythro-megakaryocytic differentiation was blocked in mice transplanted with HDAC1-overexpressing hematopoietic progenitor cells. These findings suggest that HDAC is not merely an auxiliary factor of genetic elements but plays a direct role in the cell fate decision of hematopoietic progenitors. PMID:19736310

  13. Decrease in circulating myeloid dendritic cell precursors in patients with intracranial large artery atherosclerosis.

    PubMed

    Zhang, Jin-Xia; Li, Bing-Ling; Lin, Zhong-Qiu; Zhang, Ni; Peng, Xiong; Gong, Zhi-Hua; Long, Liu-Cheng; Zhou, Xuan; Xiang, Ding-Cheng

    2015-01-01

    Intracranial large artery atherosclerosis (ILAA) is a major cause of ischemic cerebrovascular disease. The aim of this study was to investigate whether the levels of circulating dendritic cell precursors (DCP) could reflect the severity of intracranial large artery atherosclerosis (ILAA). For this purpose, a series of angiography were taken to determine the severity and extent of coronary artery and intracranial large artery stenosis, and flow cytometry were taken to determine the levels of circulating mDC precursors and pDC precursors in patients with severe intracranial large artery atherosclerosis (ILAA) (n = 101) and mild intracranial large artery atherosclerosis (ILAA) (n = 123) according to the angiography. Circulating mDC precursors were lower in patients with severe intracranial large artery atherosclerosis (ILAA) than in mild intracranial large artery atherosclerosis (ILAA) (P < 0.05), but circulating pDC precursors were not significant differences (P > 0.05). According to these data, circulating mDC precursors could predict the severity of ILAA, which also could be able to reflect the severity of ILAA.

  14. Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission - a review from the Acute Leukemia Working Party of the EBMT

    PubMed Central

    Sengsayadeth, Salyka; Savani, Bipin N.; Blaise, Didier; Malard, Florent; Nagler, Arnon; Mohty, Mohamad

    2015-01-01

    Acute myeloid leukemia is the most common indication for an allogeneic hematopoietic cell transplant. The introduction of reduced intensity conditioning has expanded the recipient pool for transplantation, which has importantly made transplant an option for the more commonly affected older age groups. Reduced intensity conditioning allogeneic transplantation is currently the standard of care for patients with intermediate or high-risk acute myeloid leukemia and is now most often employed in older patients and those with medical comorbidities. Despite being curative for a significant proportion of patients, post-transplant relapse remains a challenge in the reduced intensity conditioning setting. Herein we discuss the studies that demonstrate the feasibility of reduced intensity conditioning allogeneic transplants, compare the outcomes of reduced intensity conditioning versus chemotherapy and conventional myeloablative conditioning regimens, describe the optimal donor and stem cell source, and consider the impact of post-remission consolidation, comorbidities, center experience, and more intensive (reduced toxicity conditioning) regimens on outcomes. Additionally, we discuss the need for further prospective studies to optimize transplant outcomes. PMID:26130513

  15. Age-Related Changes in Population of Stromal Precursor Cells in Hematopoietic and Lymphoid Organs.

    PubMed

    Gorskaya, Yulia F.; Latzinik, Natalia V.; Shuklina, Ekaterina U.; Nesterenko, Vladimir G.

    2000-07-01

    It is shown that the content of precursor cells of stromal tissue (CFC-F) in the hemopoietic and lymphoid organs of SAMP (rapidly-ageing mice) and SAMR mice (mice with a normal ageing rate) decreases as the animals grow older. However the decrease in the content of CFC-F in SAMP mice begins substantially earlier - in the age group of 9-11 months, while in the SAMR mice - only in the age group of 16-19 months. It was found that the age reduction of the number to an equal degree relates to the whole population of CFC-F, in particular both the fraction of weakly-linked CFC-F, which is isolated by means of mechanical disaggregation of the tissue, and the fraction which may only be isolated using trypsin. It is shown that the concentration of inducible osteogenic precursor cells (IOPC) in the spleen of guinea pigs does not change with age, but their content in that organ in old animals (2-3 years old) drops by two times. It was found that in elderly animals the mass of the ectopic osseous tissue, formed by the implantation of an osteoinductor (autologous epithelium of the urinary bladder) in a system open for entrance of cells, decreases by two times. After curettage of the medullary cavity of guinea pig tibia (i.e. under conditions of an increased demand for osteogenic cells) the mass of induced ectopic osseous tissue decreases by 4 times, which indicates to the possible functional relationship between the pool of determined and inducible osteogenic precursor cells. On the whole, the obtained data show that during ageing there is a reduction in the number of stromal precursor cells (CFC-F and IOPC), which form a specific microenvironment for hemopoietic and lymphoid organs, which is important to understand the role of these cells in the development of age pathologies, in particular senile osteoporosis. PMID:12687170

  16. SCL expression at critical points in human hematopoietic lineage commitment.

    PubMed

    Zhang, Yanjia; Payne, Kimberly J; Zhu, Yuhua; Price, Mary A; Parrish, Yasmin K; Zielinska, Ewa; Barsky, Lora W; Crooks, Gay M

    2005-01-01

    The stem cell leukemia (SCL or tal-1) gene was initially identified as a translocation partner in a leukemia that possessed both lymphoid and myeloid differentiation potential. Mice that lacked SCL expression showed a complete block in hematopoiesis; thus, SCL was associated with hematopoietic stem cell (HSC) function. More recent studies show a role for SCL in murine erythroid differentiation. However, the expression pattern and the role of SCL during early stages of human hematopoietic differentiation are less clear. In this study we chart the pattern of human SCL expression from HSCs, through developmentally sequential populations of lymphoid and myeloid progenitors to mature cells of the hematopoietic lineages. Using recently defined surface immunophenotypes, we fluorescence-activated cell-sorted (FACS) highly purified populations of primary human hematopoietic progenitors for reverse transcription-polymerase chain reaction (RT-PCR) analysis of SCL expression. Our data show that SCL mRNA is easily detectable in all hematopoietic populations with erythroid potential, including HSCs, multipotential progenitors, common myeloid progenitors, megakaryocyte/erythrocyte progenitors, and nucleated erythroid lineage cells. SCL mRNA expression was present but rapidly downregulated in the common lymphoid progenitor and granulocyte/monocyte progenitor populations that lack erythroid potential. SCL expression was undetectable in immature cells of nonerythroid lineages, including pro-B cells, early thymic progenitors, and myeloid precursors expressing the M-CSF receptor. SCL expression was also absent from all mature cells of the nonerythroid lineages. Although low levels of SCL were detected in lymphoid- and myeloid-restricted progenitors, our studies show that abundant SCL expression is normally tightly linked with erythroid differentiation potential.

  17. Evaluation of hematopoietic cells and myeloid/erythroid ratio in the bone marrow of the pheasant (Phasianus colchicus).

    PubMed

    Tadjalli, Mina; Nazifi, Saeed; Haghjoo, Rahil

    2013-01-01

    In order to study the normal hematopoiesis, cellular components and myeloid/erythroid (M/E) ratio in the bone marrow of the pheasant (Phasianus colchicus), bone marrow samples were collected from the proximal tibiotarsus bone of 16 clinically healthy adult pheasant. The bone marrow smears were stained using the Giemsa stain. The results indicated that the development and formation of blood cells in the bone marrow of pheasant were similar to other birds, whereas the morphology of the cells was similar to chickens, ducks, quail, and black-head gull. The mean M/E ratio was 1.24, the mean erythroid percentage was 42.24, the mean myeloid percentage was 52.62, and the mean percentage of all other cells percentage was 5.38. There was no significant difference in any of the cellular composition between male and female.

  18. Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study.

    PubMed

    Gratwohl, Alois; Iacobelli, Simona; Bootsman, Natalia; van Biezen, Anja; Baldomero, Helen; Arcese, William; Arnold, Renate; Bron, Dominique; Cordonnier, Catherine; Ernst, Peter; Ferrant, Augustin; Frassoni, Francesco; Gahrton, Gösta; Richard, Carlos; Kolb, Hans Jochem; Link, Hartmut; Niederwieser, Dietger; Ruutu, Tapani; Schattenberg, Anton; Schmitz, Norbert; Torres-Gomez, Antonio; Zwaan, Ferry; Apperley, Jane; Olavarria, Eduardo; Kröger, Nicolaus

    2016-05-01

    In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor. PMID:26994010

  19. Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation.

    PubMed

    Zeiser, R; Spyridonidis, A; Wäsch, R; Ihorst, G; Grüllich, C; Bertz, H; Finke, J

    2005-05-01

    Both conventional chimerism analysis (CCA) and lineage-specific chimerism analysis (LCA) have potential pitfalls as diagnostic means for the detection of minimal residual disease after allogeneic hematopoietic cell transplantation (aHCT). Therefore, the present study examines the results of both methods in order to determine how predictive consecutive evaluations were, with respect to the risk that the patient would relapse during post-transplant follow-up and with respect to responsiveness to immunomodulatory treatment. A total of 168 individuals with acute myeloid leukemia (AML) (n = 137) and myelo dysplastic syndrome (n = 31) were investigated with CCA and LCA at mean intervals of 24 days (range: 11-116). The median follow-up after myeloablative aHCT was 22 months (range: 4-49). Of 168 patients, 65 experienced a clinical relapse after aHCT. CCA and LCA were comparatively sensitive and specific for relapse at the intervals of chimerism testing employed in this study. Of 32 patients, 10 who were offered donor lymphocyte infusions (DLI) treatment for increasing (n = 29) or stable (n = 3) mixed chimerism (MC) achieved at least transitory CC. The observation that all patients with increasing MC relapsed despite DLI treatment (54%) or withdrawal of immune suppression (24%) indicates that novel strategies to deal with rapidly evolving relapse in AML patients, such as shortening of chimerism monitoring intervals, need to be evaluated.

  20. HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress.

    PubMed

    Rouault-Pierre, Kevin; Lopez-Onieva, Lourdes; Foster, Katie; Anjos-Afonso, Fernando; Lamrissi-Garcia, Isabelle; Serrano-Sanchez, Martin; Mitter, Richard; Ivanovic, Zoran; de Verneuil, Hubert; Gribben, John; Taussig, David; Rezvani, Hamid Reza; Mazurier, Frédéric; Bonnet, Dominique

    2013-11-01

    Hematopoietic stem and progenitor cells (HSPCs) are exposed to low levels of oxygen in the bone marrow niche, and hypoxia-inducible factors (HIFs) are the main regulators of cellular responses to oxygen variation. Recent studies using conditional knockout mouse models have unveiled a major role for HIF-1α in the maintenance of murine HSCs; however, the role of HIF-2α is still unclear. Here, we show that knockdown of HIF-2α, and to a much lesser extent HIF-1α, impedes the long-term repopulating ability of human CD34(+) umbilical cord blood cells. HIF-2α-deficient HSPCs display increased production of reactive oxygen species (ROS), which subsequently stimulates endoplasmic reticulum (ER) stress and triggers apoptosis by activation of the unfolded-protein-response (UPR) pathway. HIF-2α deregulation also significantly decreased engraftment ability of human acute myeloid leukemia (AML) cells. Overall, our data demonstrate a key role for HIF-2α in the maintenance of human HSPCs and in the survival of primary AML cells. PMID:24095676

  1. Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia: No Impact of Pre-transplant Extramedullary Disease on Outcome

    PubMed Central

    Goyal, Sagun D.; Zhang, Mei-Jie; Wang, Hai-Lin; Akpek, Görgün; Copelan, Edward A.; Freytes, César; Gale, Robert Peter; Hamadani, Mehdi; Inamoto, Yoshihiro; Kamble, Rammurti T.; Lazarus, Hillard M.; Marks, David I.; Nishihori, Taiga; Olsson, Richard F.; Reshef, Ran; Ritchie, David S.; Saber, Wael; Savani, Bipin N.; Seber, Adriana; Shea, Thomas C.; Tallman, Martin S.; Wirk, Baldeep; Bunjes, Donald W.; Devine, Steven M.; de Lima, Marcos; Weisdorf, Daniel J.; Uy, Geoffrey L.

    2015-01-01

    The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) we compared the outcomes of patients who had EMD of AML at any time prior to transplant to a cohort of AML patients without EMD. We reviewed data AML from 9,797 patients including 814 with EMD from 310 reporting centers and 44 different countries who underwent alloHCT between and 1995–2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate, and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (HR 1.00, 95% CI 0.91–1.09), LFS (0.98, 0.89–1.09), TRM (RR 0.92, 95% CI 0.80–1.16, p=0.23) or relapse (RR =1.03, 95% CI, 0.92–1.16; p=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature. PMID:25915806

  2. Impact of Cranial Irradiation Added to Intrathecal Conditioning in Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia With Central Nervous System Involvement

    SciTech Connect

    Mayadev, Jyoti S.; Douglas, James G.; Storer, Barry E.; Appelbaum, Frederick R.; Storb, Rainer

    2011-05-01

    Purpose: Neither the prognostic importance nor the appropriate management of central nervous system (CNS) involvement is known for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We examined the impact of a CNS irradiation boost to standard intrathecal chemotherapy (ITC). Methods and Materials: From 1995 to 2005, a total of 648 adult AML patients received a myeloablative HCT: 577 patients were CNS negative (CNS-), and 71 were CNS positive (CNS+). Of the 71 CNS+ patients, 52 received intrathecal chemotherapy alone (CNS+ITC), and 19 received ITC plus an irradiation boost (CNS+RT). Results: The CNS-, CNS+ITC, and CNS+RT patients had 1- and 5-year relapse-free survivals (RFS) of 43% and 35%, 15% and 6%, and 37% and 32%, respectively. CNS+ITC patients had a statistically significant worse RFS compared with CNS- patients (hazard ratio [HR], 2.65; 95% confidence interval [CI], 2.0-3.6; p < 0.0001). CNS+RT patients had improved relapse free survival over that of CNS+ITC patients (HR, 0.45; 95% CI, 0.2-0.8; p = 0.01). The 1- and 5-year overall survivals (OS) of patients with CNS-, CNS+ITC, and CNS+RT, were 50% and 38%, 21% and 6%, and 53% and 42%, respectively. The survival of CNS+RT were significantly better than CNS+ITC patients (p = 0.004). After adjusting for known risk factors, CNS+RT patients had a trend toward lower relapse rates and reduced nonrelapse mortality. Conclusions: CNS+ AML is associated with a poor prognosis. The role of a cranial irradiation boost to intrathecal chemotherapy appears to mitigate the risk of CNS disease, and needs to be further investigated to define optimal treatment strategies.

  3. Mixed T Lymphocyte Chimerism after Allogeneic Hematopoietic Transplantation Is Predictive for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    PubMed

    Lee, Hans C; Saliba, Rima M; Rondon, Gabriela; Chen, Julianne; Charafeddine, Yasmeen; Medeiros, L Jeffrey; Alatrash, Gheath; Andersson, Borje S; Popat, Uday; Kebriaei, Partow; Ciurea, Stefan; Oran, Betul; Shpall, Elizabeth; Champlin, Richard

    2015-11-01

    Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort (P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation. PMID:26183077

  4. Mixed T Lymphocyte Chimerism after Allogeneic Hematopoietic Transplantation Is Predictive for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    PubMed

    Lee, Hans C; Saliba, Rima M; Rondon, Gabriela; Chen, Julianne; Charafeddine, Yasmeen; Medeiros, L Jeffrey; Alatrash, Gheath; Andersson, Borje S; Popat, Uday; Kebriaei, Partow; Ciurea, Stefan; Oran, Betul; Shpall, Elizabeth; Champlin, Richard

    2015-11-01

    Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort (P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation.

  5. Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia.

    PubMed

    Aoki, Jun; Kanamori, Heiwa; Tanaka, Masatsugu; Yamasaki, Satoshi; Fukuda, Takahiro; Ogawa, Hiroyasu; Iwato, Koji; Ohashi, Kazuteru; Okumura, Hirokazu; Onizuka, Makoto; Maesako, Yoshitomo; Teshima, Takanori; Kobayashi, Naoki; Morishima, Yasuo; Hirokawa, Makoto; Atsuta, Yoshiko; Yano, Shingo; Takami, Akiyoshi

    2016-03-01

    Previous studies have repeatedly reported that increasing age is a significant risk factor for worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among patients with acute myeloid leukemia (AML). However, more recent studies reported conflicting results regarding the association between age and outcomes in elderly patients. Therefore, we conducted a large-scale, nationwide retrospective study to examine the impact of age on outcomes of allo-HSCT with reduced intensity conditioning (RIC) for AML patients who were older than 50 years. Of the 757 patients, 89 patients (11.8%) were 50-54, 249 patients (32.9%) were 55-59, 301 patients (39.8%) were 60-64 and 118 patients (15.6%) were ≥65 years old. The 3-year overall survival (OS) (47.8, 45.2, 37.9, and 36.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.24) and nonrelapse mortality (NRM) (24.0, 22.8, 29.2, and 27.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.49) were not significantly different among the four age groups. Multivariate analysis revealed that increased age had no significant effect on OS or NRM after adjusting for covariates. These results suggested that advanced patient age is not a contraindication for RIC allo-HSCT in elderly AML patients. PMID:26663096

  6. The human placenta is a hematopoietic organ during the embryonic and fetal periods of development

    PubMed Central

    Bárcena, Alicia; Kapidzic, Mirhan; Muench, Marcus O.; Gormley, Matthew; Scott, Marvin A.; Weier, Jingly F.; Ferlatte, Christy; Fisher, Susan J.

    2008-01-01

    We studied the potential role of the human placenta as a hematopoietic organ during embryonic and fetal development. Placental samples contained two cell populations—CD34++CD45low and CD34+CD45low—that were found in chorionic villi and in the chorioamniotic membrane. CD34++CD45low cells express many cell surface antigens found on multipotent primitive hematopoietic progenitors and hematopoietic stem cells. CD34++CD45low cells contained colony-forming units culture (CFU-C) with myeloid and erythroid potential in clonogenic in vitro assays, and they generated CD56+ natural killer cells and CD19+CD20+sIgM+ B cells in polyclonal liquid cultures. CD34+CD45low cells mostly comprised erythroid- and myeloid-committed progenitors, while CD34− cells lacked CFU-C. The placenta-derived precursors were fetal in origin, as demonstrated by FISH using repeat-sequence chromosome-specific probes for X and Y. The number of CD34++CD45low cells increased with gestational age, but their density (cells per gram of tissue) peaked at 5–8 wk, decreasing more than sevenfold at the onset of the fetal phase (9 wk of gestation). In addition to multipotent progenitors, the placenta contained myeloid- and erythroid-committed progenitors indicative of active in situ hematopoiesis. These data suggest that the human placenta is an important hematopoietic organ, raising the possibility of banking placental hematopoietic stem cells along with cord blood for transplantation. PMID:19073167

  7. Normal Hematopoietic Progenitor Subsets Have Distinct Reactive Oxygen Species, BCL2 and Cell-Cycle Profiles That Are Decoupled from Maturation in Acute Myeloid Leukemia

    PubMed Central

    Hills, Robert K.; Knapper, Steve; Steadman, Lora; Qureshi, Ushna; Rector, Jerrald L.; Bradbury, Charlotte; Russell, Nigel H.; Vyas, Paresh; Burnett, Alan K.; Grimwade, David; Hole, Paul S.; Freeman, Sylvie D.

    2016-01-01

    In acute myeloid leukemia (AML) quiescence and low oxidative state, linked to BCL2 mitochondrial regulation, endow leukemic stem cells (LSC) with treatment-resistance. LSC in CD34+ and more mature CD34− AML have heterogeneous immunophenotypes overlapping with normal stem/progenitor cells (SPC) but may be differentiated by functional markers. We therefore investigated the oxidative/reactive oxygen species (ROS) profile, its relationship with cell-cycle/BCL2 for normal SPC, and whether altered in AML and myelodysplasia (MDS). In control BM (n = 24), ROS levels were highest in granulocyte-macrophage progenitors (GMP) and CD34− myeloid precursors but megakaryocyte-erythroid progenitors had equivalent levels to CD34+CD38low immature-SPC although they were ki67high. BCL2 upregulation was specific to GMPs. This profile was also observed for CD34+SPC in MDS-without-excess-blasts (MDS-noEB, n = 12). Erythroid CD34− precursors were, however, abnormally ROS-high in MDS-noEB, potentially linking oxidative stress to cell loss. In pre-treatment AML (n = 93) and MDS-with-excess-blasts (MDS-RAEB) (n = 14), immunophenotypic mature-SPC had similar ROS levels to co-existing immature-SPC. However ROS levels varied between AMLs; Flt3ITD+/NPM1wild-type CD34+SPC had higher ROS than NPM1mutated CD34+ or CD34− SPC. An aberrant ki67lowBCL2high immunophenotype was observed in CD34+AML (most prominent in Flt3ITD AMLs) but also in CD34− AMLs and MDS-RAEB, suggesting a shared redox/pro-survival adaptation. Some patients had BCL2 overexpression in CD34+ ROS-high as well as ROS-low fractions which may be indicative of poor early response to standard chemotherapy. Thus normal SPC subsets have distinct ROS, cell-cycle, BCL2 profiles that in AML /MDS-RAEB are decoupled from maturation. The combined profile of these functional properties in AML subpopulations may be relevant to differential treatment resistance. PMID:27669008

  8. CD133 is a modifier of hematopoietic progenitor frequencies but is dispensable for the maintenance of mouse hematopoietic stem cells

    PubMed Central

    Arndt, Kathrin; Grinenko, Tatyana; Mende, Nicole; Reichert, Doreen; Portz, Melanie; Ripich, Tatsiana; Carmeliet, Peter; Corbeil, Denis; Waskow, Claudia

    2013-01-01

    Pentatransmembrane glycoprotein prominin-1 (CD133) is expressed at the cell surface of multiple somatic stem cells, and it is widely used as a cell surface marker for the isolation and characterization of human hematopoietic stem cells (HSCs) and cancer stem cells. CD133 has been linked on a cell biological basis to stem cell-fate decisions in human HSCs and emerges as an important physiological regulator of stem cell maintenance and expansion. Its expression and physiological relevance in the murine hematopoietic system is nevertheless elusive. We show here that CD133 is expressed by bone marrow-resident murine HSCs and myeloid precursor cells with the developmental propensity to give rise to granulocytes and monocytes. However, CD133 is dispensable for the pool size and function of HSCs during steady-state hematopoiesis and after transplantation, demonstrating a substantial species difference between mouse and man. Blood cell numbers in the periphery are normal; however, CD133 appears to be a modifier for the development of growth-factor responsive myeloerythroid precursor cells in the bone marrow under steady state and mature red blood cells after hematopoietic stress. Taken together, these studies show that CD133 is not a critical regulator of hematopoietic stem cell function in mouse but that it modifies frequencies of growth-factor responsive hematopoietic progenitor cells during steady state and after myelotoxic stress in vivo. PMID:23509298

  9. The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation Over Chemotherapy Alone in the Treatment of Acute Myeloid Leukemia Patients with Mixed Lineage Leukemia (MLL) Rearrangements

    PubMed Central

    Yang, Hua; Huang, Sai; Zhu, Cheng-Ying; Gao, Li; Zhu, Hai-Yan; Lv, Na; Jing, Yu; Yu, Li

    2016-01-01

    Background Acute myeloid leukemia (AML) patients with mixed lineage leukemia (MLL) gene rearrangements always had a very poor prognosis. In this study, we report the incidence of MLL rearrangements in AML patients using gene analysis, as well as the clinical significance and prognostic features of these rearrangements. Material/Methods This retrospective study took place from April 2008 to November 2011 in the People’s Liberation Army General Hospital. A total 433 AML patients were screened by multiple nested reverse transcription polymerase chain reaction (RT-PCR) to determine the incidence of the 11 MLL gene rearrangements. There were 68 cases of MLL gene rearrangements, for a positive rate of 15.7%. A total of 24 patients underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and 34 patients received at least 4 cycles of chemotherapy. Ten patients were lost to follow-up. Results The median follow-up was 29 months. The complete remission (CR) rate was 85.4%. The overall survival (OS) was 57.4±5.9 months for the Allo-HSCT group and 21.0±2.1 months for the chemotherapy group. The Allo-HSCT group had superior survival compared with the chemotherapy group (5-year OS: 59±17% vs. 13±8%, P<0.01; 5-year disease-free survival [DFS]: 65±10% vs. 40±16%, P>0.05). Multivariate analysis showed that transplantation, platelets >50×109/L at onset, and CR are associated with a better OS in MLL rearranged AML patients. Patients with thrombocytopenia and extramedullary involvement were prone to relapse. Conclusions Our results suggest that Allo-HSCT is superior to chemotherapy alone for treating MLL rearranged AML patients. Patients treated with Allo-HSCT have a better prognosis and a longer survival. CR is an independent prognostic factor for OS, and extramedullary involvement is an independent prognostic factor for DFS. MLL rearranged AML patients with thrombocytopenia at onset <50×109 had very bad OS and DFS. PMID:27373985

  10. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage.

    PubMed

    Quek, Lynn; Otto, Georg W; Garnett, Catherine; Lhermitte, Ludovic; Karamitros, Dimitris; Stoilova, Bilyana; Lau, I-Jun; Doondeea, Jessica; Usukhbayar, Batchimeg; Kennedy, Alison; Metzner, Marlen; Goardon, Nicolas; Ivey, Adam; Allen, Christopher; Gale, Rosemary; Davies, Benjamin; Sternberg, Alexander; Killick, Sally; Hunter, Hannah; Cahalin, Paul; Price, Andrew; Carr, Andrew; Griffiths, Mike; Virgo, Paul; Mackinnon, Stephen; Grimwade, David; Freeman, Sylvie; Russell, Nigel; Craddock, Charles; Mead, Adam; Peniket, Andrew; Porcher, Catherine; Vyas, Paresh

    2016-07-25

    Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within CD34(-) and CD34(+) LSC-containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34(-) LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34(-) mature granulocyte-macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis. PMID:27377587

  11. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage.

    PubMed

    Quek, Lynn; Otto, Georg W; Garnett, Catherine; Lhermitte, Ludovic; Karamitros, Dimitris; Stoilova, Bilyana; Lau, I-Jun; Doondeea, Jessica; Usukhbayar, Batchimeg; Kennedy, Alison; Metzner, Marlen; Goardon, Nicolas; Ivey, Adam; Allen, Christopher; Gale, Rosemary; Davies, Benjamin; Sternberg, Alexander; Killick, Sally; Hunter, Hannah; Cahalin, Paul; Price, Andrew; Carr, Andrew; Griffiths, Mike; Virgo, Paul; Mackinnon, Stephen; Grimwade, David; Freeman, Sylvie; Russell, Nigel; Craddock, Charles; Mead, Adam; Peniket, Andrew; Porcher, Catherine; Vyas, Paresh

    2016-07-25

    Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within CD34(-) and CD34(+) LSC-containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34(-) LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34(-) mature granulocyte-macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis.

  12. ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors.

    PubMed

    Becker, Amy M; Walcheck, Bruce; Bhattacharya, Deepta

    2015-01-01

    All-lymphoid progenitors (ALPs) yield few myeloid cells in vivo, but readily generate such cells in vitro. The basis for this difference remains unknown. We hypothesized that ALPs limit responsiveness to in vivo concentrations of myeloid-promoting cytokines by reducing expression of the corresponding receptors, potentially through posttranscriptional mechanisms. Consistent with such a mechanism, ALPs express higher levels of CSF1R transcripts than their upstream precursors, yet show limited cell-surface protein expression of colony-stimulating factor 1 receptor (CSF1R). All-lymphoid progenitors and other hematopoietic progenitors deficient in A disintegrin and metalloproteinase domain 17 (ADAM17), display elevated cell surface CSF1R expression. ADAM17(-/-) ALPs, however, fail to yield myeloid cells upon transplantation into irradiated recipients. Moreover, ADAM17(-/-) ALPs yield fewer macrophages in vitro than control ALPs at high concentrations of macrophage colony stimulating factor. Mice with hematopoietic-specific deletion of ADAM17 have normal numbers of myeloid and lymphoid progenitors and mature cells in vivo. These data demonstrate that ADAM17 limits CSF1R protein expression on hematopoietic progenitors, but that compensatory mechanisms prevent elevated CSF1R levels from altering lymphoid progenitor potential.

  13. Differential sensitivity of T lymphocytes and hematopoietic precursor cells to photochemotherapy with 8-methoxypsoralen and ultraviolet A light.

    PubMed

    Mabed, Mohamed; Coffe, Christian; Racadot, Evelyne; Angonin, Regis; Pavey, Jean-Jaques; Tiberghien, Pierre; Herve, Patrick

    2006-01-01

    The combination of 8-methoxypsoralen (8-MOP) and long wave ultraviolet radiation (UV-A) has immunomodulatory effects and might abolish both graft-vs-host and host-vs-graft reactions after allogeneic hematopoietic stem cell transplantation. In the present study, we have confirmed the sensitivity of T lymphocytes to 8-MOP treatment plus UV-A exposure as evidenced by the abrogation of the alloreactivity in mixed lymphocyte cultures as well as the inhibition of the response to phytohemagglutinin A. However, the clonogenic capacity of the bone marrow hematopoietic progenitors was inhibited with UV-A doses lower than the doses needed to inhibit T-lymphocytes alloreactivity. Moreover, long-term bone marrow cultures showed that 8-MOP plus UV-A treatment had detrimental effects on the more immature bone marrow stem cells. These data were confirmed when murine bone marrow graft was treated with 8-MOP, exposed to UV-A, then transplanted into semiallogeneic recipient mice. The treated cells could not maintain their clonogenic capacity in vivo resulting in death of all animals. Taken together, these data show that ex vivo 8-MOP plus UV-A treatment of the marrow graft cannot be used to prevent post-bone marrow transplantation alloreactivity. PMID:16208471

  14. Identification of CD13+CD36+ cells as a common progenitor for erythroid and myeloid lineages in human bone marrow

    PubMed Central

    Chen, Ling; Gao, Zhigang; Zhu, Jianqiong; Rodgers, Griffin P.

    2008-01-01

    Objective To identify bi-potential precursor cells of erythroid and myeloid development in human bone marrow. Materials and Methods Cells co-expressing CD13 and CD36 (CD13+CD36+) were investigated by analyzing cell surface marker expression during erythroid development (induced with a combination of cytokines plus erythropoietin [EPO]), or myeloid development (induced with the same cocktail of cytokines plus granulocyte-colony stimulating factor [G-CSF]) of bone marrow derived CD133 cells in liquid cultures. CD13+CD36+ subsets were also isolated on the 14th day of cultures and further evaluated for their hematopoietic clonogenic capacity in methylcellulose. Results Colony-forming analysis of sorted CD13+CD36+ cells of committed erythroid and myeloid lineages demonstrated that these cells were able to generate erythroid, granulocyte, and mixed erythroid –granulocyte colonies. In contrast, CD13+CD36− or CD13−CD36+ cells exclusively committed to granulocyte/monocyte or erythroid colonies, respectively, but failed to form mixed erythroid –granulocyte colonies; no colonies were detected in CD13−CD36− cells with lineage-supporting cytokines. In addition, our data confirmed that EPO induced both erythroid and myeloid commitment, while G-CSF only supported the differentiation of the myeloid lineage. Conclusions The present data identify some CD13+CD36+ cells as bi-potential precursors of erythroid and myeloid commitment in normal hematopoiesis. They provide a physiological explanation for the cell identification of myeloid and erythroid lineages observed in hematopoietic diseases. This unique fraction of CD13+CD36+ cells may be useful for further studies on regulating erythroid and myeloid differentiation during normal and malignant hematopoiesis. PMID:17588473

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

    PubMed

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

    2008-07-01

    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.

  16. Gradual Rarefaction of Hematopoietic Precursors and Atrophy in a Depleted microRNA 29a, b and c Environment

    PubMed Central

    Kauffman, Lauren; Balatti, Veronica; Cascione, Luciano; Fadda, Paolo; Racke, Frederick; Santhanam, Ramasamy; Costinean, Stefan

    2015-01-01

    Background The self-renewing ability of HSCs is fundamental for the maintenance of a pool of bone marrow precursors throughout the life of an individual. The genetic mechanisms underlying such a complex process are still poorly understood. Results and Significance Here, we show that constitutive in vivo deletion of miR29ab1 leads to reduced number of HSCs and that miR29ab1 deficient bone marrow cannot repopulate the bone marrow of irradiated mice. An Affymetrix analysis of the miR29ab1 knockout mice identifies key proteins that could be responsible for this phenotype, as DNMT3a and b. Moreover, our findings reveal that whereas miR29b2c knockout mice do not exhibit any spontaneous abnormality, the double knock out – miR29ab1b2c – has marked generalized atrophy, raising the possibility that the two bi-cistrons might cooperate in order to maintain the stem cell number in general, not only limited to the bone marrow. PMID:26147501

  17. Sox7-sustained expression alters the balance between proliferation and differentiation of hematopoietic progenitors at the onset of blood specification.

    PubMed

    Gandillet, Arnaud; Serrano, Alicia G; Pearson, Stella; Lie-A-Ling, Michael; Lacaud, Georges; Kouskoff, Valerie

    2009-11-26

    The molecular mechanisms that regulate the balance between proliferation and differentiation of precursors at the onset of hematopoiesis specification are poorly understood. By using a global gene expression profiling approach during the course of embryonic stem cell differentiation, we identified Sox7 as a potential candidate gene involved in the regulation of blood lineage formation from the mesoderm germ layer. In the present study, we show that Sox7 is transiently expressed in mesodermal precursors as they undergo specification to the hematopoietic program. Sox7 knockdown in vitro significantly decreases the formation of both primitive erythroid and definitive hematopoietic progenitors as well as endothelial progenitors. In contrast, Sox7-sustained expression in the earliest committed hematopoietic precursors promotes the maintenance of their multipotent and self-renewing status. Removal of this differentiation block driven by Sox7-enforced expression leads to the efficient differentiation of hematopoietic progenitors to all erythroid and myeloid lineages. This study identifies Sox7 as a novel and important player in the molecular regulation of the first committed blood precursors. Furthermore, our data demonstrate that the mere sustained expression of Sox7 is sufficient to completely alter the balance between proliferation and differentiation at the onset of hematopoiesis.

  18. Ocular manifestation in myeloid/NK cell precursor acute leukemia: a case report. Diagnosed by flow cytometry and PCR from aqueous humor

    PubMed Central

    Akaike, Sayaka; Kamoi, Koju; Tezuka, Mari; Tomizawa, Daisuke; Yoshimura, Ryoichi; Takagi, Masatoshi; Ohno-Matsui, Kyoko

    2016-01-01

    Abstract Background: Myeloid/NK cell precursor acute leukemia (MNKL) is a rare type of leukemia, and ocular complications have not previously been reported. We now report a patient with MNKL who developed intraocular infiltrates during follow-up. Methods and Results: A 13-year-old boy diagnosed with MNKL developed left eye pain 3 months after starting treatment. Examination of the left eye revealed a visual acuity of counting fingers at 20 cm, ciliary hyperemia, small corneal keratic precipitates, hypopyon, grade 4 vitreous opacities, and an obscured fundus. The differential diagnosis was between an opportunistic infection associated with immunodeficiency and an intraocular leukemic cell infiltrate. Therefore, a sample of aqueous humor was aspirated. Multiplex PCR/broad-range PCR of the aqueous humor was below detection limits for viruses, bacteria, and fungi. Flow cytometry (FCM) detected NK-related CD56-positive cells, thus leading to a diagnosis of ocular infiltrates due to MNKL. With treatment of the ocular infiltrates by consolidation systemic chemotherapy including intrathecal methotrexate (MTX), there was clearing of the vitreous opacities; and optic disc swelling, retinal hemorrhages, exudates, and protuberant lesions were now seen. With the addition of local radiation therapy to the eye, there was a dramatic treatment response, with regression of the optic disc findings and retinal lesions, and an improved visual acuity of 1.5. Conclusion: We encountered the first case of MNKL in which ocular infiltrates developed during follow-up. Multiplex PCR and FCM of the aqueous humor were useful in rapidly distinguishing leukemic cell infiltrates from an opportunistic infection. This case highlights the usefulness of intrathecal MTX and local radiotherapy in treating ocular infiltrates in patients with MNKL. PMID:27661058

  19. 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

    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

    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.

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

    PubMed Central

    Gooley, Theodore A.; Rajendran, Joseph; Fisher, Darrell R.; Wilson, Wendy A.; Sandmaier, Brenda M.; Matthews, Dana C.; Deeg, H. Joachim; Gopal, Ajay K.; Martin, Paul J.; Storb, Rainer F.; Press, Oliver W.; Appelbaum, Frederick R.

    2009-01-01

    We conducted a study to estimate the maximum tolerated dose (MTD) of 131I–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 131I-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 131I-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. PMID:19786617

  1. Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors

    PubMed Central

    Villarejo, Ana; Molina-Ortiz, Patricia; Montenegro, Yenny; Moreno-Bueno, Gema; Morales, Saleta; Santos, Vanesa; Gridley, Tom; Pérez-Moreno, Mirna A.; Peinado, Héctor; Portillo, Francisco; Calés, Carmela; Cano, Amparo

    2015-01-01

    Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 −/− mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 −/− mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression. PMID:25784375

  2. Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading?

    PubMed Central

    Eisfeld, Ann-Kathrin; Westerman, Mark; Krahl, Rainer; Leiblein, Sabine; Liebert, Uwe Gerd; Hehme, Marianne; Teupser, Daniel; Niederwieser, Dietger; Al-Ali, Haifa Kathrin

    2011-01-01

    Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre- and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P < .0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P < .0005), pre- and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P = .001) and hepcidin (P = .001). No correlation of pre- or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre- and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT. PMID:21687645

  3. [Hematopoietic stem cells and hematopoietic neoplasias].

    PubMed

    Wickenhauser, C

    2002-11-01

    Pluripotent hematopoietic stem cells have been defined as cells with extensive self-renewal capacity and lympho-hematopoietic differentiation potential. Clonal selection of a stem cell as a first step in the progression to neoplasia can be achieved by an alteration of this self-renewal potency. Our current understanding of the pathogenesis of the myeloproliferative disorders including acute myeloid leukemias, chronic myeloproliferative disorders (CMPD) and myelodysplastic syndromes (MDS), is based on the assumption that they represent a clonal disorder resulting from transformation of a hematopoietic stem cell. However, when performing methods for determining X-chromosome inactivation in female patients as a clonality marker, a significant minority of the patients with Philadelphia chromosome negative (Ph(-)) CMPD and MDS exhibit polyclonal proliferation. The implications of these results are not yet clarified and the lack of a proven target cell impairs the understanding of the underlying molecular defect. In this context, altered response to cytokine stimulation in vitro provides indirect information concerning molecular dysregulation. A subset of patients with MPD present with translocations that facilitate molecular investigation and clonality proof. They nearly always result in rearrangements of at least one transcription factor gene. Most of these fusion genes are constitutively active, sending out continuous proliferative and antiapoptotic signals or activate an overlapping set of signalling pathways. The classical example for a balanced translocation is the t(9;22) bcr-abl aberration in chronic myelogeneous leukemia. Many other karyotypic abnormalities have also been associated with CMPD and MDS and involve deletions of chromosomes 20q, 13q, 1q, 7q and 5q as well as trisomy of 8 and 9. Our increased understanding of the hematopoietic stem cell compartment and the molecular basis of regulation of its self-renewal and differentiation bears a direct impact on

  4. Comparison of Outcomes for Pediatric Patients With Acute Myeloid Leukemia in Remission and Undergoing Allogeneic Hematopoietic Cell Transplantation With Myeloablative Conditioning Regimens Based on Either Intravenous Busulfan or Total Body Irradiation: A Report From the Japanese Society for Hematopoietic Cell Transplantation.

    PubMed

    Ishida, Hiroyuki; Kato, Motohiro; Kudo, Kazuko; Taga, Takashi; Tomizawa, Daisuke; Miyamura, Takako; Goto, Hiroaki; Inagaki, Jiro; Koh, Katsuyoshi; Terui, Kiminori; Ogawa, Atsushi; Kawano, Yoshifumi; Inoue, Masami; Sawada, Akihisa; Kato, Koji; Atsuta, Yoshiko; Yamashita, Takuya; Adachi, Souichi

    2015-12-01

    Pediatric patients with acute myeloid leukemia (AML) mainly receive myeloablative conditioning regimens based on busulfan (BU) or total body irradiation (TBI) before allogeneic hematopoietic cell transplantation (allo-HCT); however, the optimal conditioning regimen remains unclear. To identify which of these regimens is better for pediatric patients, we performed a retrospective analysis of nationwide registration data collected in Japan between 2006 and 2011 to assess the outcomes of patients receiving these regimens before a first allo-HCT. Myeloablative conditioning regimens based on i.v. BU (i.v. BU-MAC) (n = 69) or TBI (TBI-MAC) (n = 151) were compared in pediatric AML patients in first or second complete remission (CR1/CR2). The incidences of sinusoid obstruction syndrome, acute and chronic graft-versus-host disease, and early nonrelapse mortality (NRM) before day 100 were similar for both conditioning groups; however, the incidence of bacterial infection during the acute period was higher in the TBI-MAC group (P = .008). Both groups showed a similar incidence of NRM, and there was no significant difference in the incidence of relapse between the groups. Univariate and multivariate analyses revealed no significant differences in the 2-year relapse-free survival rates for the i.v. BU-MAC and TBI-MAC groups in the CR1/CR2 setting (71% versus 67%, P = .36; hazard ratio, .73; 95% CI, .43 to 1.24, respectively). TBI-MAC was no better than i.v. BU-MAC for pediatric AML patients in remission. Although this retrospective registry-based analysis has several limitations, i.v. BU-MAC warrants further evaluation in a prospective trial. PMID:26271192

  5. Comparison of Outcomes for Pediatric Patients With Acute Myeloid Leukemia in Remission and Undergoing Allogeneic Hematopoietic Cell Transplantation With Myeloablative Conditioning Regimens Based on Either Intravenous Busulfan or Total Body Irradiation: A Report From the Japanese Society for Hematopoietic Cell Transplantation.

    PubMed

    Ishida, Hiroyuki; Kato, Motohiro; Kudo, Kazuko; Taga, Takashi; Tomizawa, Daisuke; Miyamura, Takako; Goto, Hiroaki; Inagaki, Jiro; Koh, Katsuyoshi; Terui, Kiminori; Ogawa, Atsushi; Kawano, Yoshifumi; Inoue, Masami; Sawada, Akihisa; Kato, Koji; Atsuta, Yoshiko; Yamashita, Takuya; Adachi, Souichi

    2015-12-01

    Pediatric patients with acute myeloid leukemia (AML) mainly receive myeloablative conditioning regimens based on busulfan (BU) or total body irradiation (TBI) before allogeneic hematopoietic cell transplantation (allo-HCT); however, the optimal conditioning regimen remains unclear. To identify which of these regimens is better for pediatric patients, we performed a retrospective analysis of nationwide registration data collected in Japan between 2006 and 2011 to assess the outcomes of patients receiving these regimens before a first allo-HCT. Myeloablative conditioning regimens based on i.v. BU (i.v. BU-MAC) (n = 69) or TBI (TBI-MAC) (n = 151) were compared in pediatric AML patients in first or second complete remission (CR1/CR2). The incidences of sinusoid obstruction syndrome, acute and chronic graft-versus-host disease, and early nonrelapse mortality (NRM) before day 100 were similar for both conditioning groups; however, the incidence of bacterial infection during the acute period was higher in the TBI-MAC group (P = .008). Both groups showed a similar incidence of NRM, and there was no significant difference in the incidence of relapse between the groups. Univariate and multivariate analyses revealed no significant differences in the 2-year relapse-free survival rates for the i.v. BU-MAC and TBI-MAC groups in the CR1/CR2 setting (71% versus 67%, P = .36; hazard ratio, .73; 95% CI, .43 to 1.24, respectively). TBI-MAC was no better than i.v. BU-MAC for pediatric AML patients in remission. Although this retrospective registry-based analysis has several limitations, i.v. BU-MAC warrants further evaluation in a prospective trial.

  6. FLT3 ligand administration after hematopoietic cell transplantation increases circulating dendritic cell precursors that can be activated by CpG oligodeoxynucleotides to enhance T-cell and natural killer cell function.

    PubMed

    Chen, Wei; Chan, Anissa S H; Dawson, Amanda J; Liang, Xueqing; Blazar, Bruce R; Miller, Jeffrey S

    2005-01-01

    Dendritic cells (DCs) are key effectors in innate immunity and play critical roles in triggering adaptive immune responses. FLT3 ligand (FLT3-L) is essential for DC development from hematopoietic progenitors. In a phase I clinical trial, we demonstrated that immunotherapy with subcutaneous injection of FLT3-L is safe and well tolerated in cancer patients recovering from autologous hematopoietic cell transplantation (HCT). FLT3-L administration significantly increased the frequency and absolute number of blood DC precursors without affecting other mature cell lineages during the 6-week course of FLT3-L therapy. After 14 days of FLT3-L administration, the number of blood CD11c + DCs, plasmacytoid DCs (PDCs), and CD14 + monocytes increased by 5.3-, 2.9-, 3.8-fold, respectively, and was maintained at increased levels throughout FLT3-L therapy. FLT3-L-increased blood DCs in HCT patients were immature and had modest enhancing effects on in vitro T-cell proliferation to antigens and natural killer (NK) cell function. The addition of type B CpG oligodeoxynucleotides (ODNs) to peripheral blood mononuclear cells obtained from HCT patients receiving FLT3-L therapy induced rapid maturation of both CD11c + DCs and PDCs and enhanced T-cell proliferative responses. In addition, CpG ODN induced potent activation of NK cells from FLT3-L-treated patients with increased surface CD69 expression and augmented cytotoxicity. CpG ODN-induced activation of NK cells was primarily via an indirect mechanism through PDCs. These findings suggest that FLT3-L mobilization of DC precursors followed by a specific DC stimulus such as CpG ODN may provide a novel strategy to manipulate antitumor immunity in patients after HCT. PMID:15625541

  7. Putative prethymic T cell precursors within the early human embryonic liver: a molecular and functional analysis

    PubMed Central

    1993-01-01

    Hematopoietic cells present in the liver in early human fetal life were characterized by phenotypic analysis using a broad panel of monoclonal antibodies. Expression of very late antigen 4 and leukocyte function- associated antigen 3 cell adhesion receptors and 4F2 cell activation molecules was found in all fetal liver hematopoietic cells before acquisition of T cell-, B cell-, or myeloid-specific surface markers, and before the time of intrathymic colonization. Molecular studies showed that expression of the interleukin 2 receptor beta (IL-2R beta) also occurred in the embryonic liver at this early ontogenic stage. In contrast, no expression of IL-2R alpha or IL-2 transcripts was found in fetal liver cells, whereas transcription of the IL-4 gene was detected in a small fetal liver cell subset. Putative T cell precursors were identified among the hematopoietic fetal liver cells by the expression of genes encoding the gamma, delta, epsilon, and zeta invariant chains of the CD3-T cell receptor (TCR) complex. However, no transcription of the polymorphic alpha and beta TCR genes was detected. Functional in vitro assays further demonstrated that fetal liver hematopoietic cells from those early embryos were capable of proliferating in response to T cell growth factors, including IL-4 and IL-2. However, whereas IL-4- induced proliferation paralleled the appearance in vitro of CD45+CD7- CD4dull cells expressing the CD14 myeloid antigen, as well as of CD34+ primitive hematopoietic progenitors, differentiation into CD45+CD7+CD8+CD3- immature T cells was observed when using IL-2. Moreover, coculture with thymic epithelial cell monolayers provided additional evidence that early fetal liver hematopoietic cells may include very primitive T cell precursors, which were able to differentiate in vitro into TCR alpha/beta+ mature T cells. Therefore, our results indicate that, after triggering of the T cell-specific maturation program in primitive fetal liver hematopoietic progenitors

  8. Type I interferon limits the capacity of bluetongue virus to infect hematopoietic precursors and dendritic cells in vitro and in vivo.

    PubMed

    Rodríguez-Calvo, Teresa; Rojas, José-Manuel; Martín, Verónica; Sevilla, Noemí

    2014-01-01

    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-α) 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.

  9. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages.

    PubMed

    Hoeffel, Guillaume; Chen, Jinmiao; Lavin, Yonit; Low, Donovan; Almeida, Francisca F; See, Peter; Beaudin, Anna E; Lum, Josephine; Low, Ivy; Forsberg, E Camilla; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Ng, Lai Guan; Chan, Jerry K Y; Greter, Melanie; Becher, Burkhard; Samokhvalov, Igor M; Merad, Miriam; Ginhoux, Florent

    2015-04-21

    Although classified as hematopoietic cells, tissue-resident macrophages (MFs) arise from embryonic precursors that seed the tissues prior to birth to generate a self-renewing population, which is maintained independently of adult hematopoiesis. Here we reveal the identity of these embryonic precursors using an in utero MF-depletion strategy and fate-mapping of yolk sac (YS) and fetal liver (FL) hematopoiesis. We show that YS MFs are the main precursors of microglia, while most other MFs derive from fetal monocytes (MOs). Both YS MFs and fetal MOs arise from erythro-myeloid progenitors (EMPs) generated in the YS. In the YS, EMPs gave rise to MFs without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal MOs that then seeded embryonic tissues and differentiated into MFs. Thus, adult tissue-resident MFs established from hematopoietic stem cell-independent embryonic precursors arise from two distinct developmental programs.

  10. Colony-Stimulating Factor-1-Responsive Macrophage Precursors Reside in the Amphibian (Xenopus laevis) Bone Marrow Rather than the Hematopoietic Sub-Capsular Liver

    PubMed Central

    Grayfer, Leon; Robert, Jacques

    2013-01-01

    Macrophage precursors originate from, and undergo lineage commitment within designated sites of hematopoiesis, such as the mammalian bone marrow. These cells subsequently differentiate in response to stimulation with macrophage colony-stimulating factor (CSF-1). The amphibian bone marrow, unlike that of mammals, has been overlooked as a source of leukocyte precursors in favor of the liver sub-capsular region, where hematopoiesis occurs in anurans. Here we report that the bone marrow rather than the liver periphery provides macrophage progenitors to the amphibian Xenopus laevis. We identified the amphibian CSF-1, examined its gene expression in developing and virally infected X. laevis and produce it in recombinant form (rXlCSF-1). This rXlCSF-1 did not bind or elicit proliferation/differentiation of sub-cortical liver cells. Surprisingly, a sub-population of bone marrow cells engaged this growth factor and formed rXlCSF-1-concentration-dependant colonies in semi-solid medium. Furthermore, rXlCSF-1-treated bone marrow (but not liver) cultures comprised of cells with characteristic macrophage morphology and high gene expression of the macrophage marker, colony stimulating factor-1 receptor (CSF-1R). Together, our findings indicate that in contrast to all other vertebrates studied to date, Xenopus committed macrophage precursors populations are not present in the central site of hematopoiesis, but reside in the bone marrow. PMID:23485675

  11. AP-1 (Fos/Jun) transcription factors in hematopoietic differentiation and apoptosis.

    PubMed

    Liebermann, D A; Gregory, B; Hoffman, B

    1998-03-01

    A combination of in vitro and in vivo molecular genetic approaches have provided evidence to suggest that AP-1 (Fos/Jun) transcription factors play multiple roles in functional development of hematopoietic precursor cells into mature blood cells along most, if not all, of the hematopoietic cell lineages. This includes the monocyte/macrophage, granulocyte, megakaryocyte, mastocyte and erythroid lineages. In addition, studies using c-fos knockout mice have established a unique role for Fos, as a member of the AP-1 transcription factor complex, in determining the differentiation and activity of progenitors of the osteoclast lineage, a population of bone-forming cells which are of hematopoietic origin as well. Evidence has also accumulated to implicate AP-1 (Fos/Jun) transcription factor complexes as both positive and negative modulators of distinct apoptotic pathways in many cell types, including cells of hematopoietic origin. Fos/Jun have been implicated as positive modulators of apoptosis induced in hematopoietic progenitor cells of the myeloid lineage, a function that may relate to the control of blood cell homeostasis, as well as in programmed cell death associated with terminal differentiation of many other cell types, and apoptosis associated with withdrawal of growth/survival factors. On the other hand, the study of apoptosis induced in mammalian cells has implicated AP-1 in the protection against apoptosis induced by DNA-damaging agents. However, evidence to the contrary has been obtained as well, suggesting that AP-1 may function to modulate stress-induced apoptosis either positively or negatively, depending on the microenvironment and the cell type in which the stress stimulus is induced.

  12. Parvovirus Infection Suppresses Long-Term Repopulating Hematopoietic Stem Cells

    PubMed Central

    Segovia, José C.; Guenechea, Guillermo; Gallego, Jesús M.; Almendral, José M.; Bueren, Juan A.

    2003-01-01

    The functional disturbance of self-renewing and multipotent hematopoietic stem cells (HSCs) in viral diseases is poorly understood. In this report, we have assessed the susceptibility of mouse HSCs to strain i of the autonomous parvovirus minute virus of mice (MVMi) in vitro and during persistent infection of an immunodeficient host. Purified 5FUr Lin− Sca-1+ primitive hematopoietic precursors were permissive for MVMi genome replication and the expression of viral gene products. The lymphoid and myeloid repopulating capacity of bone marrow (BM) cells was significantly impaired after in vitro infection, although the degree of functional effect proportionally decreased with the posttransplantation time. This indicated that MVMi targets the heterogeneous compartment of repopulating cells with differential affinity and suggests that the virus may persist in some primitive HSCs in the quiescent stage, killing those eventually recruited for proliferative activity. Immunodeficient SCID mice oronasally infected with MVMi were cured of the characteristic virus-induced lethal leukopenia by transplantation of immunocompetent BM grafts. However, two double-stranded viral DNA species, probably uncommon replicative intermediates, remained in the marrow of every transplanted mouse months after infectious virus clearance. Genetic analysis of the rescued mice showed that the infection ensured a stable engraftment of donor hematopoiesis by markedly depleting the pool of endogenous HSCs. The MVMi-induced suppression of HSC functions illustrates the accessibility of this compartment to infection during a natural viral hematological disease. These results may provide clues to understanding delayed hematopoietic syndromes associated with persistent viral infections and to prospective gene delivery to HSCs in vivo. PMID:12857918

  13. 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

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

    2010-01-01

    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.

  14. MicroRNAs in Myeloid Hematological Malignancies

    PubMed Central

    Ciccone, Maria; Calin, George Adrian

    2015-01-01

    MicroRNAs are 19-24 nucleotides noncoding RNAs which silence modulate the expression of target genes by binding to the messenger RNAs. Myeloid malignancies include a broad spectrum of acute and chronic disorders originating from from the clonal transformation of a hematopoietic stem cell. Specific genetic abnormalities may define myeloid malignancies, such as translocation t(9;22) that represent the hallmark of chronic myeloid leukemia. Although next-generation sequencing pro-vided new insights in the genetic characterization and pathogenesis of myeloid neoplasms, the molecular mechanisms underlying myeloid neoplasms are lacking in most cases. Recently, several studies have demonstrated that the expression levels of specific miRNAs may vary among patients with myeloid malignancies compared with healthy individuals and partially unveiled how miRNAs participate in the leukemic transformation process. Finally, in vitro experiments and pre-clinical model provided preliminary data of the safety and efficacy of miRNA inhibitory molecules, opening new avenue in the treatment of myeloid hematological malignancies. PMID:27047254

  15. Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation

    PubMed Central

    Goodings, Charnise; Smith, Elizabeth; Mathias, Elizabeth; Elliott, Natalina; Cleveland, Susan M.; Tripathi, Rati M.; Layer, Justin H.; Chen, Xi; Guo, Yan; Shyr, Yu; Hamid, Rizwan; Du, Yang; Davé, Utpal P.

    2015-01-01

    Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis. PMID:25968920

  16. Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.

    PubMed

    Goodings, Charnise; Smith, Elizabeth; Mathias, Elizabeth; Elliott, Natalina; Cleveland, Susan M; Tripathi, Rati M; Layer, Justin H; Chen, Xi; Guo, Yan; Shyr, Yu; Hamid, Rizwan; Du, Yang; Davé, Utpal P

    2015-08-01

    Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis.

  17. Acute hematopoietic stress in mice is followed by enhanced osteoclast maturation in the bone marrow microenvironment.

    PubMed

    Kuzmac, Sania; Grcevic, Danka; Sucur, Alan; Ivcevic, Sanja; Katavic, Vedran

    2014-11-01

    Osteoclasts are components of hematopoietic stem cell (HSC) niches, but their role as contributors to the HSC homeostasis and release are still controversial. We aimed to investigate whether an acute blood loss of 10% of total blood content, along with the consequent intense hematopoiesis, would affect osteoclast differentiation and activity. Isolated peripheral blood, spleen, and bone marrow (BM) cells from bones of hind limbs were investigated for the presence of specific subpopulations of osteoclast precursors: B220(-)CD3(-)NK1.1(-)CD11b(-/low)CD115(+)CD117(+) cells in BM, and B220(-)CD3(-)NK1.1(-)Gr-1(-)CD11b(+)CD115(+) cells in peripheral blood and spleen as well as the receptor activator of nuclear factor κ-B(+) cycle-arrested quiescent osteoclast precursors. Expression of osteoclastogenesis-related genes CD115, receptor activator of nuclear factor κ-B, and cathepsin K, the potential of BM cells to form osteoclast-like cells in vitro, and osteoclast activity in vivo were also evaluated. We observed an increase in spleen cellularity and myelopoiesis during week 1 following blood loss, without any significant effects on BM cellularity or BM myeloid precursors, including cells with high osteoclastogenic potential. However, at 1 week postbleeding, hematopoiesis significantly promoted the expression of cathepsin K, interleukin-34, and bone morphogenetic protein-6. Quiescent osteoclast precursors increased significantly in spleen 2 days following bleeding, whereas osteoclast activity remained unchanged up to 2 weeks postbleeding. Osteoclast-dependent B-cell differentiation was affected at the pre-B stage of maturation in BM, whereas the Lin(-)Sca-1(+)c-kit(+) population expanded in BM and spleen after 2 days postbleeding. Our data demonstrate that an acute blood loss promotes differentiation and maturation of osteoclasts at 1 week but does not enhance osteoresorption at 2 weeks postbleeding. Our data also identify osteoclast differentiation as a consequent and

  18. Human Term Placenta as a Source of Hematopoietic Cells

    PubMed Central

    Serikov, Vladimir; Hounshell, Catherine; Larkin, Sandra; Green, William; Ikeda, Hirokazu; Walters, Mark C.

    2012-01-01

    The main barrier to a broader clinical application of umbilical cord blood (UCB) transplantation is its limiting cellular content. Thus, the discovery of hematopoietic progenitor cells in murine placental tissue led us investigate whether the human placenta contains hematopoietic cells, sites of hematopoiesis, and to develop a procedure of processing and storing placental hematopoietic cells for transplantation. Here we show that the human placenta contains large numbers of CD34-expressing hematopoietic cells, with the potential to provide a cellular yield several-fold greater than that of a typical UCB harvest. Cells from fresh or cryopreserved placental tissue generated erythroid and myeloid colonies in culture, and also produced lymphoid cells after transplantation in immunodeficient mice. These results suggest that human placenta could become an important new source of hematopoietic cells for allogeneic transplantation. PMID:19429852

  19. Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage.

    PubMed

    Woolthuis, Carolien M; Park, Christopher Y

    2016-03-10

    The classical model of hematopoiesis has long held that hematopoietic stem cells (HSCs) sit at the apex of a developmental hierarchy in which HSCs undergo long-term self-renewal while giving rise to cells of all the blood lineages. In this model, self-renewing HSCs progressively lose the capacity for self-renewal as they transit into short-term self-renewing and multipotent progenitor states, with the first major lineage commitment occurring in multipotent progenitors, thus giving rise to progenitors that initiate the myeloid and lymphoid branches of hematopoiesis. Subsequently, within the myeloid lineage, bipotent megakaryocyte-erythrocyte and granulocyte-macrophage progenitors give rise to unipotent progenitors that ultimately give rise to all mature progeny. However, over the past several years, this developmental scheme has been challenged, with the origin of megakaryocyte precursors being one of the most debated subjects. Recent studies have suggested that megakaryocytes can be generated from multiple pathways and that some differentiation pathways do not require transit through a requisite multipotent or bipotent megakaryocyte-erythrocyte progenitor stage. Indeed, some investigators have argued that HSCs contain a subset of cells with biased megakaryocyte potential, with megakaryocytes directly arising from HSCs under steady-state and stress conditions. In this review, we discuss the evidence supporting these nonclassical megakaryocytic differentiation pathways and consider their relative strengths and weaknesses as well as the technical limitations and potential pitfalls in interpreting these studies. Ultimately, such pitfalls will need to be overcome to provide a comprehensive and definitive understanding of megakaryopoiesis. PMID:26787736

  20. Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies

    ClinicalTrials.gov

    2016-05-04

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Hematopoietic/Lymphoid Cancer; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia

  1. Reduced-Intensity Conditioning Combined with (188)Rhenium Radioimmunotherapy before Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: The Role of In Vivo T Cell Depletion.

    PubMed

    Schneider, Sebastian; Strumpf, Annette; Schetelig, Johannes; Wunderlich, Gerd; Ehninger, Gerhard; Kotzerke, Jörg; Bornhäuser, Martin

    2015-10-01

    The combination of reduced-intensity conditioning, (188)rhenium anti-CD66 radioimmunotherapy, and in vivo T cell depletion was successfully applied in elderly patients with acute myeloid leukemia or myelodysplastic syndrome. Within a prospective phase II protocol, we investigated whether a dose reduction of alemtuzumab (from 75 mg to 50 mg MabCampath) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients (median age, 67 years; range, 54 to 76) received radioimmunotherapy followed by fludarabine 150 mg/m(2) and busulfan 8 mg/kg combined with either 75 mg (n = 26) or 50 mg (n = 32) alemtuzumab. Although we observed a trend towards a shorter duration of neutropenia in the 50 mg group (median, 19 versus 21 days; P = .07), the time from transplantation to neutrophil and platelet engraftment as well as the overall incidence of engraftment did not differ. The incidence of severe acute graft-versus-host disease tended to be higher after the lower alemtuzumab dose (17% versus 4%; P = .15). No significant differences in the cumulative incidences of relapse (38% versus 35%; P = .81) or nonrelapse mortality (46% versus 27%; P = .31) were observed. Accordingly, disease-free and overall survival were not significantly different between groups. Although the feasibility of radioimmunotherapy plus reduced-intensity conditioning could be demonstrated in elderly patients, the dose reduction of alemtuzumab had no positive impact on overall outcome.

  2. Hypocellular acute myeloid leukemia in adults: analysis of the clinical outcome of 123 patients

    PubMed Central

    Al-Kali, Aref; Konoplev, Sergej; Lin, Erpei; Kadia, Tapan; Faderl, Stefan; Ravandi, Farhad; Ayoubi, Mohamad; Brandt, Mark; Cortes, Jorge E.; Kantarjian, Hagop; Borthakur, Gautam

    2012-01-01

    Background The hypocellular variant of acute myeloid leukemia accounts for less than 10% of all cases of adult acute myeloid leukemia. It is defined by having less than 20 percent of cellular bone marrow in a biopsy at presentation. It is unclear in the literature whether the outcome of hypocellular acute myeloid leukemia differs from that of non-hypocellular acute myeloid leukemia. Design and Methods We retrospectively analyzed all the cases reported to be hypocellular acute myeloid leukemia between 2000 and 2009. A second pathology review was conducted and the diagnosis was confirmed in all cases. Results One hundred twenty-three (9%) patients were identified: patients with hypocellular acute myeloid leukemia were older than those with non-hypocellular acute myeloid leukemia (P=0.009) and more frequently presented with cytopenias (P<0.001). Forty-one patients with hypocellular acute myeloid leukemia had an antecedent hematologic disorder and 11 patients had received prior chemo-radiotherapy for non-hematopoietic neoplasms. On multivariate analysis, overall survival, remission duration and event-free survival were comparable to those of other patients with acute myeloid leukemia. Conclusions The outcome of hypocellular acute myeloid leukemia does not differ from that of non-hypocellular acute myeloid leukemia. PMID:22058194

  3. SWEF Proteins Distinctly Control Maintenance and Differentiation of Hematopoietic Stem Cells.

    PubMed

    Ripich, Tatsiana; Chacón-Martínez, Carlos Andrés; Fischer, Luise; Pernis, Alessandra; Kiessling, Nadine; Garbe, Annette I; Jessberger, Rolf

    2016-01-01

    SWAP-70 and DEF6, two proteins that feature similar domain and motif arrangements, are mainly known for their functions in differentiated hematopoietic cells. Both proteins interact with and regulate RhoGTPases and F-actin dynamics, yet their role in hematopoietic stem and precursor cells (HSPCs) remained unexplored. Here, the role of the SWEF proteins SWAP-70 and DEF6 in HSPCs was examined. Both SWEF proteins are expressed in HSCs. HSCs and different precursor populations were analyzed in mice deficient for SWAP-70, DEF6, SWAP-70 and DEF6 (double knockout, DKO), and wild-type controls. HSPCs isolated from these strains were used for competitive adoptive transfer into irradiated wild-type mice. Reconstitution of the myeloid and lymphoid lineages in the recipient mice was determined. The numbers of HSPCs in the bone marrow of Swap-70-/- and Swap-70-/-Def6-/- mice were >3-fold increased. When transplanted into lethally irradiated wild-type recipients, the reconstitution potential of Swap-70-/- HSPCs was intrinsically impaired in competing with wild-type HSPCs for contribution to hematopoiesis. Def6-/- HSPCs show wild type-like reconstitution potential under the same transplantation conditions. DKO HSPCs reconstituted to only 25% of wild-type levels, indicating a partial rescue by DEF6 deficiency in the Swap-70-/- background. Our study reveals the two SWEF proteins as important contributors to HSPC biology. Despite their similarity these two proteins regulate HSC/progenitor homeostasis, self-renewal, lineage contributions and repopulation in a distinct and mostly antagonistic manner. PMID:27561029

  4. SWEF Proteins Distinctly Control Maintenance and Differentiation of Hematopoietic Stem Cells

    PubMed Central

    Ripich, Tatsiana; Chacón-Martínez, Carlos Andrés; Fischer, Luise; Pernis, Alessandra; Kiessling, Nadine; Garbe, Annette I.; Jessberger, Rolf

    2016-01-01

    SWAP-70 and DEF6, two proteins that feature similar domain and motif arrangements, are mainly known for their functions in differentiated hematopoietic cells. Both proteins interact with and regulate RhoGTPases and F-actin dynamics, yet their role in hematopoietic stem and precursor cells (HSPCs) remained unexplored. Here, the role of the SWEF proteins SWAP-70 and DEF6 in HSPCs was examined. Both SWEF proteins are expressed in HSCs. HSCs and different precursor populations were analyzed in mice deficient for SWAP-70, DEF6, SWAP-70 and DEF6 (double knockout, DKO), and wild-type controls. HSPCs isolated from these strains were used for competitive adoptive transfer into irradiated wild-type mice. Reconstitution of the myeloid and lymphoid lineages in the recipient mice was determined. The numbers of HSPCs in the bone marrow of Swap-70-/- and Swap-70-/-Def6-/- mice were >3-fold increased. When transplanted into lethally irradiated wild-type recipients, the reconstitution potential of Swap-70-/- HSPCs was intrinsically impaired in competing with wild-type HSPCs for contribution to hematopoiesis. Def6-/- HSPCs show wild type-like reconstitution potential under the same transplantation conditions. DKO HSPCs reconstituted to only 25% of wild-type levels, indicating a partial rescue by DEF6 deficiency in the Swap-70-/- background. Our study reveals the two SWEF proteins as important contributors to HSPC biology. Despite their similarity these two proteins regulate HSC/progenitor homeostasis, self-renewal, lineage contributions and repopulation in a distinct and mostly antagonistic manner. PMID:27561029

  5. MYC and PIM2 co-expression in mouse bone marrow cells readily establishes permanent myeloid cell lines that can induce lethal myeloid sarcoma in vivo.

    PubMed

    Jang, Su Hwa; Chung, Hee Yong

    2012-08-01

    The hematopoietic cell malignancy is one of the most prevalent type of cancer and the disease has multiple pathologic molecular signatures. Research on the origin of hematopoietic cancer stem cells and the mode of subsequent maintenance and differentiation needs robust animal models that can reproduce the transformation and differentiation event in vivo. Here, we show that co-transduction of MYC and PIM2 proto-oncogenes into mouse bone marrow cells readily establishes permanent cell lines that can induce lethal myeloid sarcoma in vivo. Unlike the previous doubly transgenic mouse model in which coexpression of MYC and PIM2 transgenes exclusively induced B cell lymphoma, we were able to show that the same combination of genes can also transform primary bone marrow myeloid cells in vitro resulting in permanent cell lines which induce myeloid sarcoma upon in vivo transplantation. By inducing cancerous transformation of fresh bone marrow cells in a controlled environment, the model we established will be useful for detailed study of the molecular events involved in initial transformation process of primary myeloid bone marrow cells and provides a model that can give insight to the molecular pathologic characteristics of human myeloid sarcoma, a rare presentation of solid tumors of undifferentiated myeloid blast cells associated with various types of myeloid leukemia. PMID:22843119

  6. Retroviral transduction of hematopoietic progenitors derived from human embryonic stem cells.

    PubMed

    Menendez, Pablo; Wang, Lisheng; Cerdan, Chantal; Bhatia, Mickie

    2006-01-01

    It has been recently identified that cytokines and BMP-4 promote hematopoiesis from human embryonic stem cells (hESC) and that, before hematopoietic commitment, a rare subpopulation of cells lacking CD45, but expressing PECAM-1, Flk-1, and VE-cadherin (hereinafter termed CD45(neg)PFV precursors), are exclusively responsible for hematopoietic cell fate on cytokine stimulation. Efficient strategies to stably transduce these hematopoietic precursors specifically generated from hESCs would provide a novel and desirable tool to study hematopoietic development through the introduction and characterization of candidate genes suspected to regulate self-renewal processes of hESC-derived hematopoietic cells or dynamically track hESC-derived hematopoietic stem cells in vivo. To date, only transient transfection and stable transduction using lentiviral vectors have been reported in undifferentiated hESC followed by random and spontaneous differentiation into different cell types. However, protocols for stable transduction of hematopoietic progenitors prospectively derived from hESC need to be developed yet. In the present chapter, we described detailed methods on the recently characterized and optimized GALV-pseudotyped retroviral gene transfer strategy to stably transduce the hematopoietic progenitor cells prospectively derived from CD45(neg)PFV hemogenic precursors as a vital tool to study hematopoietic development and to characterize candidate genes suspected to eventually confer robust and sustained repopulating ability to hESC-derived hematopoietic cells.

  7. Hematopoietic tissue repair under chronic low daily dose irradiation

    NASA Astrophysics Data System (ADS)

    Seed, T. M.

    The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). In our laboratory we have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d^-1). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific (three major responding subgroups identified) and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup 1), the failure to augment basic repair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments (particularly marked within erythroid compartments) that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccommodated and either prone- or not prone to ML, subgroup 2 & 3) appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high-tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity. The kinetics of these repair-mediated, regenerative hematopoietic

  8. Epigenetic Regulation of Hematopoietic Stem Cells.

    PubMed

    Sharma, Shilpa; Gurudutta, Gangenahalli

    2016-05-30

    Hematopoietic stem cells are endowed with a distinct potential to bolster self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. Both hematopoietic stem cells and mature cells have the same genome, but their gene expression is controlled by an additional layer of epigenetics such as DNA methylation and post-translational histone modifications, enabling each cell-type to acquire various forms and functions. Until recently, several studies have largely focussed on the transcription factors andniche factors for the understanding of the molecular mechanisms by which hematopoietic cells replicate and differentiate. Several lines of emerging evidence suggest that epigenetic modifications eventually result in a defined chromatin structure and an "individual" gene expression pattern, which play an essential role in the regulation of hematopoietic stem cell self-renewal and differentiation. Distinct epigenetic marks decide which sets of genes may be expressed and which genes are kept silent. Epigenetic mechanisms are interdependent and ensure lifelong production of blood and bone marrow, thereby contributing to stem cell homeostasis. The epigenetic analysis of hematopoiesis raises the exciting possibility that chromatin structure is dynamic enough for regulated expression of genes. Though controlled chromatin accessibility plays an essential role in maintaining blood homeostasis; mutations in chromatin impacts on the regulation of genes critical to the development of leukemia. In this review, we explored the contribution of epigenetic machinery which has implications for the ramification of molecular details of hematopoietic self-renewal for normal development and underlying events that potentially co-operate to induce leukemia.

  9. Proinflammatory signaling regulates hematopoietic stem cell emergence

    PubMed Central

    Espín-Palazón, Raquel; Stachura, David L.; Campbell, Clyde A.; García-Moreno, Diana; Cid, Natasha Del; Kim, Albert D.; Candel, Sergio; Meseguer, José; Mulero, Victoriano; Traver, David

    2014-01-01

    Summary Hematopoietic stem cells (HSCs) underlie the production of blood and immune cells for the lifetime of an organism. In vertebrate embryos, HSCs arise from the unique transdifferentiation of hemogenic endothelium comprising the floor of the dorsal aorta during a brief developmental window. To date, this process has not been replicated in vitro from pluripotent precursors, partly because the full complement of required signaling inputs remains to be determined. Here, we show that TNFR2 via TNFα activates the Notch and NF-κB signaling pathways to establish HSC fate, indicating a requirement for inflammatory signaling in HSC generation. We determine that primitive neutrophils are the major source of TNFα, assigning a role for transient innate immune cells in establishing the HSC program. These results demonstrate that proinflammatory signaling, in the absence of infection, is utilized by the developing embryo to generate the lineal precursors of the adult hematopoietic system. PMID:25416946

  10. Sox4 cooperates with CREB in myeloid transformation

    PubMed Central

    Sandoval, Salemiz; Kraus, Christina; Cho, Er-Chieh; Cho, Michelle; Bies, Juraj; Manara, Elena; Accordi, Benedetta; Landaw, Elliot M.; Wolff, Linda; Pigazzi, Martina

    2012-01-01

    The cAMP response element-binding protein (CREB) is a nuclear transcription factor that is critical for normal and neoplastic hematopoiesis. Previous studies have demonstrated that CREB is a proto-oncogene whose overexpression promotes cellular proliferation in hematopoietic cells. Transgenic mice that overexpress CREB in myeloid cells develop a myeloproliferative disease with splenomegaly and aberrant myelopoiesis. However, CREB overexpressing mice do not spontaneously develop acute myeloid leukemia. In this study, we used retroviral insertional mutagenesis to identify genes that accelerate leukemia in CREB transgenic mice. Our mutagenesis screen identified several integration sites, including oncogenes Gfi1, Myb, and Ras. The Sox4 transcription factor was identified by our screen as a gene that cooperates with CREB in myeloid leukemogenesis. We show that the transduction of CREB transgenic mouse bone marrow cells with a Sox4 retrovirus increases survival and self-renewal of cells in vitro. Furthermore, leukemic blasts from the majority of acute myeloid leukemia patients have higher CREB, phosphorylated CREB, and Sox 4 protein expression. Sox4 transduction of mouse bone marrow cells results in increased expression of CREB target genes. We also demonstrate that CREB is a direct target of Sox4 by chromatin immunoprecipitation assays. These results indicate that Sox4 and CREB cooperate and contribute to increased proliferation of hematopoietic progenitor cells. PMID:22627767

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

    PubMed Central

    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

    2014-01-01

    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 (Pafah1b1) is critically required for blood formation and hematopoietic stem cell function. Conditional deletion of Lis1 in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, the loss of Lis1 accelerated cell differentiation, in part through defects in spindle positioning and inheritance of cell fate determinants. Finally, deletion of Lis1 blocked propagation of myeloid leukemia and led to a marked improvement in animal survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells, and mark the directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development. PMID:24487275

  12. Hematopoietic differentiation of pluripotent stem cells in culture.

    PubMed

    Mills, Jason A; Paluru, Prasuna; Weiss, Mitchell J; Gadue, Paul; French, Deborah L

    2014-01-01

    This chapter describes a two-dimensional "monolayer" system for differentiating human pluripotent stem cells (PSCs) into "primitive" hematopoietic progenitor cells (HPCs) resembling those produced in vivo by the early embryonic yolk sac. This experimental system utilizes defined conditions without serum or feeder cells. Cytokines are added sequentially to stimulate the formation of mesoderm and its subsequent patterning to hematopoietic progenitors. The HPCs produced by this protocol have multi-lineage potential (erythroid, megakaryocyte, and myeloid) and can be isolated as a homogeneous population for use in standard hematopoietic studies including liquid expansion to mature lineages and colony assays. In addition, the HPCs can be cryopreserved for distribution or analysis at later times. The HPCs generated by this protocol have been used successfully to better define intrinsic variation in hematopoietic potential between different PSC lines and to model human hematopoietic diseases using patient-derived induced pluripotent stem cells. PMID:25062629

  13. Biology of hematopoietic stem cells and progenitors: implications for clinical application.

    PubMed

    Kondo, Motonari; Wagers, Amy J; Manz, Markus G; Prohaska, Susan S; Scherer, David C; Beilhack, Georg F; Shizuru, Judith A; Weissman, Irving L

    2003-01-01

    Stem cell biology is scientifically, clinically, and politically a current topic. The hematopoietic stem cell, the common ancestor of all types of blood cells, is one of the best-characterized stem cells in the body and the only stem cell that is clinically applied in the treatment of diseases such as breast cancer, leukemias, and congenital immunodeficiencies. Multicolor cell sorting enables the purification not only of hematopoietic stem cells, but also of their downstream progenitors such as common lymphoid progenitors and common myeloid progenitors. Recent genetic approaches including gene chip technology have been used to elucidate the gene expression profile of hematopoietic stem cells and other progenitors. Although the mechanisms that control self-renewal and lineage commitment of hematopoietic stem cells are still ambiguous, recent rapid advances in understanding the biological nature of hematopoietic stem and progenitor cells have broadened the potential application of these cells in the treatment of diseases. PMID:12615892

  14. Cutaneous Infection Caused by Macrophomina phaseolina in a Child with Acute Myeloid Leukemia▿

    PubMed Central

    Srinivasan, Ashok; Wickes, Brian L.; Romanelli, Anna M.; Debelenko, Larisa; Rubnitz, Jeffrey E.; Sutton, Deanna A.; Thompson, Elizabeth H.; Fothergill, Annette W.; Rinaldi, Michael G.; Hayden, Randall T.; Shenep, Jerry L.

    2009-01-01

    We report a case of Macrophomina phaseolina skin infection in an immunocompromised child with acute myeloid leukemia, which was treated successfully with posaconazole without recurrence after a hematopoietic stem cell transplant. The fungus was identified by DNA sequencing using both the internal transcribed spacer and D1/D2 region of the 28S ribosomal DNA gene. PMID:19386841

  15. Dnmt3a Regulates Myeloproliferation and Liver-Specific Expansion of Hematopoietic Stem and Progenitor Cells

    PubMed Central

    Guryanova, Olga A.; Lieu, Yen K.; Garrett-Bakelman, Francine E.; Spitzer, Barbara; Glass, Jacob L.; Shank, Kaitlyn; Valencia Martinez, Ana Belen; Rivera, Sharon A.; Durham, Benjamin H.; Rapaport, Franck; Keller, Matthew D.; Pandey, Suveg; Bastian, Lennart; Tovbin, Daniel; Weinstein, Abby R.; Teruya-Feldstein, Julie; Abdel-Wahab, Omar; Santini, Valeria; Mason, Christopher E.; Melnick, Ari M.; Mukherjee, Siddhartha; Levine, Ross L.

    2015-01-01

    DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo. PMID:26710888

  16. Overexpression of primary microRNA 221/222 in acute myeloid leukemia

    PubMed Central

    2013-01-01

    Background Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations. Methods The expression of 636 human miRNAs was compared between samples from 52 patients with AML and 13 healthy individuals by highly specific locked nucleic acid (LNA) based microarray technology. The levels of individual mature miRNAs and of primary miRNAs (pri-miRs) were determined by quantitative reverse transcriptase (qRT) PCR. Transfections and infections of human cell lines were performed using standard procedures. Results 64 miRNAs were significantly differentially expressed between AML and controls. Further studies on the clustered miRNAs 221 and 222, already known to act as oncogenes in other tumor types, revealed a deficiency of human myeloid cell lines to process vector derived precursor transcripts. Moreover, endogenous pri-miR-221/222 was overexpressed to a substantially higher extent than its mature products in most primary AML samples, indicating that its transcription was enhanced, but processing was rate limiting, in these cells. Comparison of samples from the times of diagnosis, remission, and relapse of AML demonstrated that pri-miR-221/222 levels faithfully reflected the stage of disease. Conclusions Expression of some miRNAs is strongly regulated at the posttranscriptional level in AML. Pri-miR-221/222 represents a novel molecular marker and putative oncogene in this disease. PMID:23895238

  17. IGK with conserved IGKV/IGKJ repertoire is expressed in acute myeloid leukemia and promotes leukemic cell migration

    PubMed Central

    Sun, Xiaoping; He, Zhiqiao; Hu, Fanlei; Chen, Lei; Bueso-Ramos, Carlos E.

    2015-01-01

    We have previously reported that immunoglobulin heavy chain genes were expressed in myeloblasts and mature myeloid cells. In this study, we further demonstrated that rearranged Ig κ light chain was also frequently expressed in acute myeloid leukemia cell lines (6/6), primary myeloblasts from patients with acute myeloid leukemia (17/18), and mature monocytes (11/12) and neutrophils (3/12) from patients with non-hematopoietic neoplasms, but not or only rarely expressed in mature neutrophils (0/8) or monocytes (1/8) from healthy individuals. Interestingly, myeloblasts and mature monocytes/neutrophils shared several restricted IGKV and IGKJ gene usages but with different expression frequency. Surprisingly, almost all of the acute myeloid leukemia-derived IGKV showed somatic hypermutation; in contrast, mature myeloid cells-derived IGKV rarely had somatic hypermutation. More importantly, although IGK expression appeared not to affect cell proliferation, reduced IGK expression led to a decrease in cell migration in acute myeloid leukemia cell lines HL-60 and NB4, whereas increased IGK expression promoted their motility. In summary, IGK is expressed in myeloblasts and mature myeloid cells from patients with non-hematopoietic neoplasms, and is involved in cell migration. These results suggest that myeloid cells-derived IgK may have a role in leukemogenesis and may serve as a novel tumor marker for monitoring minimal residual disease and developing target therapy. PMID:26429876

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

    PubMed Central

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

    2016-01-01

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

  19. Immunotherapy for acute myeloid leukemia.

    PubMed

    Jurcic, Joseph G

    2005-09-01

    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

  20. Hematopoietic tissue repair under chronic low daily dose irradiation

    SciTech Connect

    Seed, T.M.

    1994-12-01

    The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). We have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3{minus}26.3 cGy d{sup {minus}1}). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup (1), the failure to augment basic m-pair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments particularly marked within erythroid compartments. that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 & 3 appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity.

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

    PubMed

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

    2014-04-01

    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.

  2. A monoclonal antibody reactive with normal and leukemic human myeloid progenitor cells.

    PubMed

    Griffin, J D; Linch, D; Sabbath, K; Larcom, P; Schlossman, S F

    1984-01-01

    Anti-MY9 is an IgG2b murine monoclonal antibody selected for reactivity with immature normal human myeloid cells. The MY9 antigen is expressed by blasts, promyelocytes and myelocytes in the bone marrow, and by monocytes in the peripheral blood. Erythrocytes, lymphocytes and platelets are MY9 negative. All myeloid colony-forming cells (CFU-GM), a fraction of erythroid burst-forming cells (BFU-E) and multipotent progenitors (CFU-GEMM) are MY9 positive. This antigen is further expressed by the leukemic cells of a majority of patients with AML and myeloid CML-BC. Leukemic stem cells (leukemic colony-forming cells, L-CFC) from most patients tested were also MY9 positive. In contrast, MY9 was not detected on lymphocytic leukemias. Anti-MY9 may be a valuable reagent for the purification of hematopoietic colony-forming cells and for the diagnosis of myeloid-lineage leukemias.

  3. Functions of TET Proteins in Hematopoietic Transformation.

    PubMed

    Han, Jae-A; An, Jungeun; Ko, Myunggon

    2015-11-01

    DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abnormal expression of oncogenes, tumor suppressor genes or repair genes. Ten-eleven-translocation (TET) proteins are recently characterized dioxygenases that catalyze progressive oxidation of 5-methylcytosine to produce 5-hydroxymethylcytosine and further oxidized derivatives. These oxidized methylcytosines not only potentiate DNA demethylation but also behave as independent epigenetic modifications per se. The expression or activity of TET proteins and DNA hydroxymethylation are highly dysregulated in a wide range of cancers including hematologic and non-hematologic malignancies, and accumulating evidence points TET proteins as a novel tumor suppressor in cancers. Here we review DNA demethylation-dependent and -independent functions of TET proteins. We also describe diverse TET loss-of-function mutations that are recurrently found in myeloid and lymphoid malignancies and their potential roles in hematopoietic transformation. We discuss consequences of the deficiency of individual Tet genes and potential compensation between different Tet members in mice. Possible mechanisms underlying facilitated oncogenic transformation of TET-deficient hematopoietic cells are also described. Lastly, we address non-mutational mechanisms that lead to suppression or inactivation of TET proteins in cancers. Strategies to restore normal 5mC oxidation status in cancers by targeting TET proteins may provide new avenues to expedite the development of promising anti-cancer agents.

  4. The Triterpenoid CDDO-Me Promotes Hematopoietic Progenitor Expansion and Myelopoiesis in Mice

    PubMed Central

    Ames, Erik; Harouna, Salif; Meyer, Colin; Welniak, Lisbeth A.; Murphy, William J.

    2012-01-01

    The synthetic triterpenoid CDDO-Me has been shown to directly inhibit the growth of myeloid leukemias and lends itself to a wide array of therapeutic indications, including inflammatory conditions, due to its inhibition of NFκB. We have previously demonstrated protection from acute graft-versus-host disease (GVHD) after CDDO-Me administration in an allogeneic bone marrow transplant (BMT) model (Li, et al. BBMT, 2010). In the current study, we observed that CDDO-Me promoted myelopoiesis in both naïve and transplanted mice. This effect was dose-dependent as high doses of CDDO-Me inhibited myeloid growth in vitro. All lineages (CFU-GM, BFU-E) were promoted by CDDO-Me. We then compared the effects with G-CSF, a known inducer of myeloid expansion and mobilization from the bone marrow. Whereas both drugs induced terminal myeloid expansion in the spleen, peripheral blood and bone marrow, G-CSF only induced CFU-GM precursors in the spleen while CDDO-Me increased these precursors in the spleen and bone marrow. After sublethal total body irradiation, mice pretreated with CDDO-me further displayed an accelerated recovery of myeloid progenitors and total nucleated cells in the spleen. A similar expansion of myeloid and myeloid progenitors was noted with CDDO-Me treatment after syngeneic BMT. Combined, these data suggest that CDDO-Me may be of use post-transplant to accelerate myeloid recovery in addition to the prevention of GVHD. PMID:22100978

  5. What Is Acute Myeloid Leukemia?

    MedlinePlus

    ... about acute myeloid leukemia? What is acute myeloid leukemia? Cancer starts when cells in a part of ... the body from doing their jobs. Types of leukemia Not all leukemias are the same. There are ...

  6. The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

    PubMed

    Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M; Liddicoat, Brian; Russell, Megan R; Walkley, Carl R; Karlsson, Stefan

    2014-04-01

    The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.

  7. [Cytogenetic abnormalities and gene mutations in myeloid leukemia].

    PubMed

    Kato, Naoko; Kitamura, Toshio

    2009-10-01

    Myeloid leukemia is a clinically and genetically heterogeneous disease. Cytogenetic studies have revealed specific chromosomal abnormalities, such as translocations, and inversions. Fusion proteins derived from these abnormalities were identified in various subtypes of leukemia. Because most of these fusion proteins were not sufficient to induce leukemia by themselves in mouse models, additional oncogenic events have been thought to be necessary for leukemogenesis. Recently, a hypothesis called "two-hit model" for leukemia has been proposed. Two broad classes of mutations that proliferative or survival advantage of hematopoietic progenitors and impaired differentiation are required for inducing leukemia. In this article, we summarize some typical chromosomal abnormalities or gene mutations associated with myeloid leukemia on the basis of this hypothesis.

  8. Cellular complexity of the bone marrow hematopoietic stem cell niche.

    PubMed

    Calvi, Laura M; Link, Daniel C

    2014-01-01

    The skeleton serves as the principal site for hematopoiesis in adult terrestrial vertebrates. The function of the hematopoietic system is to maintain homeostatic levels of all circulating blood cells, including myeloid cells, lymphoid cells, red blood cells, and platelets. This action requires the daily production of more than 500 billion blood cells. The vast majority of these cells are synthesized in the bone marrow, where they arise from a limited number of hematopoietic stem cells (HSCs) that are multipotent and capable of extensive self-renewal. These attributes of HSCs are best demonstrated by marrow transplantation, where even a single HSC can repopulate the entire hematopoietic system. HSCs are therefore adult stem cells capable of multilineage repopulation, poised between cell fate choices which include quiescence, self-renewal, differentiation, and apoptosis. While HSC fate choices are in part determined by multiple stochastic fluctuations of cell autonomous processes, according to the niche hypothesis, signals from the microenvironment are also likely to determine stem cell fate. While it had long been postulated that signals within the bone marrow could provide regulation of hematopoietic cells, it is only in the past decade that advances in flow cytometry and genetic models have allowed for a deeper understanding of the microenvironmental regulation of HSCs. In this review, we will highlight the cellular regulatory components of the HSC niche.

  9. Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplasms.

    PubMed

    Chalk, Alistair M; Liddicoat, Brian J J; Walkley, Carl R; Singbrant, Sofie

    2014-12-01

    The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced gene signatures associated with hematopoietic stem cells and myeloid differentiation. Here we provide detailed experimental methods and analysis for the gene expression profiling described in our recently published study of Singbrant et al. (2014) in Haematologica. Our data sets (available at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE39457) provide a resource for exploring the underlying molecular mechanisms of the involvement of the proto-oncogene SKI in hematopoietic stem cell function and development of myeloid neoplasms.

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

    SciTech Connect

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

    2005-10-07

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

  11. A Rare Complication Developing After Hematopoietic Stem Cell Transplantation: Wernicke’s Encephalopathy

    PubMed Central

    Solmaz, Soner; Gereklioğlu, Çiğdem; Tan, Meliha; Demir, Şenay; Yeral, Mahmut; Korur, Aslı; Boğa, Can; Özdoğu, Hakan

    2015-01-01

    Thiamine is a water-soluble vitamin. Thiamine deficiency can present as a central nervous system disorder known as Wernicke’s encephalopathy, which classically manifests as confusion, ataxia, and ophthalmoplegia. Wernicke’s encephalopathy has rarely been reported following hematopoietic stem cell transplantation. Herein, we report Wernicke’s encephalopathy in a patient with acute myeloid leukemia who had been receiving prolonged total parenteral nutrition after haploidentical allogeneic hematopoietic stem cell transplantation. To the best of our knowledge, this is the first case reported from Turkey in the literature. PMID:25912759

  12. MYC oncogene in myeloid neoplasias.

    PubMed

    Delgado, M Dolores; Albajar, Marta; Gomez-Casares, M Teresa; Batlle, Ana; León, Javier

    2013-02-01

    MYC is a transcription factor that regulates many critical genes for cell proliferation, differentiation, and biomass accumulation. MYC is one of the most prevalent oncogenes found to be altered in human cancer, being deregulated in about 50 % of tumors. Although MYC deregulation has been more frequently associated to lymphoma and lymphoblastic leukemia than to myeloid malignancies, a body of evidence has been gathered showing that MYC plays a relevant role in malignancies derived from the myeloid compartment. The myeloid leukemogenic activity of MYC has been demonstrated in different murine models. Not surprisingly, MYC has been found to be amplified or/and deregulated in the three major types of myeloid neoplasms: acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, including chronic myeloid leukemia. Here, we review the recent literature describing the involvement of MYC in myeloid tumors.

  13. Loss of Dnmt3a and endogenous KrasG12D/+ cooperate to regulate hematopoietic stem and progenitor cell functions in leukemogenesis

    PubMed Central

    Chang, Yuan-I; You, Xiaona; Kong, Guangyao; Ranheim, Erik A.; Wang, Jinyong; Du, Juan; Liu, Yangang; Zhou, Yun; Ryu, Myung-Jeom; Zhang, Jing

    2015-01-01

    Oncogenic NRAS and KRAS mutations are prevalent in human juvenile and chronic myelomonocytic leukemia (JMML/CMML). However, additional genetic mutations cooperating with oncogenic RAS in JMML/CMML progression and/or their transformation to acute myeloid leukemia (AML) remain largely unknown. Here, we tested the potential genetic interaction of DNMT3A mutations and oncogenic RAS mutations in leukemogenesis. We found that Dnmt3a−/− induces multiple hematopoietic phenotypes after a prolonged latency, including T cell expansion in peripheral blood, stress erythropoiesis in spleen, and myeloid malignancies in liver. Dnmt3a−/− significantly promoted JMML/CMML progression and shortened the survival of KrasG12D/+ mice in a cell-autonomous manner. Similarly, downregulating Dnmt3a also promoted myeloid malignancies in NrasG12D/+ mice. Further studies show that Dnmt3a deficiency rescues KrasG12D/+-mediated depletion of hematopoietic stem cells and increases self-renewal of KrasG12D/+ myeloid progenitors. Moreover, ~33% of animals developed an AML-like disease, which is driven by KrasG12D/+; Dnmt3a−/− myeloid progenitors. Consistent with our result, COSMIC database mining demonstrates that the combination of oncogenic RAS and DNMT3A mutations exclusively occurred in patients with JMML, CMML, or AML. Our results suggest that DNMT3A mutations and oncogenic RAS cooperate to regulate hematopoietic stem and progenitor cells and promote myeloid malignancies. PMID:25801914

  14. EVOLUTION OF MYELOID CELLS

    PubMed Central

    Barreda, Daniel R.; Neely, Harold R.; Flajnik, Martin F.

    2015-01-01

    In 1882, Elie Metchnikoff identified myeloid-like cells from starfish larvae responding to the invasion by a foreign body (rose thorn). This marked the origins of the study of innate immunity, and an appreciation that cellular immunity is already well established in these “primitive” organisms. This chapter focuses on these myeloid cells as well as the newest members of this family, the dendritic cells (DC), and explores their evolutionary origins. Our goal is to provide evolutionary context for the development of the multilayered immune system of mammals, where myeloid cells now serve as central effectors of innate immunity and regulators of adaptive immunity. Overall, we find that core contributions of myeloid cells to the regulation of inflammation are based on mechanisms that have been honed over hundreds of millions of years of evolution. Using phagocytosis as a platform, we show how fairly simple beginnings have offered a robust foundation onto which additional control features have been integrated, resulting in central regulatory nodes that now manage multi-factorial aspects of homeostasis and immunity. PMID:27337471

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

    PubMed Central

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

    2016-01-01

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

  16. Redefining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying B | Division of Cancer Prevention

    Cancer.gov

    DESCRIPTION (provided by applicant): Redefining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying Biomarkers for Early Detection and Risk Assessment. This application addresses Program Announcement PA-09-197: Biomarkers for Early Detection of Hematopoietic Malignancies (R01). The overall aim of this project is to identify novel biomarkers that may be used to diagnose and treat patients with Langerhans Cell Histiocytosis (LCH). LCH occurs with similar frequency as other rare malignancies including Hodgkin's lymphoma and AML. |

  17. [Key molecular mechanisms associated with cell malignant transformation in acute myeloid leukemia].

    PubMed

    Orlova, N N; Lebedev, T D; Spirin, P V; Prassolov, V S

    2016-01-01

    Cancer, along with cardiovascular disorders, is one of the most important problems of healthcare. Pathologies of the hematopoietic system are the most prevalent in patients under 30 years of age, including acute myeloid leukemia (AML), which is widespread and difficult to treat. The review considers the mechanisms that play a significant role in AML cell malignant transformation and shows the contributions of certain genes to both remission and resistance of AML cells to various treatments.

  18. Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia.

    PubMed

    Kikushige, Yoshikane; Miyamoto, Toshihiro

    2015-11-01

    Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.

  19. Two Hemocyte Lineages Exist in Silkworm Larval Hematopoietic Organ

    PubMed Central

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-01-01

    Background Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. Methodology/Principal Findings To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. Conclusions/Significance From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori. PMID:20676370

  20. Dendritic Cell-Based Immunotherapy for Myeloid Leukemias

    PubMed Central

    Schürch, Christian M.; Riether, Carsten; Ochsenbein, Adrian F.

    2013-01-01

    Acute and chronic myeloid leukemia (AML, CML) are hematologic malignancies arising from oncogene-transformed hematopoietic stem/progenitor cells known as leukemia stem cells (LSCs). LSCs are selectively resistant to various forms of therapy including irradiation or cytotoxic drugs. The introduction of tyrosine kinase inhibitors has dramatically improved disease outcome in patients with CML. For AML, however, prognosis is still quite dismal. Standard treatments have been established more than 20 years ago with only limited advances ever since. Durable remission is achieved in less than 30% of patients. Minimal residual disease (MRD), reflected by the persistence of LSCs below the detection limit by conventional methods, causes a high rate of disease relapses. Therefore, the ultimate goal in the treatment of myeloid leukemia must be the eradication of LSCs. Active immunotherapy, aiming at the generation of leukemia-specific cytotoxic T cells (CTLs), may represent a powerful approach to target LSCs in the MRD situation. To fully activate CTLs, leukemia antigens have to be successfully captured, processed, and presented by mature dendritic cells (DCs). Myeloid progenitors are a prominent source of DCs under homeostatic conditions, and it is now well established that LSCs and leukemic blasts can give rise to “malignant” DCs. These leukemia-derived DCs can express leukemia antigens and may either induce anti-leukemic T cell responses or favor tolerance to the leukemia, depending on co-stimulatory or -inhibitory molecules and cytokines. This review will concentrate on the role of DCs in myeloid leukemia immunotherapy with a special focus on their generation, application, and function and how they could be improved in order to generate highly effective and specific anti-leukemic CTL responses. In addition, we discuss how DC-based immunotherapy may be successfully integrated into current treatment strategies to promote remission and potentially cure myeloid leukemias

  1. Functional Integration of Acute Myeloid Leukemia into the Vascular Niche

    PubMed Central

    Leon, Ronald P.; Masri, Azzah Al; Clark, Hilary A.; Asbaghi, Steven A.; Tyner, Jeffrey W.; Dunlap, Jennifer; Fan, Guang; Kovacsovics, Tibor; Liu, Qiuying; Meacham, Amy; Hamlin, Kimberly L.; Hromas, Robert A.; Scott, Edward W.; Fleming, William H.

    2014-01-01

    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 up-regulation of CD105, a receptor associated with activated endothelium. Remarkably, endothelial-integrated V-AML shows an almost 4-fold reduction in proliferative activity compared to non-vascular associated AML. Primary AML cells can be induced to down regulate 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. Taken together, 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 acute myeloid leukemia. PMID:24637335

  2. NrasG12D/+ promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions

    PubMed Central

    Wang, Jinyong; Kong, Guangyao; Liu, Yangang; Du, Juan; Chang, Yuan-I; Tey, Sin Ruow; Zhang, Xinmin; Ranheim, Erik A.; Saba-El-Leil, Marc K.; Meloche, Sylvain; Damnernsawad, Alisa; Zhang, Jingfang; Zhang, Jing

    2013-01-01

    Oncogenic NRAS mutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (NrasG12D/+) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN). However, acute expression of NrasG12D/+ in a pure C57BL/6 background does not induce hyperactivated granulocyte macrophage colony-stimulating factor signaling or increased proliferation in myeloid progenitors. It is thus unclear how NrasG12D/+ signaling promotes leukemogenesis. Here, we show that hematopoietic stem cells (HSCs) expressing NrasG12D/+ serve as MPN-initiating cells. They undergo moderate hyperproliferation with increased self-renewal. The aberrant NrasG12D/+ HSC function is associated with hyperactivation of ERK1/2 in HSCs. Conversely, downregulation of MEK/ERK by pharmacologic and genetic approaches attenuates the cycling of NrasG12D/+ HSCs and prevents the expansion of NrasG12D/+ HSCs and myeloid progenitors. Our data delineate critical mechanisms of oncogenic Nras signaling in HSC function and leukemogenesis. PMID:23687087

  3. miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer.

    PubMed

    Mühlberg, Leonie; Kühnemuth, Benjamin; Costello, Eithne; Shaw, Victoria; Sipos, Bence; Huber, Magdalena; Griesmann, Heidi; Krug, Sebastian; Schober, Marvin; Gress, Thomas M; Michl, Patrick

    2016-06-01

    Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu. PMID:27471627

  4. Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress

    PubMed Central

    Delbridge, Alex R. D.; Opferman, Joseph T.; Grabow, Stephanie

    2015-01-01

    Understanding the critical factors that govern recovery of the hematopoietic system from stress, such as during anticancer therapy and bone marrow transplantation, is of clinical significance. We investigated the importance of the prosurvival proteins myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma–extra large (BCL-XL) in stem/progenitor cell survival and fitness during hematopoietic recovery from stress. Loss of a single Mcl-1 allele, which reduced MCL-1 protein levels, severely compromised hematopoietic recovery from myeloablative challenge and following bone marrow transplantation, whereas BCL-XL was dispensable in both contexts. We identified inhibition of proapoptotic p53 upregulated modulator of apoptosis (PUMA) as the key role of MCL-1 in both settings, with Mcl-1+/−;Puma−/− mice completely protected from the deleterious effects of loss of 1 Mcl-1 allele. These results reveal the molecular mechanisms that govern cell survival during hematopoietic recovery from stress. PMID:25847014

  5. The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone.

    PubMed

    Cho, Sun Wook; Pirih, Flavia Q; Koh, Amy J; Michalski, Megan; Eber, Matthew R; Ritchie, Kathryn; Sinder, Benjamin; Oh, Seojin; Al-Dujaili, Saja A; Lee, JoonHo; Kozloff, Ken; Danciu, Theodora; Wronski, Thomas J; McCauley, Laurie K

    2013-03-01

    Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6(+/+) and IL-6(-/-) mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6(-/-) compared with IL-6(+/+) bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6(-/-) earlier than IL-6(+/+) marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6(-/-) marrow. In the skeletal system, although intermittent PTH administration to IL-6(+/+) and IL-6(-/-) mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-β1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system.

  6. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation

    PubMed Central

    Iwasaki, Hiromi; Somoza, Chamorro; Shigematsu, Hirokazu; Duprez, Estelle A.; Iwasaki-Arai, Junko; Mizuno, Shin-ichi; Arinobu, Yojiro; Geary, Kristin; Zhang, Pu; Dayaram, Tajhal; Fenyus, Maris L.; Elf, Shannon; Chan, Susan; Kastner, Philippe; Huettner, Claudia S.; Murray, Richard; Tenen, Daniel G.; Akashi, Koichi

    2005-01-01

    The PU.1 transcription factor is a key regulator of hematopoietic development, but its role at each hematopoietic stage remains unclear. In particular, the expression of PU.1 in hematopoietic stem cells (HSCs) could simply represent “priming” of genes related to downstream myelolymphoid lineages. By using a conditional PU.1 knock-out model, we here show that HSCs express PU.1, and its constitutive expression is necessary for maintenance of the HSC pool in the bone marrow. Bone marrow HSCs disrupted with PU.1 in situ could not maintain hematopoiesis and were outcompeted by normal HSCs. PU.1-deficient HSCs also failed to generate the earliest myeloid and lymphoid progenitors. PU.1 disruption in granulocyte/monocyte-committed progenitors blocked their maturation but not proliferation, resulting in myeloblast colony formation. PU.1 disruption in common lymphoid progenitors, however, did not prevent their B-cell maturation. In vivo disruption of PU.1 in mature B cells by the CD19-Cre locus did not affect B-cell maturation, and PU.1-deficient mature B cells displayed normal proliferation in response to mitogenic signals including the cross-linking of surface immunoglobulin M (IgM). Thus, PU.1 plays indispensable and distinct roles in hematopoietic development through supporting HSC self-renewal as well as commitment and maturation of myeloid and lymphoid lineages. PMID:15914556

  7. IL12B expression is sustained by a heterogenous population of myeloid lineages during tuberculosis

    PubMed Central

    Reeme, Allison E.; Miller, Halli E.; Robinson, Richard T.

    2015-01-01

    Summary IL12B is required for resistance to Mycobacterium tuberculosis (Mtb) infection, promoting the initiation and maintenance of Mtb-specific effector responses. While this makes the IL12-pathway an attractive target for experimental tuberculosis (TB) therapies, data regarding what lineages express IL12B after infection is established are limited. This is not obvious in the lung, an organ in which both hematopoietic and non-hematopoietic lineages produce IL12p40 upon pathogen encounter. Here, we use radiation bone marrow chimeras and Yet40 reporter mice to determine what lineages produce IL12p40 during experimental TB. We observed that hematopoietic IL12p40-production was sufficient to control Mtb, with no contribution by non-hematopoietic lineages. Furthermore, rather than being produced by a single subset, IL12p40 was produced by cells that were heterogenous in their size, granularity, autofluorescence and expression of CD11c, CD11b and CD8α. While depending on the timepoint and tissue examined, the surface phenotype of IL12p40-producers most closely resembled macrophages based on previous surveys of lung myeloid lineages. Importantly, depletion of CDllchi cells during infection had no affect on lung IL12p40-concentrations. Collectively, our data demonstrate that IL12p40 production is sustained by a heterogenous population of myeloid lineages during experimental TB, and that redundant mechanisms of IL12p40-production exist when CD11chi lineages are absent. PMID:23491716

  8. Discovery of survival factor for primitive chronic myeloid leukemia cells using induced pluripotent stem cells

    PubMed Central

    Suknuntha, Kran; Ishii, Yuki; Tao, Lihong; Hu, Kejin; McIntosh, Brian E.; Yang, David; Swanson, Scott; Stewart, Ron; Wang, Jean Y.J.; Thomson, James; Slukvin, Igor

    2016-01-01

    A definitive cure for chronic myeloid leukemia (CML) requires identifying novel therapeutic targets to eradicate leukemia stem cells (LSCs). However, the rarity of LSCs within the primitive hematopoietic cell compartment remains a major limiting factor for their study in humans. Here we show that primitive hematopoietic cells with typical LSC features, including adhesion defect, increased long-term survival and proliferation, and innate resistance to tyrosine kinase inhibitor (TKI) imatinib, can be generated de novo from reprogrammed primary CML cells. Using CML iPSC-derived primitive leukemia cells, we discovered olfactomedin 4 (OLFM4) as a novel factor that contributes to survival and growth of somatic lin−CD34+ cells from bone marrow of patients with CML in chronic phase, but not primitive hematopoietic cells from normal bone marrow. Overall, this study shows the feasibility and advantages of using reprogramming technology to develop strategies for targeting primitive leukemia cells. PMID:26561938

  9. Discovery of survival factor for primitive chronic myeloid leukemia cells using induced pluripotent stem cells.

    PubMed

    Suknuntha, Kran; Ishii, Yuki; Tao, Lihong; Hu, Kejin; McIntosh, Brian E; Yang, David; Swanson, Scott; Stewart, Ron; Wang, Jean Y J; Thomson, James; Slukvin, Igor

    2015-11-01

    A definitive cure for chronic myeloid leukemia (CML) requires identifying novel therapeutic targets to eradicate leukemia stem cells (LSCs). However, the rarity of LSCs within the primitive hematopoietic cell compartment remains a major limiting factor for their study in humans. Here we show that primitive hematopoietic cells with typical LSC features, including adhesion defect, increased long-term survival and proliferation, and innate resistance to tyrosine kinase inhibitor (TKI) imatinib, can be generated de novo from reprogrammed primary CML cells. Using CML iPSC-derived primitive leukemia cells, we discovered olfactomedin 4 (OLFM4) as a novel factor that contributes to survival and growth of somatic lin(-)CD34(+) cells from bone marrow of patients with CML in chronic phase, but not primitive hematopoietic cells from normal bone marrow. Overall, this study shows the feasibility and advantages of using reprogramming technology to develop strategies for targeting primitive leukemia cells. PMID:26561938

  10. Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-08-10

    Adult Acute Myeloid Leukemia in Remission; Donor; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  11. Large-Scale Hematopoietic Differentiation of Human Induced Pluripotent Stem Cells Provides Granulocytes or Macrophages for Cell Replacement Therapies

    PubMed Central

    Lachmann, Nico; Ackermann, Mania; Frenzel, Eileen; Liebhaber, Steffi; Brennig, Sebastian; Happle, Christine; Hoffmann, Dirk; Klimenkova, Olga; Lüttge, Doreen; Buchegger, Theresa; Kühnel, Mark Philipp; Schambach, Axel; Janciauskiene, Sabina; Figueiredo, Constanca; Hansen, Gesine; Skokowa, Julia; Moritz, Thomas

    2015-01-01

    Summary Interleukin-3 (IL-3) is capable of supporting the proliferation of a broad range of hematopoietic cell types, whereas granulocyte colony-stimulating factor (G-CSF) and macrophage CSF (M-CSF) represent critical cytokines in myeloid differentiation. When this was investigated in a pluripotent-stem-cell-based hematopoietic differentiation model, IL-3/G-CSF or IL-3/M-CSF exposure resulted in the continuous generation of myeloid cells from an intermediate myeloid-cell-forming complex containing CD34+ clonogenic progenitor cells for more than 2 months. Whereas IL-3/G-CSF directed differentiation toward CD45+CD11b+CD15+CD16+CD66b+ granulocytic cells of various differentiation stages up to a segmented morphology displaying the capacity of cytokine-directed migration, respiratory burst response, and neutrophil-extracellular-trap formation, exposure to IL-3/M-CSF resulted in CD45+CD11b+CD14+CD163+CD68+ monocyte/macrophage-type cells capable of phagocytosis and cytokine secretion. Hence, we show here that myeloid specification of human pluripotent stem cells by IL-3/G-CSF or IL-3/M-CSF allows for prolonged and large-scale production of myeloid cells, and thus is suited for cell-fate and disease-modeling studies as well as gene- and cell-therapy applications. PMID:25680479

  12. Early postradition recovery of hematopoietic stromal precursor cells

    SciTech Connect

    Todriya, T.V.

    1985-04-01

    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.

  13. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia

    PubMed Central

    Boutzen, Héléna; Saland, Estelle; Larrue, Clément; de Toni, Fabienne; Gales, Lara; Castelli, Florence A.; Cathebas, Mathilde; Zaghdoudi, Sonia; Stuani, Lucille; Kaoma, Tony; Riscal, Romain; Yang, Guangli; Hirsch, Pierre; David, Marion; De Mas-Mansat, Véronique; Delabesse, Eric; Vallar, Laurent; Delhommeau, François; Jouanin, Isabelle; Ouerfelli, Ouathek; Le Cam, Laurent; Linares, Laetitia K.; Junot, Christophe; Portais, Jean-Charles; Vergez, François; Récher, Christian

    2016-01-01

    Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD–Scid–IL2rγnull mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies. PMID:26951332

  14. The regulation of hematopoietic stem cell populations

    PubMed Central

    Mayani, Hector

    2016-01-01

    Evidence presented over the last few years indicates that the hematopoietic stem cell (HSC) compartment comprises not just one but a number of different cell populations. Based on HSCs’ proliferation and engraftment potential, it has been suggested that there are two classes of HSC, with long- and short-term engraftment potential. HSC heterogeneity seems to involve differentiation capacities as well, since it has been shown that some HSC clones are able to give rise to both myeloid and lymphoid progeny, whereas others are lymphoid deficient. It has been recognized that HSC function depends on intrinsic cell regulators, which are modulated by external signals. Among the former, we can include transcription factors and non-coding RNAs as well as epigenetic modifiers. Among the latter, cytokines and extracellular matrix molecules have been implicated. Understanding the elements and mechanisms that regulate HSC populations is of significant relevance both in biological and in clinical terms, and research in this area still has to face several complex and exciting challenges. PMID:27408695

  15. Myeloid derived suppressor cells

    PubMed Central

    Waldron, Todd J.; Quatromoni, Jon G.; Karakasheva, Tatiana A.; Singhal, Sunil; Rustgi, Anil K.

    2013-01-01

    The goal of achieving measurable response with cancer immunotherapy requires counteracting the immunosuppressive characteristics of tumors. One of the mechanisms that tumors utilize to escape immunosurveillance is the activation of myeloid derived suppressor cells (MDSCs). Upon activation by tumor-derived signals, MDSCs inhibit the ability of the host to mount an anti-tumor immune response via their capacity to suppress both the innate and adaptive immune systems. Despite their relatively recent discovery and characterization, anti-MDSC agents have been identified, which may improve immunotherapy efficacy. PMID:23734336

  16. Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines.

    PubMed

    Zhang, Y Y; Vik, T A; Ryder, J W; Srour, E F; Jacks, T; Shannon, K; Clapp, D W

    1998-06-01

    Neurofibromin, the protein encoded by the NF1 tumor-suppressor gene, negatively regulates the output of p21(ras) (Ras) proteins by accelerating the hydrolysis of active Ras-guanosine triphosphate to inactive Ras-guanosine diphosphate. Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile chronic myelogenous leukemia (JCML) and other malignant myeloid disorders, and heterozygous Nf1 knockout mice spontaneously develop a myeloid disorder that resembles JCML. Both human and murine leukemias show loss of the normal allele. JCML cells and Nf1-/- hematopoietic cells isolated from fetal livers selectively form abnormally high numbers of colonies derived from granulocyte-macrophage progenitors in cultures supplemented with low concentrations of granulocyte-macrophage colony stimulating factor (GM-CSF). Taken together, these data suggest that neurofibromin is required to downregulate Ras activation in myeloid cells exposed to GM-CSF. We have investigated the growth and proliferation of purified populations of hematopoietic progenitor cells isolated from Nf1 knockout mice in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF), as well as to GM-CSF. We found abnormal proliferation of both immature and lineage-restricted progenitor populations, and we observed increased synergy between SCF and either IL-3 or GM-CSF in Nf1-/- progenitors. Nf1-/- fetal livers also showed an absolute increase in the numbers of immature progenitors. We further demonstrate constitutive activation of the Ras-Raf-MAP (mitogen-activated protein) kinase signaling pathway in primary c-kit+ Nf1-/- progenitors and hyperactivation of MAP kinase after growth factor stimulation. The results of these experiments in primary hematopoietic cells implicate Nf1 as playing a central role in regulating the proliferation and survival of primitive and lineage-restricted myeloid progenitors in response to multiple cytokines by modulating Ras output.

  17. Neuropeptide Y (NPY) synthesis in lymphoblasts and increased plasma NPY in pediatric B-cell precursor leukemia.

    PubMed

    Kogner, P; Ericsson, A; Barbany, G; Persson, H; Theodorsson, E; Björk, O

    1992-09-01

    Neuropeptide Y (NPY), a regulatory peptide in both the central and peripheral nervous systems, has recently been found in neuroendocrine tumors as well as in the bone marrow of rat and certain autoimmune mice, but not in human bone marrow. To investigate a possible role for NPY in the human hematopoietic system, we have prospectively studied NPY-like immunoreactivity in plasma (P-NPY-LI) and NPY mRNA in bone marrow from children with acute leukemia. Northern blot showed high levels of NPY mRNA in bone marrow and peripheral lymphoblasts from children with B-cell precursor leukemia. In situ hybridization showed NPY mRNA in malignant B-cell precursor lymphoblasts. No NPY mRNA was detected in the bone marrow of children with T-cell leukemia. P-NPY-LI was higher (P less than .001) in 51 children with leukemia (200:50 to 385 pmol/L, median:interquartile range) compared to 51 age-matched healthy controls (37:20 to 52 pmol/L). P-NPY-LI was higher (P less than .001) in those with favorable clinical risk classification. Elevated P-NPY-LI, compared with the upper age-adjusted reference limit, was only found in children with B-cell precursor leukemia (31 of 40), whereas all children with B-cell, T-cell, or myeloid leukemia (n = 11) had normal P-NPY-LI (P less than .001). During the 2- to 46-month follow-up, children with elevated P-NPY-LI had better (P less than .001) outcome compared to those with normal P-NPY-LI (79.4% v 34.6% probability for event-free survival).

  18. Misfolded N-CoR is Linked to the Ectopic Reactivation of CD34/Flt3-Based Stem-Cell Phenotype in Promyelocytic and Monocytic Acute Myeloid Leukemia

    PubMed Central

    Nin, Dawn Sijin; Li, Feng; Visvanathan, Sridevi; Khan, Matiullah

    2015-01-01

    Nuclear receptor co-repressor (N-CoR) is the key component of generic co-repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC) self-renewal and growth, and that de-repression of Flt3 by the misfolded N-CoR plays an important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML). The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation toward cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen-based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34-based HSC phenotypes. These findings collectively suggest that N-CoR is crucial

  19. General Information about Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

    MedlinePlus

    ... Other Myeloid Malignancies Treatment (PDQ®)–Patient Version General Information About Childhood Acute Myeloid Leukemia and Other Myeloid ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  20. Development of mature and functional human myeloid subsets in HSC engrafted NOD/SCID/IL2rγKO mice

    PubMed Central

    Tanaka, Satoshi; Saito, Yoriko; Kunisawa, Jun; Kurashima, Yosuke; Wake, Taichi; Suzuki, Nahoko; Shultz, Leonard D.; Kiyono, Hiroshi; Ishikawa, Fumihiko

    2012-01-01

    While physiological development of human lymphoid subsets has become well documented in humanized mice, in vivo development of human myeloid subsets in a xenotransplantation setting has remained unevaluated. Therefore, we investigated in vivo differentiation and function of human myeloid subsets in NOD/SCID/IL2rγnull (NSG) mouse recipients transplanted with purified lineage−CD34+CD38− cord blood hematopoietic stem cells. At four to six months post-transplantation, we identified the development of human neutrophils, basophils, mast cells, monocytes, as well as conventional and plasmacytoid dendritic cells in the recipient hematopoietic organs. The tissue distribution and morphology of these human myeloid cells were similar to those identified in humans. Following cytokine stimulation in vitro, phosphorylation of STAT molecules was observed in neutrophils and monocytes. In vivo administration of human G-CSF resulted in the recruitment of human myeloid cells into the recipient circulation. Flow cytometry and confocal imaging demonstrated that human bone marrow monocytes and alveolar macrophages in the recipients displayed intact phagocytic function. Human BM-derived monocytes/macrophages were further confirmed to exhibit phagocytosis and killing of Salmonella Typhimurium upon the IFN-γ stimulation. These findings demonstrate the development of mature and functionally intact human myeloid subsets in vivo in the NSG recipients. In vivo human myelopoiesis established in the NSG humanized mouse system may facilitate the investigation of human myeloid cell biology including in vivo analyses of infectious diseases and therapeutic interventions. PMID:22611244

  1. Co-activation of AMPK and mTORC1 as a new therapeutic option for acute myeloid leukemia

    PubMed Central

    Sujobert, Pierre; Tamburini, Jerome

    2016-01-01

    ABSTRACT We report the therapeutic potential of GSK621, an AMP-activated protein kinase (AMPK) agonist, in acute myeloid leukemia (AML). GSK621-induced cytotoxicity is restricted to AML cells compared to normal hematopoietic progenitors due to a unique synthetic lethal interaction of co-activation of AMPK and mammalian target of rapamycin complex 1 (mTORC1) that involves the stress response pathway. AMPK activation thus represents an attractive perspective for cancer therapy. PMID:27652311

  2. Co-activation of AMPK and mTORC1 as a new therapeutic option for acute myeloid leukemia.

    PubMed

    Sujobert, Pierre; Tamburini, Jerome

    2016-07-01

    We report the therapeutic potential of GSK621, an AMP-activated protein kinase (AMPK) agonist, in acute myeloid leukemia (AML). GSK621-induced cytotoxicity is restricted to AML cells compared to normal hematopoietic progenitors due to a unique synthetic lethal interaction of co-activation of AMPK and mammalian target of rapamycin complex 1 (mTORC1) that involves the stress response pathway. AMPK activation thus represents an attractive perspective for cancer therapy. PMID:27652311

  3. What Is Chronic Myeloid Leukemia?

    MedlinePlus

    ... leukemia? Next Topic Normal bone marrow and blood What is chronic myeloid leukemia? Cancer starts when cells ... their treatment is the same as for adults. What is leukemia? Leukemia is a cancer that starts ...

  4. Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells.

    PubMed

    Valk, P; Verbakel, S; Vankan, Y; Hol, S; Mancham, S; Ploemacher, R; Mayen, A; Löwenberg, B; Delwel, R

    1997-08-15

    We recently demonstrated that the gene encoding the peripheral cannabinoid receptor (Cb2) may be a proto-oncogene involved in murine myeloid leukemias. We show here that Cb2 may have a role in hematopoietic development. RNAse protection analysis showed that Cb2 is normally expressed in spleen and thymus. Cb2 mRNA is also expressed in 45 of 51 cell lines of distinct hematopoietic lineages, ie, myeloid, macrophage, mast, B-lymphoid, T-lymphoid, and erythroid cells. The effect of the fatty acid anandamide, an endogenous ligand for cannabinoid receptors, on primary murine marrow cells and hematopoietic growth factor (HGF)-dependent cell lines was then investigated. In vitro colony cultures of normal mouse bone marrow cells showed anandamide to potentiate interleukin-3 (IL-3)-induced colony growth markedly. Whereas HGFs alone stimulate proliferation of the various cell lines in serum-free culture only weakly, anandamide enhances the proliferative response of the cell lines to HGFs profoundly. This was apparent for responses induced by IL-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. Anandamide was already effective at concentrations as low as 0.1 to 0.3 micromol/L and plateau effects were reached at 0.3 to 3 micromol/L. The addition of anandamide as single growth factor had no effect. The costimulatory effect of anandamide was not evident when cells were cultured with fetal calf serum (FCS), suggesting that FCS contains anandamide or another ligand capable of activating the peripheral cannabinoid receptor. Other cannabinoid ligands did not enhance the proliferative responsiveness of hematopoietic cells to HGFs. Transfection experiments of Cb2 in myeloid 32D cells showed that anandamide specifically activates proliferation through activation of the peripheral cannabinoid receptor. Anandamide appears to be a novel and synergistic growth stimulator for hematopoietic cells. PMID:9269762

  5. Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress

    PubMed Central

    Rissone, Alberto; Weinacht, Katja Gabriele; la Marca, Giancarlo; Bishop, Kevin; Giocaliere, Elisa; Jagadeesh, Jayashree; Felgentreff, Kerstin; Dobbs, Kerry; Al-Herz, Waleed; Jones, Marypat; Chandrasekharappa, Settara; Kirby, Martha; Wincovitch, Stephen; Simon, Karen Lyn; Itan, Yuval; DeVine, Alex; Schlaeger, Thorsten; Schambach, Axel; Sood, Raman

    2015-01-01

    Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD. PMID:26150473

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

    PubMed Central

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

    2014-01-01

    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 Cebpα 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

  7. Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection

    PubMed Central

    Dudek, M; Puttur, F; Arnold-Schrauf, C; Kühl, A A; Holzmann, B; Henriques-Normark, B; Berod, L; Sparwasser, T

    2016-01-01

    The Gram-positive bacterium Streptococcus pneumoniae causes life-threatening infections, especially among immunocompromised patients. The host's immune system senses S. pneumoniae via different families of pattern recognition receptors, in particular the Toll-like receptor (TLR) family that promotes immune cell activation. Yet, while single TLRs are dispensable for initiating inflammatory responses against S. pneumoniae, the central TLR adapter protein myeloid differentiation factor 88 (MyD88) is of vital importance, as MyD88-deficient mice succumb rapidly to infection. Since MyD88 is ubiquitously expressed in hematopoietic and non-hematopoietic cells, the extent to which MyD88 signaling is required in different cell types to control S. pneumoniae is unknown. Therefore, we used novel conditional knockin mice to investigate the necessity of MyD88 signaling in distinct lung-resident myeloid and epithelial cells for the initiation of a protective immune response against S. pneumoniae. Here, we show that MyD88 signaling in lysozyme M (LysM)– and CD11c-expressing myeloid cells, as well as in pulmonary epithelial cells, is critical to restore inflammatory cytokine and antimicrobial peptide production, leading to efficient neutrophil recruitment and enhanced bacterial clearance. Overall, we show a novel synergistic requirement of compartment-specific MyD88 signaling in S. pneumoniae immunity. PMID:26627460

  8. Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection.

    PubMed

    Dudek, M; Puttur, F; Arnold-Schrauf, C; Kühl, A A; Holzmann, B; Henriques-Normark, B; Berod, L; Sparwasser, T

    2016-09-01

    The Gram-positive bacterium Streptococcus pneumoniae causes life-threatening infections, especially among immunocompromised patients. The host's immune system senses S. pneumoniae via different families of pattern recognition receptors, in particular the Toll-like receptor (TLR) family that promotes immune cell activation. Yet, while single TLRs are dispensable for initiating inflammatory responses against S. pneumoniae, the central TLR adapter protein myeloid differentiation factor 88 (MyD88) is of vital importance, as MyD88-deficient mice succumb rapidly to infection. Since MyD88 is ubiquitously expressed in hematopoietic and non-hematopoietic cells, the extent to which MyD88 signaling is required in different cell types to control S. pneumoniae is unknown. Therefore, we used novel conditional knockin mice to investigate the necessity of MyD88 signaling in distinct lung-resident myeloid and epithelial cells for the initiation of a protective immune response against S. pneumoniae. Here, we show that MyD88 signaling in lysozyme M (LysM)- and CD11c-expressing myeloid cells, as well as in pulmonary epithelial cells, is critical to restore inflammatory cytokine and antimicrobial peptide production, leading to efficient neutrophil recruitment and enhanced bacterial clearance. Overall, we show a novel synergistic requirement of compartment-specific MyD88 signaling in S. pneumoniae immunity. PMID:26627460

  9. Occupational exposure to formaldehyde, hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells

    PubMed Central

    Zhang, Luoping; Tang, Xiaojiang; Rothman, Nathaniel; Vermeulen, Roel; Ji, Zhiying; Shen, Min; Qiu, Chuangyi; Guo, Weihong; Liu, Songwang; Reiss, Boris; Laura Beane, Freeman; Ge, Yichen; Hubbard, Alan E.; Hua, Ming; Blair, Aaron; Galvan, Noe; Ruan, Xiaolin; Alter, Blanche P.; Xin, Kerry X.; Li, Senhua; Moore, Lee E.; Kim, Sungkyoon; Xie, Yuxuan; Hayes, Richard B.; Azuma, Mariko; Hauptmann, Michael; Xiong, Jun; Stewart, Patricia; Li, Laiyu; Rappaport, Stephen M.; Huang, Hanlin; Fraumeni, Joseph F.; Smith, Martyn T.; Lan, Qing

    2010-01-01

    There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing and other industries. Epidemiological studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on formaldehyde’s ability to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse impact on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures. PMID:20056626

  10. Novel Prognostic and Therapeutic Mutations in Acute Myeloid Leukemia.

    PubMed

    Medinger, Michael; Lengerke, Claudia; Passweg, Jakob

    Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence increases with age. Cytogenetics and mutation testing remain important prognostic tools for treatment after induction therapy. The post-induction treatment is dependent on risk stratification. Despite rapid advances in determination of gene mutations involved in the pathophysiology and biology of AML, and the rapid development of new drugs, treatment improvements changed slowly over the past 30 years, with the majority of patients eventually experiencing relapse and dying of their disease. Allogenic hematopoietic stem cell transplantation remains the best chance of cure for patients with intermediate- or high-risk disease. This review gives an overview about advances in prognostic markers and novel treatment options for AML, focusing on new prognostic and probably therapeutic mutations, and novel drug therapies such as tyrosine kinase inhibitors. PMID:27566651

  11. [Molecular biology in myelodysplastic syndromes and acute myeloid leukemias "smoldering"].

    PubMed

    Martinelli, Giovanni; Sartor, Chiara; Papayannidis, Cristina; Iacobucci, Ilaria; Paolini, Stefania; Clissa, Cristina; Ottaviani, Emanuela; Finelli, Carlo

    2014-03-01

    Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders of the myeloid lineage characterized by peripheral cytopenias and frequent leukemic evolution. MDS differ for clinical presentation, disease behavior and progression and this is the reflection of remarkable variability at molecular level. To this moment disease diagnosis is still dependent on bone marrow morphology that, although high concordance rates among experts are reported, remains subjective. Karyotype analysis is mandatory but diagnosis may be difficult in presence of normal karyotype or non-informative cytogenetics. Standardized molecular markers are needed to better define diagnosis, prediction of disease progression and prognosis. Furthermore, a molecular biology analysis could provide an important therapeutic tool towards tailored therapy and new insights in the disease's biology.

  12. Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-11-06

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

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

    ClinicalTrials.gov

    2016-05-18

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  14. High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity.

    PubMed

    Lynn, R C; Feng, Y; Schutsky, K; Poussin, M; Kalota, A; Dimitrov, D S; Powell, D J

    2016-06-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here we isolated a high-affinity (HA) folate receptor beta (FRβ)-specific single-chain variable fragment (2.48 nm KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ(+) AML in vitro and in vivo compared with a low-affinity FRβ CAR (54.3 nm KD). Using the HA-FRβ immunoglobulin G, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34(+) hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T cells lysed mature CD14(+) monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T cells retained effective antitumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T cells is highly effective against AML and reduces the risk for long-term myeloid toxicity.

  15. miR-382-5p Controls Hematopoietic Stem Cell Differentiation Through the Downregulation of MXD1.

    PubMed

    Zini, Roberta; Rossi, Chiara; Norfo, Ruggiero; Pennucci, Valentina; Barbieri, Greta; Ruberti, Samantha; Rontauroli, Sebastiano; Salati, Simona; Bianchi, Elisa; Manfredini, Rossella

    2016-10-01

    microRNAs are key regulators of gene expression that control stem cell fate by posttranscriptional downregulation of hundreds of target genes through seed pairing in their 3' untranslated region. In fact, miRNAs tightly regulate fundamental stem cell processes, like self-renewal, proliferation, and differentiation; therefore, miRNA deregulation may contribute to the development of solid tumors and hematological malignancies. miR-382-5p has been found to be upregulated in patients with myeloid neoplasms, but its role in normal hematopoiesis is still unknown. In this study, we demonstrated that miR-382-5p overexpression in CD34(+) hematopoietic stem/progenitor cells (HSPCs) leads to a significant decrease of megakaryocyte precursors coupled to increase of granulocyte ones. Furthermore, by means of a computational analysis using different prediction algorithms, we identified several putative mRNA targets of miR-382-5p that are downregulated upon miRNA overexpression (ie, FLI1, GATA2, MAF, MXD1, RUNX1, and SGK1). Among these, we validated MXD1 as real target of miR-382-5p by luciferase reporter assay. Finally, we showed that MXD1 knockdown mimics the effects of miR-382-5p overexpression on granulocyte and megakaryocyte differentiation of CD34(+) cells. Overall, our results demonstrated that miR-382-5p expression favors the expansion of granulocyte lineage and impairs megakaryocyte commitment through MXD1 downregulation. Therefore, our data showed for the first time that the miR-382-5p/MXD1 axis plays a critical role in myelopoiesis by affecting the lineage choice of CD34(+) HSPCs. PMID:27520398

  16. Vosaroxin and Infusional Cytarabine in Treating Patients With Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-03-10

    Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia With Multilineage Dysplasia; Myeloid Sarcoma; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Therapy-Related Myelodysplastic Syndrome

  17. Multi-Parameter Fluorescence-Activated Cell Sorting and Analysis of Stem and Progenitor Cells in Myeloid Malignancies

    PubMed Central

    Will, Britta; Steidl, Ulrich

    2010-01-01

    Owing to the discovery that rare leukemia-initiating cells (or leukemia stem cells, LSC) give origin to and propagate a hierarchical cellular organization of variably differentiated leukemic blasts, the analysis of precisely defined stem and progenitor cells has increasingly gained importance. Emergence of multi-parameter high-speed fluorescence-activated cell sorting (FACS) for the subfractionation of hematopoietic progenitor cells has allowed research on the biology of the cell-of-origin for LSCs and of LSCs as potential (or essential) therapeutic targets that may escape chemotherapy and consequently contribute to disease relapse. This review introduces the current state-of-the-art methods for the fractionation of hematopoietic stem and progenitor cells, with particular focus on myeloid malignancies. As many aspects of human normal and malignant hematopoiesis are frequently modeled in animal studies, we also provide an overview of hematopoietic stem and progenitor cell purification methods that are commonly utilized for research in murine models of disease. PMID:21112038

  18. Hematopoietic stem cell transplantation in China: current status and prospects

    PubMed Central

    Huang, Xiao-Jun

    2011-01-01

    During the past four decades, a substantial progress has been made in the field of hematopoietic stem cell transplantation (HSCT). From July, 2007 to December, 2010, a transplant survey from 42 HSCT units indicates that the types of transplantation performed are related identical (43%), related mismatched/haploidentical (28%), unrelated donor matched (11%), unrelated donor mismatched (7%), umbilical cord blood (UCB, 2%) and autologous (9%). The distribution of disease entities being transplanted in allogeneic settings is acute myeloid leukemia (AML) (34%), acute lymphoblastic leukemia(ALL) (24%), chronic myeloid leukemia (CML) (20%), myelodysplastic syndrome (MDS) (8%), aplastic anemia (AA) (7%), Mediterranean anemia (MIA) (2%), non-Hodgkin's lymphoma (NHL) (3%), and other diseases (3%). Clinical data from Peking University Institute of Hematology and other transplant centers suggest that haploidentical transplantation has been a choice of the best alternative source of stem cells for individual patients without matched sibling donors. A modified donor lymphocyte infusion (DLI) approach can be safely used for prophylaxis and treatment of leukemia relapse in patients with advanced leukemia following mismatched transplant. The number of transplants from unrelated donor or related mismatched/haploidentical donor has increased significantly during recent years. Double UCBT is a promising strategy for the therapy of hematological disease. In addition, mesenchymal stem cell (MSC) transplantation may be a potential therapeutic approach for treating systemic lupus erythematosus (SLE). PMID:22432069

  19. Progress toward curing HIV infection with hematopoietic cell transplantation.

    PubMed

    Petz, Lawrence D; Burnett, John C; Li, Haitang; Li, Shirley; Tonai, Richard; Bakalinskaya, Milena; Shpall, Elizabeth J; Armitage, Sue; Kurtzberg, Joanne; Regan, Donna M; Clark, Pamela; Querol, Sergio; Gutman, Jonathan A; Spellman, Stephen R; Gragert, Loren; Rossi, John J

    2015-01-01

    HIV-1 infection afflicts more than 35 million people worldwide, according to 2014 estimates from the World Health Organization. For those individuals who have access to antiretroviral therapy, these drugs can effectively suppress, but not cure, HIV-1 infection. Indeed, the only documented case for an HIV/AIDS cure was a patient with HIV-1 and acute myeloid leukemia who received allogeneic hematopoietic cell transplantation (HCT) from a graft that carried the HIV-resistant CCR5-∆32/∆32 mutation. Other attempts to establish a cure for HIV/AIDS using HCT in patients with HIV-1 and malignancy have yielded mixed results, as encouraging evidence for virus eradication in a few cases has been offset by poor clinical outcomes due to the underlying cancer or other complications. Such clinical strategies have relied on HIV-resistant hematopoietic stem and progenitor cells that harbor the natural CCR5-∆32/∆32 mutation or that have been genetically modified for HIV-resistance. Nevertheless, HCT with HIV-resistant cord blood remains a promising option, particularly with inventories of CCR5-∆32/∆32 units or with genetically modified, human leukocyte antigen-matched cord blood. PMID:26251620

  20. Hematopoietic Neoplasias in Horses: Myeloproliferative and Lymphoproliferative Disorders

    PubMed Central

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

    2010-01-01

    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

  1. Ophthalmic Manifestations of Hematopoietic Malignancy

    PubMed Central

    2016-01-01

    Purpose. To report the ocular findings in patients with hematopoietic malignancy with optic nerve involvement and abducens nerve palsy. Methods. The medical records of all cases of hematopoietic cancer with ophthalmic involvements seen in the Department of Ophthalmology of the National Center for Global Health and Medicine between 2009 and 2014 were reviewed. Results. Eight patients with hematopoietic cancer with optic nerve invasion or abducens nerve palsy were studied. The primary diseases were 3 cases of multiple myeloma, 1 case of acute lymphocytic leukemia, 1 case of follicular lymphoma, and 3 cases of AIDS-related lymphoma. Six cases had optic nerve invasion, 2 cases had abducens nerve palsy, and 1 case had optic nerve invasion of both eyes. The median visual acuity of eyes with optic nerve invasion was 0.885 logarithm of the minimum angle of resolution (logMAR) units. The final visual acuity of eyes with optic nerve invasion was 1.25 logMAR units, and that of those with sixth-nerve palsy was −0.1 logMAR units. Six cases died during the five-year follow-up period. An ophthalmic involvement in patients with hematopoietic cancer, especially AIDS-related lymphoma, was associated with poor prognosis. Conclusion. Because ophthalmic involvement in patients with hematopoietic malignancy has a poor prognosis, an early diagnosis of the cancers by the ophthalmologic findings by ophthalmologists could improve the prognosis. PMID:27375913

  2. General Information about Adult Acute Myeloid Leukemia

    MedlinePlus

    ... Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  3. Treatment Options for Adult Acute Myeloid Leukemia

    MedlinePlus

    ... Treatment Childhood AML Treatment Research Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health Professional Version Key Points Adult ...

  4. Stages of Adult Acute Myeloid Leukemia

    MedlinePlus

    ... Treatment Childhood AML Treatment Research Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health Professional Version Key Points Adult ...

  5. Treatment Option Overview (Adult Acute Myeloid Leukemia)

    MedlinePlus

    ... Treatment Childhood AML Treatment Research Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health Professional Version Key Points Adult ...

  6. Complete response of myeloid sarcoma with cardiac involvement to radiotherapy

    PubMed Central

    Yang, Wen-Chi; Yao, Ming; Chen, Yu-Hsuan

    2016-01-01

    We present a rare case of intracardiac myeloid sarcoma (MS) of acute myeloid leukemia (AML) and who responds completely well to low-dose radiotherapy. This 19-year-old young man initially presented with AML and received standard chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, he developed intracardiac isolated MS relapse with the presentation of exertional dyspnea and superior vena cava (SVC) syndrome 3 years later. He then received radiotherapy with 24 Gy at a 12 daily fractions using forward “field in field” intensity modulated radiotherapy technique. He dramatically had improved clinical symptoms, and complete remission was achieved one month after completing radiotherapy. Our result is in line with anecdotal case reports showed that radiotherapy with 15 Gy in 10 fractions or with 24 Gy in 12 fractions resulted in good response and less toxicity of 2 cases of MS with cardiac involvement. These results indicate that a modest radiotherapy dose, 24 Gy, achieves good local control of MS with cardiac involvement. PMID:27293853

  7. Acute myeloid leukemia in children: Current status and future directions.

    PubMed

    Taga, Takashi; Tomizawa, Daisuke; Takahashi, Hiroyuki; Adachi, Souichi

    2016-02-01

    Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML-DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all-trans retinoic acid (ATRA)-combined regimen with an 80-90% OS. Children with ML-DS are treated with a less intensive regimen compared with non-DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high-risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials. PMID:26645706

  8. Complete response of myeloid sarcoma with cardiac involvement to radiotherapy.

    PubMed

    Yang, Wen-Chi; Yao, Ming; Chen, Yu-Hsuan; Kuo, Sung-Hsin

    2016-06-01

    We present a rare case of intracardiac myeloid sarcoma (MS) of acute myeloid leukemia (AML) and who responds completely well to low-dose radiotherapy. This 19-year-old young man initially presented with AML and received standard chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, he developed intracardiac isolated MS relapse with the presentation of exertional dyspnea and superior vena cava (SVC) syndrome 3 years later. He then received radiotherapy with 24 Gy at a 12 daily fractions using forward "field in field" intensity modulated radiotherapy technique. He dramatically had improved clinical symptoms, and complete remission was achieved one month after completing radiotherapy. Our result is in line with anecdotal case reports showed that radiotherapy with 15 Gy in 10 fractions or with 24 Gy in 12 fractions resulted in good response and less toxicity of 2 cases of MS with cardiac involvement. These results indicate that a modest radiotherapy dose, 24 Gy, achieves good local control of MS with cardiac involvement. PMID:27293853

  9. Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals.

    PubMed

    Sawai, Catherine M; Babovic, Sonja; Upadhaya, Samik; Knapp, David J H F; Lavin, Yonit; Lau, Colleen M; Goloborodko, Anton; Feng, Jue; Fujisaki, Joji; Ding, Lei; Mirny, Leonid A; Merad, Miriam; Eaves, Connie J; Reizis, Boris

    2016-09-20

    Hematopoietic stem cells (HSCs) sustain long-term reconstitution of hematopoiesis in transplantation recipients, yet their role in the endogenous steady-state hematopoiesis remains unclear. In particular, recent studies suggested that HSCs provide a relatively minor contribution to immune cell development in adults. We directed transgene expression in a fraction of HSCs that maintained reconstituting activity during serial transplantations. Inducible genetic labeling showed that transgene-expressing HSCs gave rise to other phenotypic HSCs, confirming their top position in the differentiation hierarchy. The labeled HSCs rapidly contributed to committed progenitors of all lineages and to mature myeloid cells and lymphocytes, but not to B-1a cells or tissue macrophages. Importantly, labeled HSCs gave rise to more than two-thirds of all myeloid cells and platelets in adult mice, and this contribution could be accelerated by an induced interferon response. Thus, classically defined HSCs maintain immune cell development in the steady state and during systemic cytokine responses. PMID:27590115

  10. TGFα expression in myeloid malignancies

    PubMed Central

    Mirzai, Bob; Fuller, Kathy; Erber, Wendy N

    2016-01-01

    Background Transforming growth factor α (TGFα) is a peptide growth factor known to be expressed in normal haemopoiesis. It is also expressed in a range of epithelial neoplasms but has not been assessed in haemopoietic malignancies. We have performed an immunohistochemical evaluation of TGFα in acute and chronic myeloid malignancies. Methods TGFα expression was semiquantitatively assessed in 69 normal bone marrow trephines and 157 cases of myeloid malignancy using an immunohistochemical approach. Results Blast cells of myeloid origin in acute myeloid leukaemia (AML), myelodysplasia and accelerated and blast phases of chronic myeloid leukaemia (CML) were TGFα positive. In acute promyelocytic leukaemia the neoplastic cells had significantly weaker TGFα expression than seen in other forms of AML. The blast cells in CML-accelerated and blast phases were positive with similar expression to AML. Conclusions TGFα is expressed in neoplastic myeloblasts and could, therefore, be used as blast cell biomarker in diagnostic haematopathology. In addition, TGFα immunohistochemistry may be of use in identifying a therapeutic target. PMID:26984929

  11. Septic shock caused by Sphingomonas paucimobilis bacteremia in a patient with hematopoietic stem cell transplantation.

    PubMed

    Al-Anazi, K A; Abu Jafar, S; Al-Jasser, A M; Al-Shangeeti, A; Chaudri, N A; Al Jurf, M D; Al-Mohareb, F I

    2008-04-01

    Sphingomonas paucimobilis is an aerobic gram-negative bacillus that causes a variety of infections in healthy as well as in immunocompromised individuals. The organism is usually susceptible to tetracycline, chloramphenicol, aminoglycosides, trimethoprim-sulfamethoxazole, and carbapenems. However, resistance to penicillins and the first-generation cephalosporins is commonly encountered. Reported here is a patient with acute myeloid leukemia who developed S. paucimobilis bacteremia complicated by septic shock just before receiving an autologous hematopoietic stem cell transplant (SCT) at King Faisal Specialist Hospital and Research Centre in Riyadh. The septic episode was successfully treated in the intensive care unit. To our knowledge, this is the first case report of septic shock caused by S. paucimobilis bacteremia in a hematopoietic SCT recipient.

  12. T Cells Contribute to Tumor Progression by Favoring Pro-Tumoral Properties of Intra-Tumoral Myeloid Cells in a Mouse Model for Spontaneous Melanoma

    PubMed Central

    Caron, Jonathan; Douguet, Laetitia; Garcette, Marylène; Kato, Masashi; Avril, Marie-Françoise; Abastado, Jean-Pierre; Bercovici, Nadège; Lucas, Bruno; Prévost-Blondel, Armelle

    2011-01-01

    Tumors affect myelopoeisis and induce the expansion of myeloid cells with immunosuppressive activity. In the MT/ret model of spontaneous metastatic melanoma, myeloid cells are the most abundant tumor infiltrating hematopoietic population and their proportion is highest in the most aggressive cutaneous metastasis. Our data suggest that the tumor microenvironment favors polarization of myeloid cells into type 2 cells characterized by F4/80 expression, a weak capacity to secrete IL-12 and a high production of arginase. Myeloid cells from tumor and spleen of MT/ret mice inhibit T cell proliferation and IFNγ secretion. Interestingly, T cells play a role in type 2 polarization of myeloid cells. Indeed, intra-tumoral myeloid cells from MT/ret mice lacking T cells are not only less suppressive towards T cells than corresponding cells from wild-type MT/ret mice, but they also inhibit more efficiently melanoma cell proliferation. Thus, our data support the existence of a vicious circle, in which T cells may favor cancer development by establishing an environment that is likely to skew myeloid cell immunity toward a tumor promoting response that, in turn, suppresses immune effector cell functions. PMID:21633700

  13. Diagnosing and managing advanced chronic myeloid leukemia.

    PubMed

    Deininger, Michael W

    2015-01-01

    Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged. Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression of tyrosine kinase inhibitor (TKI)-resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell transplantation (HSCT). PMID:25993200

  14. Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level.

    PubMed

    Nilsson, L; Astrand-Grundström, I; Arvidsson, I; Jacobsson, B; Hellström-Lindberg, E; Hast, R; Jacobsen, S E

    2000-09-15

    Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. Within MDS, 5q- syndrome constitutes a distinct clinical entity characterized by an isolated deletion of the long arm of chromosome 5 (5q-), a relatively good prognosis, and infrequent transformation to acute leukemia. The cell of origin in 5q- syndrome as well as in other 5q-deleted MDS patients has not been established, but evidence for involvement of multiple myeloid (but not lymphoid) lineages has suggested that a myeloid-restricted progenitor rather than a pluripotent (lympho-myeloid) stem cell might be the primary target in most patients. Although in 9 patients no evidence of peripheral blood T-cell and only 1 case of B-cell involvement was found, the data herein support that 5q deletions occur in hematopoietic stem cells (HSCs) with a combined lympho-myeloid potential. First, in all investigated patients a minimum of 94% of cells in the minor CD34(+)CD38(-) HSC compartment were 5q deleted as determined by fluorescence in situ hybridization. Second, in 3 of 5 patients 5q aberrations were detected in a large fraction (25% to 90%) of purified CD34(+)CD19(+) pro-B cells. Furthermore, extensive functional characterization with regard to responsiveness to early-acting cytokines, long-term culture-initiating cells, and nonobese diabetic/severe combined immunodeficiency repopulating cells supported that MDS HSCs in 5q-deleted patients are CD34(+)CD38(-), but inefficient at reconstituting hematopoiesis.

  15. Cancer-Associated Myeloid Regulatory Cells

    PubMed Central

    De Vlaeminck, Yannick; González-Rascón, Anna; Goyvaerts, Cleo; Breckpot, Karine

    2016-01-01

    Myeloid cells are critically involved in the pathophysiology of cancers. In the tumor microenvironment (TME), they comprise tumor-associated macrophages (TAMs), neutrophils (TANs), dendritic cells, and myeloid-derived suppressor cells, which are further subdivided into a monocytic subset and a granulocytic subset. Some of these myeloid cells, in particular TAMs and TANs, are divided into type 1 or type 2 cells, according to the paradigm of T helper type 1 or type 2 cells. Type 1-activated cells are generally characterized as cells that aid tumor rejection, while all other myeloid cells are shown to favor tumor progression. Moreover, these cells are often at the basis of resistance to various therapies. Much research has been devoted to study the biology of myeloid cells. This endeavor has proven to be challenging, as the markers used to categorize myeloid cells in the TME are not restricted to particular subsets. Also from a functional and metabolic point of view, myeloid cells share many features. Finally, myeloid cells are endowed with a certain level of plasticity, which further complicates studying them outside their environment. In this article, we challenge the exclusive use of cell markers to unambiguously identify myeloid cell subsets in the TME. We further propose to divide myeloid cells into myeloid regulatory or stimulatory cells according to their pro- or antitumor function, because we contend that for therapeutic purposes it is not targeting the cell subsets but rather targeting their protumor traits; hence, myeloid regulatory cells will push antitumor immunotherapy to the next level. PMID:27065074

  16. ‘Acute myeloid leukemia: a comprehensive review and 2016 update'

    PubMed Central

    De Kouchkovsky, I; Abdul-Hay, M

    2016-01-01

    Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an incidence of over 20 000 cases per year in the United States alone. Large chromosomal translocations as well as mutations in the genes involved in hematopoietic proliferation and differentiation result in the accumulation of poorly differentiated myeloid cells. AML is a highly heterogeneous disease; although cases can be stratified into favorable, intermediate and adverse-risk groups based on their cytogenetic profile, prognosis within these categories varies widely. The identification of recurrent genetic mutations, such as FLT3-ITD, NMP1 and CEBPA, has helped refine individual prognosis and guide management. Despite advances in supportive care, the backbone of therapy remains a combination of cytarabine- and anthracycline-based regimens with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens, and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of AML. PMID:27367478

  17. [Research Progress on the Role of Chromatin Remodeling Factor BRG1 in Acute Myeloid Leukemia].

    PubMed

    Gao, Shuo; Xu, Xue-Jing; Zhang, Kui

    2016-06-01

    BRG1 (Brahma-related gene 1, BRG1) is the ATPase subunit of SWI/SNF chromatin remodeling complexes, which plays an important role in cell cycle regulation, DNA repair and tumor development. Unlike the evidence as tumor suppressor genes in the past reports, latest researches show that BRG1 plays an important role in sustaining the growth of leukemia cells in acute myeloid leukemia, and these effects on normal hematopoietic stem cells are dispensable. Further studies of the role and mechanism of BRG1 in acute myeloid leukemia will contribute to the development of a new and promising targeted therapy strategy. This article reviews the role of BRG1 on leukemia cells and leukemia stem cells in AML and discusses the related mechanism, which providing some reference for the targeted treatment strategy of AML. PMID:27342536

  18. Essential role for telomerase in chronic myeloid leukemia induced by BCR-ABL in mice

    PubMed Central

    Vicente-Dueñas, Carolina; Barajas-Diego, Marcos; Romero-Camarero, Isabel; González-Herrero, Inés; Flores, Teresa; Sánchez-García, Isidro

    2012-01-01

    The telomerase protein is constitutively activated in malignant cells from many patients with cancer, including the chronic myeloid leukemia (CML), but whether telomerase is essential for the pathogenesis of this disease is not known. Here, we used telomerase deficient mice to determine the requirement for telomerase in CML induced by BCR-ABL in mouse models of CML. Loss of one telomerase allele or complete deletion of telomerase prevented the development of leukemia induced by BCR-ABL. However, BCR-ABL was expressed and active in telomerase heterozygous and null leukemic hematopoietic stem cells. These results demonstrate that telomerase is essential for oncogene-induced reprogramming of hematopoietic stem cells in CML development and validate telomerase and the genes it regulates as targets for therapy in CML. PMID:22408137

  19. An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation

    PubMed Central

    Avellino, Roberto; Havermans, Marije; Erpelinck, Claudia; Sanders, Mathijs A.; Hoogenboezem, Remco; van de Werken, Harmen J. G.; Rombouts, Elwin; van Lom, Kirsten; van Strien, Paulina M. H.; Gebhard, Claudia; Rehli, Michael; Pimanda, John; Beck, Dominik; Erkeland, Stefan; Kuiken, Thijs; de Looper, Hans; Gröschel, Stefan; Touw, Ivo; Bindels, Eric

    2016-01-01

    Neutrophilic differentiation is dependent on CCAAT enhancer-binding protein α (C/EBPα), a transcription factor expressed in multiple organs including the bone marrow. Using functional genomic technologies in combination with clustered regularly-interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 genome editing and in vivo mouse modeling, we show that CEBPA is located in a 170-kb topological-associated domain that contains 14 potential enhancers. Of these, 1 enhancer located +42 kb from CEBPA is active and engages with the CEBPA promoter in myeloid cells only. Germ line deletion of the homologous enhancer in mice in vivo reduces Cebpa levels exclusively in hematopoietic stem cells (HSCs) and myeloid-primed progenitor cells leading to severe defects in the granulocytic lineage, without affecting any other Cebpa-expressing organ studied. The enhancer-deleted progenitor cells lose their myeloid transcription program and are blocked in differentiation. Deletion of the enhancer also causes loss of HSC maintenance. We conclude that a single +42-kb enhancer is essential for CEBPA expression in myeloid cells only. PMID:26966090

  20. Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?

    PubMed

    Minucci, S; Nervi, C; Lo Coco, F; Pelicci, P G

    2001-05-28

    Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

  1. C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia.

    PubMed

    Alberich-Jordà, Meritxell; Wouters, Bas; Balastik, Martin; Shapiro-Koss, Clara; Zhang, Hong; Di Ruscio, Annalisa; DiRuscio, Annalisa; Radomska, Hanna S; Ebralidze, Alexander K; Amabile, Giovanni; Ye, Min; Zhang, Junyan; Lowers, Irene; Avellino, Roberto; Melnick, Ari; Figueroa, Maria E; Valk, Peter J M; Delwel, Ruud; Tenen, Daniel G

    2012-12-01

    C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs.

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

    PubMed Central

    Maestas, Erika; Jain, Shikha; Stiff, Patrick

    2016-01-01

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

  3. In vitro generation of hematopoietic stem cells from an embryonic stem cell line.

    PubMed Central

    Palacios, R; Golunski, E; Samaridis, J

    1995-01-01

    Hematopoietic stem cells (HSC) are unique in that they give rise both to new stem cells (self-renewal) and to all blood cell types. The cellular and molecular events responsible for the formation of HSC remain unknown mainly because no system exists to study it. Embryonic stem (ES) cells were induced to differentiate by coculture with the stromal cell line RP010 and the combination of interleukin (IL) 3, IL-6, and F (cell-free supernatants from cultures of the FLS4.1 fetal liver stromal cell line). Cell cytometry analysis of the mononuclear cells produced in the cultures was consistent with the presence of PgP-1+ Lin- early hematopoietic (B-220- Mac-1- JORO 75- TER 119-) cells and of fewer B-220+ IgM- B-cell progenitors and JORO 75+ T-lymphocyte progenitors. The cell-sorter-purified PgP-1+ Lin- cells produced by induced ES cells could repopulate the lymphoid, myeloid, and erythroid lineages of irradiated mice. The ES-derived PgP-1+ Lin- cells must possess extensive self-renewal potential, as they were able to produce hematopoietic repopulation of secondary mice recipients. Indeed, marrow cells from irradiated mice reconstituted (15-18 weeks before) with PgP-1+ Lin- cell-sorter-purified cells generated by induced ES cells repopulated the lymphoid, myeloid, and erythroid lineages of secondary mouse recipients assessed 16-20 weeks after their transfer into irradiated secondary mice. The results show that the culture conditions described here support differentiation of ES cells into hematopoietic cells with functional properties of HSC. It should now be possible to unravel the molecular events leading to the formation of HSC. Images Fig. 3 PMID:7638225

  4. Therapeutically targeting SELF-reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

    PubMed

    Bernasconi, Paolo; Farina, Mirko; Boni, Marina; Dambruoso, Irene; Calvello, Celeste

    2016-05-01

    A tight relationship between the acute myeloid leukemia (AML) population and the bone marrow (BM) microenvironment has been convincingly established. The AML clone contains leukemic stem cells (LSCs) that compete with normal hematopoietic stem cells (HSCs) for niche occupancy and remodel the niche; whereas, the BM microenvironment might promote AML development and progression not only through hypoxia and homing/adhesion molecules, but also through genetic defects. Although it is still unknown whether the niche influences treatment results or contains any potential target for treatment, this dynamic AML-niche interaction might be a promising therapeutic objective to significantly improve the AML cure rate. PMID:26822317

  5. Gemtuzumab Ozogamicin in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-09-23

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  6. Coordinated regulation of myeloid cells by tumours.

    PubMed

    Gabrilovich, Dmitry I; Ostrand-Rosenberg, Suzanne; Bronte, Vincenzo

    2012-03-22

    Myeloid cells are the most abundant nucleated haematopoietic cells in the human body and are a collection of distinct cell populations with many diverse functions. The three groups of terminally differentiated myeloid cells - macrophages, dendritic cells and granulocytes - are essential for the normal function of both the innate and adaptive immune systems. Mounting evidence indicates that the tumour microenvironment alters myeloid cells and can convert them into potent immunosuppressive cells. Here, we consider myeloid cells as an intricately connected, complex, single system and we focus on how tumours manipulate the myeloid system to evade the host immune response.

  7. Molecular Pathways: Myeloid Complicity in Cancer

    PubMed Central

    Stromnes, Ingunn M.; Greenberg, Philip D.; Hingorani, Sunil R.

    2014-01-01

    Cancer-induced inflammation results in accumulation of myeloid cells. It has become increasingly evident that tumor-dependent factors condition myeloid cells toward an immunosuppressive and pro-tumorigenic phenotype. These myeloid cells include progenitors and progeny of monocytes, granulocytes, macrophages, and dendritic cells. Myeloid cells are not simply bystanders in malignancy or barometers of disease burden. Reflecting their dynamic and plastic nature, myeloid cells manifesta continuum of cellular differentiation and are intimately involved at all stages of neoplastic progression. They can promote tumorigenesis through both immune-dependent and independent mechanisms and can dictate response to therapies. A greater understanding of the inherent plasticity and relationships among myeloid subsets is needed to inform therapeutic targeting. New clinical trials are being designed to modulate the activities of myeloid cells in cancer, which may be essential to maximize the efficacy of both conventional cytotoxic and immune-based therapies for solid tumors. PMID:25047706

  8. Fluorescence in situ hybridization (FISH) detection of trisomy 8 in myeloid cells in chronic myeloid leukemia (CML): a study of archival blood and bone marrow smears.

    PubMed

    Nguyen, P L; Arthur, D C; Litz, C E; Brunning, R D

    1994-10-01

    Patients in accelerated phase or blast crisis of chronic myeloid leukemia (CML) frequently develop clonal cytogenetic abnormalities in addition to the Philadelphia chromosome. Using a DNA probe directed to the centromere of chromosome 8, we performed fluorescence in situ hybridization (FISH) on archival Wright-stained blood and bone marrow smears of seven patients with CML and with a known +8 clone by metaphase cytogenetics to determine the distribution of +8 in interphase cells. All slides had been stored at ambient temperature for 12-26 months. The bone marrow aspirate smears of 21 non-leukemic patients served as controls. Trisomy 8 was demonstrated in all myeloid cell lines including the neutrophils, basophils, eosinophils, monocytes, and erythroid precursors, but not in the lymphocytes. The extra chromosome 8 was present in mature segmented granulocytes as well as more immature precursors. The percentage of +8 cells was highest in specimens from patients with CML in myeloid blast crisis (mean 64%), followed by those in accelerated phase (mean 39%). Three specimens from patients in morphologic chronic phase showed the lowest percentage of +8 cells (mean 13%). One patient was studied twice and showed a substantial expansion of +8 cells with progression from accelerated phase to myeloid blast crisis. Compared to metaphase cytogenetics, the proportion of +8 cells detected by FISH was often lower. We conclude that the acquisition of trisomy 8 in CML occurs in a pluripotent myeloid stem cell apparently incapable of expressing mature lymphoid phenotype, and that morphologic progression of disease is generally associated with an expansion of the +8 component.

  9. Simultaneous measurement of human hematopoietic stem and progenitor cells in blood using multicolor flow cytometry.

    PubMed

    Cimato, Thomas R; Furlage, Rosemary L; Conway, Alexis; Wallace, Paul K

    2016-09-01

    Hematopoietic stem cells are the source of all inflammatory cell types. Discovery of specific cell surface markers unique to human hematopoietic stem (HSC) and progenitor (HSPC) cell populations has facilitated studies of their development from stem cells to mature cells. The specific marker profiles of HSCs and HSPCs can be used to understand their role in human inflammatory diseases. The goal of this study is to simultaneously measure HSCs and HSPCs in normal human venous blood using multicolor flow cytometry. Our secondary aim is to determine how G-CSF mobilization alters the quantity of each HSC and HSPC population. Here we show that cells within the CD34+ fraction of human venous blood contains cells with the same cell surface markers found in human bone marrow samples. Mobilization with G-CSF significantly increases the quantity of total CD34+ cells, blood borne HSCs, multipotent progenitors, common myeloid progenitors, and megakaryocyte erythroid progenitors as a percentage of total MNCs analyzed. The increase in blood borne common lymphoid and granulocyte macrophage progenitors with G-CSF treatment did not reach significance. G-CSF treatment predominantly increased the numbers of HSCs and multipotent progenitors in the total CD34+ cell population; common myeloid progenitors and megakaryocyte erythroid progenitors were enriched relative to total MNCs analyzed, but not relative to total CD34+ cells. Our findings illustrate the utility of multicolor flow cytometry to quantify circulating HSCs and HSPCs in venous blood samples from human subjects. © 2016 International Clinical Cytometry Society. PMID:26663713

  10. Dasatinib promotes the activation of quiescent hematopoietic stem cells in mice.

    PubMed

    Duyvestyn, Johanna M; Taylor, Samuel J; Dagger, Samantha A; Langdon, Wallace Y

    2016-05-01

    Dasatinib is an orally available broad-spectrum tyrosine kinase inhibitor that is widely used to treat chronic myeloid leukemia. It is also in clinical trials for the treatment of other malignancies, including solid tumors. Despite its wide use, little is known of its effects on normal hematopoietic stem and progenitor cells. Here, we study wild-type mice dosed with dasatinib and find that it causes the transient induction of proliferation of quiescent hematopoietic stem cells (HSCs). This finding was unexpected given the ability of dasatinib to inhibit c-Kit signaling and promote cell cycle arrest in many cell types. The transient induction of HSC proliferation in dasatinib-dosed mice coincided with a marked induction in the expression of Sca-1 and phospho-S6. Also evident at this time was a rapid but transient loss of lineage-committed hematopoietic progenitors that express high levels of c-Kit and the induction of stem cell factor in the serum. These findings suggest that activation of quiescent HSCs is part of a rapid rescue response that restores hematopoietic progenitors to pretreatment levels. This restoration coincides with HSCs returning to quiescence, and the expression of Sca-1 and phospho-S6 reverting to pre-treatment levels, even though dasatinib dosing is maintained. These data suggest that equilibrium is reached between the opposing forces of dasatinib and hematopoietic growth factors. The transient induction of HSC proliferation provided a window of opportunity whereby these cells became sensitive to killing by the cytotoxic drug 5-fluorouracil. PMID:26921649

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

    PubMed Central

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

    2006-01-01

    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 activated, promotes HSC differentiation. We observe that the retinoic acid receptor (RAR)γ is selectively expressed in primitive hematopoietic precursors and that the bone marrow of RARγ knockout mice exhibit markedly reduced numbers of HSCs associated with increased numbers of more mature progenitor cells compared with wild-type mice. In contrast, RARα is widely expressed in hematopoietic cells, but RARα knockout mice do not exhibit any HSC or progenitor abnormalities. Primitive hematopoietic precursors overexpressing RARα differentiate predominantly to granulocytes in short-term culture, whereas those overexpressing RARγ exhibit a much more undifferentiated phenotype. Furthermore, loss of RARγ abrogated the potentiating effects of all-trans retinoic acid on the maintenance of HSCs in ex vivo culture. Finally, pharmacological activation of RARγ ex vivo promotes HSC self-renewal, as demonstrated by serial transplant studies. We conclude that the RARs have distinct roles in hematopoiesis and that RARγ is a critical physiological and pharmacological regulator of the balance between HSC self-renewal and differentiation. PMID:16682494

  12. Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb.

    PubMed

    Zhao, Liang; Glazov, Evgeny A; Pattabiraman, Diwakar R; Al-Owaidi, Faisal; Zhang, Ping; Brown, Matthew A; Leo, Paul J; Gonda, Thomas J

    2011-06-01

    To gain insight into the mechanisms by which the Myb transcription factor controls normal hematopoiesis and particularly, how it contributes to leukemogenesis, we mapped the genome-wide occupancy of Myb by chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) in ERMYB myeloid progenitor cells. By integrating the genome occupancy data with whole genome expression profiling data, we identified a Myb-regulated transcriptional program. Gene signatures for leukemia stem cells, normal hematopoietic stem/progenitor cells and myeloid development were overrepresented in 2368 Myb regulated genes. Of these, Myb bound directly near or within 793 genes. Myb directly activates some genes known critical in maintaining hematopoietic stem cells, such as Gfi1 and Cited2. Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb. Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression. We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation.

  13. Nonmyeloablative allogeneic hematopoietic cell transplantation

    PubMed Central

    Storb, Rainer; Sandmaier, Brenda M.

    2016-01-01

    Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease. PMID:27132278

  14. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.

    PubMed

    Kadono, Moe; Kanai, Akinori; Nagamachi, Akiko; Shinriki, Satoru; Kawata, Jin; Iwato, Koji; Kyo, Taiichi; Oshima, Kumi; Yokoyama, Akihiko; Kawamura, Takeshi; Nagase, Reina; Inoue, Daichi; Kitamura, Toshio; Inaba, Toshiya; Ichinohe, Tatsuo; Matsui, Hirotaka

    2016-08-01

    The DDX41 gene, encoding a DEAD-box type ATP-dependent RNA helicase, is rarely but reproducibly mutated in myeloid diseases. The acquired mutation in DDX41 is highly concentrated at c.G1574A (p.R525H) in the conserved motif VI located at the C-terminus of the helicase core domain where ATP interacts and is hydrolyzed. Therefore, it is likely that the p.R525H mutation perturbs ATPase activity in a dominant-negative manner. In this study, we screened for the DDX41 mutation of CD34-positive tumor cells based on mRNA sequencing and identified the p.R525H mutation in three cases among 23 patients. Intriguingly, these patients commonly exhibited acute myeloid leukemia (AML) with peripheral blood cytopenias and low blast counts, suggesting that the mutation inhibits the growth and differentiation of hematopoietic cells. Data from cord blood cells and leukemia cell lines suggest a role for DDX41 in preribosomal RNA processing, in which the expression of the p.R525H mutant causes a certain ribosomopathy phenotype in hematopoietic cells by suppressing MDM2-mediated RB degradation, thus triggering the inhibition of E2F activity. This study uncovered a pathogenic role of p.R525H DDX41 in the slow growth rate of tumor cells. Age-dependent epigenetic alterations or other somatic changes might collaborate with the mutation to cause AML.

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

    PubMed Central

    Gold, Katrina S.; Brückner, Katja

    2016-01-01

    Fish, mice and men rely on two coexisting myeloid blood cell systems. One is sustained by hematopoietic progenitor cells, which reside in specialized microenvironments 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, 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 achieve optimal fitness of the animal. PMID:24946019

  16. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.

    PubMed

    Kadono, Moe; Kanai, Akinori; Nagamachi, Akiko; Shinriki, Satoru; Kawata, Jin; Iwato, Koji; Kyo, Taiichi; Oshima, Kumi; Yokoyama, Akihiko; Kawamura, Takeshi; Nagase, Reina; Inoue, Daichi; Kitamura, Toshio; Inaba, Toshiya; Ichinohe, Tatsuo; Matsui, Hirotaka

    2016-08-01

    The DDX41 gene, encoding a DEAD-box type ATP-dependent RNA helicase, is rarely but reproducibly mutated in myeloid diseases. The acquired mutation in DDX41 is highly concentrated at c.G1574A (p.R525H) in the conserved motif VI located at the C-terminus of the helicase core domain where ATP interacts and is hydrolyzed. Therefore, it is likely that the p.R525H mutation perturbs ATPase activity in a dominant-negative manner. In this study, we screened for the DDX41 mutation of CD34-positive tumor cells based on mRNA sequencing and identified the p.R525H mutation in three cases among 23 patients. Intriguingly, these patients commonly exhibited acute myeloid leukemia (AML) with peripheral blood cytopenias and low blast counts, suggesting that the mutation inhibits the growth and differentiation of hematopoietic cells. Data from cord blood cells and leukemia cell lines suggest a role for DDX41 in preribosomal RNA processing, in which the expression of the p.R525H mutant causes a certain ribosomopathy phenotype in hematopoietic cells by suppressing MDM2-mediated RB degradation, thus triggering the inhibition of E2F activity. This study uncovered a pathogenic role of p.R525H DDX41 in the slow growth rate of tumor cells. Age-dependent epigenetic alterations or other somatic changes might collaborate with the mutation to cause AML. PMID:27174803

  17. Role of Hematopoietic Stem Cells in Inflammation of the Pancreas during Diabetes Mellitus.

    PubMed

    Dygai, A M; Skurikhin, E G; Pershina, O V; Ermakova, N N; Krupin, V A; Ermolaeva, L A; Stakheeva, M N; Choinzonov, E L; Goldberg, V E; Reikhart, D V; Ellinidi, V N; Kravtsov, V Yu

    2016-02-01

    The model of streptozotocin-induced diabetes mellitus in C57Bl/6 mice was employed to study the role of precursors of insulin-producing β-cells, hematopoietic stem cells, and progenitor hematopoietic cells in inflammation. In addition to provoking hyperglycemia, streptozotocin elevated serum levels of IL-1β and hyaluronic acid, induced edema in the pancreatic insular tissue and its infiltration by inflammatory cells (neutrophils, lymphocytes, and macrophages) and fibroblasts. Inflammation in pancreatic islets was accompanied by necrotic processes and decreasing counts of multipotent progenitor β-cells (CD45(-), TER119(-), c-kit-1(-), and Flk-1(-)), oligopotent progenitor β-cells (CD45(-), TER119(-), CD133(+), and CD49f(low)), and insulinproducing β-cells (Pdx1(+)). Pancreatic infl ammation was preceded by elevation of the number of short-term hematopoietic stem cells (Lin-Sca-1(+)c-kit(+)CD34(+)) relative to long-term cells (Lin(-)Sca-1(+)c-kit(+)CD34(-)) in the bone marrow as well as recruitment of hematopoietic stem and progenitor cells into circulation. Transplantation of bone marrow hematopoietic stem and progenitor cells from diabetic C57Bl/6 donor mice to recipient CBA mice with 5-fluorouracilinduced leukopenia accelerated regeneration of granulocytopoiesis in recipient mice. PMID:26906195

  18. Embryonic hematopoiesis in vertebrate somites gives rise to definitive hematopoietic stem cells.

    PubMed

    Qiu, Juhui; Fan, Xiaoying; Wang, Yixia; Jin, Hongbin; Song, Yixiao; Han, Yang; Huang, Shenghong; Meng, Yaping; Tang, Fuchou; Meng, Anming

    2016-08-01

    Hematopoietic stem cells (HSCs) replenish all types of blood cells. It is debating whether HSCs in adults solely originate from the aorta-gonad-mesonephros (AGM) region, more specifically, the dorsal aorta, during embryogenesis. Here, we report that somite hematopoiesis, a previously unwitnessed hematopoiesis, can generate definitive HSCs (dHSCs) in zebrafish. By transgenic lineage tracing, we found that a subset of cells within the forming somites emigrate ventromedially and mix with lateral plate mesoderm-derived primitive hematopoietic cells before the blood circulation starts. These somite-derived hematopoietic precursors and stem cells (sHPSCs) subsequently enter the circulation and colonize the kidney of larvae and adults. RNA-seq analysis reveals that sHPSCs express hematopoietic genes with sustained expression of many muscle/skeletal genes. Embryonic sHPSCs transplanted into wild-type embryos expand during growth and survive for life time with differentiation into various hematopoietic lineages, indicating self-renewal and multipotency features. Therefore, the embryonic origin of dHSCs in adults is not restricted to the AGM.

  19. Genetics Home Reference: core binding factor acute myeloid leukemia

    MedlinePlus

    ... acute myeloid leukemia core binding factor acute myeloid leukemia Enable Javascript to view the expand/collapse boxes. ... Close All Description Core binding factor acute myeloid leukemia (CBF-AML) is one form of a cancer ...

  20. Myeloid Sarcoma: Current Approach and Therapeutic Options

    PubMed Central

    Avni, Batia; Koren-Michowitz, Maya

    2011-01-01

    Myeloid sarcoma is a rare disease that can present as an isolated extramedullary leukemic tumor, concurrently with or at relapse of acute myeloid leukemia. Owing to the rarity of this disorder, most of the literature comprises small retrospective studies and case reports. The aim of this review is to summarize the current published data regarding the clinical presentation, morphological, cytogenetic and molecular features, prognosis and treatment of myeloid sarcoma. PMID:23556098

  1. Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes.

    PubMed

    Zambetti, Noemi A; Bindels, Eric M J; Van Strien, Paulina M H; Valkhof, Marijke G; Adisty, Maria N; Hoogenboezem, Remco M; Sanders, Mathijs A; Rommens, Johanna M; Touw, Ivo P; Raaijmakers, Marc H G P

    2015-10-01

    Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome. PMID:26185170

  2. Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes

    PubMed Central

    Zambetti, Noemi A.; Bindels, Eric M. J.; Van Strien, Paulina M. H.; Valkhof, Marijke G.; Adisty, Maria N.; Hoogenboezem, Remco M.; Sanders, Mathijs A.; Rommens, Johanna M.; Touw, Ivo P.; Raaijmakers, Marc H. G. P.

    2015-01-01

    Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome. PMID:26185170

  3. Progress in acute myeloid leukemia.

    PubMed

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

    2015-03-01

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

  4. Postsplenectomy sclerosing extramedullary hematopoietic tumor with unexpected good clinical evolution: morphologic, immunohistochemical, and molecular analysis of one case and review of the literature.

    PubMed

    Gualco, Gabriela; Ojopi, Elida B P; Chioato, Lucimara; Cordeiro, Danielle Leão; Negretti, Fabio; Bacchi, Carlos E

    2010-05-01

    Sclerosing extramedullary hematopoietic tumor has been described as a rare manifestation of chronic myeloproliferative neoplasm. The lack of knowledge about this entity has caused it to be mistaken for many types of nonhematopoietic and hematopoietic tumors. We present the case of a 71-year-old lady with a long history of primary myelofibrosis, which developed multiple abdominal sclerosing extramedullary hematopoietic tumors with good clinical evolution. Nonchronic myeloid leukemia myeloproliferative neoplasm included a JAK2 mutation as part of the diagnosis algorithm. Particularly, idiopathic myelofibrosis is related with a JAK2 mutation in 50% of the cases with a pejorative prognosis. The absence of JAK2 demonstrated in the paraffin samples of the tumors may be related to the unusual evolution in this particular case. Morphologically differential diagnoses considered in the evaluation of this entity and in our case included sarcomas mainly liposarcoma, anaplastic carcinoma, and Hodgkin lymphoma.

  5. Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion.

    PubMed

    Chen, Jichun; Bryant, Mark A; Dent, James J; Sun, Yu; Desierto, Marie J; Young, Neal S

    2015-12-01

    A deletion of a telomerase RNA component (Terc(-/-)) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b(+) myeloid cells and decreased red blood cells and CD45R(+) B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit(+)Sca-1(+)Lin(-) (KSL) cells in old Terc(-/-) mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc(-/-) donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc(-/-) mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b(+) myeloid cells and a decrease in CD45R(+) B cells, similar to those observed in old Terc(-/-) mice. Treatment of 11-13 month old Terc(-/-) mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc(-/-) animals. PMID:26523501

  6. Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion.

    PubMed

    Chen, Jichun; Bryant, Mark A; Dent, James J; Sun, Yu; Desierto, Marie J; Young, Neal S

    2015-12-01

    A deletion of a telomerase RNA component (Terc(-/-)) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b(+) myeloid cells and decreased red blood cells and CD45R(+) B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit(+)Sca-1(+)Lin(-) (KSL) cells in old Terc(-/-) mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc(-/-) donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc(-/-) mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b(+) myeloid cells and a decrease in CD45R(+) B cells, similar to those observed in old Terc(-/-) mice. Treatment of 11-13 month old Terc(-/-) mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc(-/-) animals.

  7. Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

    PubMed

    Kahl, Christoph; Storer, Barry E; Sandmaier, Brenda M; Mielcarek, Marco; Maris, Michael B; Blume, Karl G; Niederwieser, Dietger; Chauncey, Thomas R; Forman, Stephen J; Agura, Edward; Leis, Jose F; Bruno, Benedetto; Langston, Amelia; Pulsipher, Michael A; McSweeney, Peter A; Wade, James C; Epner, Elliot; Bo Petersen, Finn; Bethge, Wolfgang A; Maloney, David G; Storb, Rainer

    2007-10-01

    Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m(2); n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.

  8. Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning

    PubMed Central

    Kahl, Christoph; Storer, Barry E.; Sandmaier, Brenda M.; Mielcarek, Marco; Maris, Michael B.; Blume, Karl G.; Niederwieser, Dietger; Chauncey, Thomas R.; Forman, Stephen J.; Agura, Edward; Leis, Jose F.; Bruno, Benedetto; Langston, Amelia; Pulsipher, Michael A.; McSweeney, Peter A.; Wade, James C.; Epner, Elliot; Bo Petersen, Finn; Bethge, Wolfgang A.; Maloney, David G.

    2007-01-01

    Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m2; n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT. PMID:17595333

  9. Hematopoietic stem-cell transplantation in the developing world: experience from a center in Western India.

    PubMed

    Shah, Chirag A; Karanwal, Arun; Desai, Maharshi; Pandya, Munjal; Shah, Ravish; Shah, Rutvij

    2015-01-01

    We describe our experience of first 50 consecutive hematopoietic stem-cell transplants (HSCT) done between 2007 and 2012 at the Apollo Hospital, Gandhinagar, 35 autologous HSCT and 15 allogeneic HSCT. Indications for autologous transplant were multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, and acute myeloid leukemia, and indications for allogeneic transplants were thalassemia major, aplastic anaemia, chronic myeloid leukemia, and acute lymphoblastic and myeloid leukaemia. The median age of autologous and allogeneic patient's cohort was 50 years and 21 years, respectively. Median follow-up period for all patients was 39 months. Major early complications were infections, mucositis, acute graft versus host disease, and venoocclusive disease. All of our allogeneic and autologous transplant patients survived during the first month of transplant. Transplant related mortality (TRM) was 20% (N = 3) in our allogeneic and 3% (N = 1) in autologous patients. Causes of these deaths were disease relapse, sepsis, hemorrhagic complications, and GVHD. 46% of our autologous and 47% of our allogeneic patients are in complete remission phase after a median follow-up of 39 months. 34% of our autologous patients and 13% of our allogeneic patients had disease relapse. Overall survival rate in our autologous and allogeneic patients is 65.7% and 57.1%, respectively. Our results are comparable to many national and international published reports. PMID:25722722

  10. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

    PubMed Central

    Mullenders, Jasper; Aranda-Orgilles, Beatriz; Lhoumaud, Priscillia; Keller, Matthew; Pae, Juhee; Wang, Kun; Kayembe, Clarisse; Rocha, Pedro P.; Raviram, Ramya; Gong, Yixiao; Premsrirut, Prem K.; Tsirigos, Aristotelis; Bonneau, Richard; Skok, Jane A.; Cimmino, Luisa; Hoehn, Daniela

    2015-01-01

    The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy. PMID:26438359

  11. Hematopoietic stem-cell transplantation in the developing world: experience from a center in Western India.

    PubMed

    Shah, Chirag A; Karanwal, Arun; Desai, Maharshi; Pandya, Munjal; Shah, Ravish; Shah, Rutvij

    2015-01-01

    We describe our experience of first 50 consecutive hematopoietic stem-cell transplants (HSCT) done between 2007 and 2012 at the Apollo Hospital, Gandhinagar, 35 autologous HSCT and 15 allogeneic HSCT. Indications for autologous transplant were multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, and acute myeloid leukemia, and indications for allogeneic transplants were thalassemia major, aplastic anaemia, chronic myeloid leukemia, and acute lymphoblastic and myeloid leukaemia. The median age of autologous and allogeneic patient's cohort was 50 years and 21 years, respectively. Median follow-up period for all patients was 39 months. Major early complications were infections, mucositis, acute graft versus host disease, and venoocclusive disease. All of our allogeneic and autologous transplant patients survived during the first month of transplant. Transplant related mortality (TRM) was 20% (N = 3) in our allogeneic and 3% (N = 1) in autologous patients. Causes of these deaths were disease relapse, sepsis, hemorrhagic complications, and GVHD. 46% of our autologous and 47% of our allogeneic patients are in complete remission phase after a median follow-up of 39 months. 34% of our autologous patients and 13% of our allogeneic patients had disease relapse. Overall survival rate in our autologous and allogeneic patients is 65.7% and 57.1%, respectively. Our results are comparable to many national and international published reports.

  12. Reconstitution of SCID mice with human lymphoid and myeloid cells after transplantation with human fetal bone marrow without the requirement for exogenous human cytokines.

    PubMed

    Kollmann, T R; Kim, A; Zhuang, X; Hachamovitch, M; Goldstein, H

    1994-08-16

    Investigation of human hematopoietic maturation has been hampered by the lack of in vivo models. Although engraftment of irradiated C.B-17 scid/scid (SCID) mice with human progenitor cells occurred after infusion with human pediatric bone marrow cells, significant engraftment of the mouse bone marrow with human cells was dependent upon continuous treatment with exogenous human cytokines. Furthermore, despite cytokine treatment, only minimal peripheral engraftment of these mice with human cells was observed. In the present study, after infusion of irradiated SCID mice with pre-cultured human fetal bone marrow cells (BM-SCID-hu mice), their bone marrow became significantly engrafted with human precursor cells and their peripheral lymphoid compartment became populated with human B cells and monocytes independently of the administration of extraneous human cytokines. Examination of the bone marrow of the BM-SCID-hu mice for human cytokine mRNA gene expression demonstrated human leukemia inhibitory factor mRNA and interleukin 7 mRNA in nine of nine BM-SCID-hu mice and macrophage-colony-stimulating factor mRNA in seven of eight BM-SCID-hu mice. This was an intriguing observation because these cytokines regulate different stages of human hematopoiesis. Since engraftment occurs in the absence of exogenous cytokine treatment, the BM-SCID-hu mouse model described should provide a useful in vivo system for studying factors important in the maturation of human myeloid and lymphoid cells in the bone marrow and the behavior of the mature human cells after dissemination into the peripheral lymphoid tissue.

  13. Reconstitution of SCID mice with human lymphoid and myeloid cells after transplantation with human fetal bone marrow without the requirement for exogenous human cytokines.

    PubMed Central

    Kollmann, T R; Kim, A; Zhuang, X; Hachamovitch, M; Goldstein, H

    1994-01-01

    Investigation of human hematopoietic maturation has been hampered by the lack of in vivo models. Although engraftment of irradiated C.B-17 scid/scid (SCID) mice with human progenitor cells occurred after infusion with human pediatric bone marrow cells, significant engraftment of the mouse bone marrow with human cells was dependent upon continuous treatment with exogenous human cytokines. Furthermore, despite cytokine treatment, only minimal peripheral engraftment of these mice with human cells was observed. In the present study, after infusion of irradiated SCID mice with pre-cultured human fetal bone marrow cells (BM-SCID-hu mice), their bone marrow became significantly engrafted with human precursor cells and their peripheral lymphoid compartment became populated with human B cells and monocytes independently of the administration of extraneous human cytokines. Examination of the bone marrow of the BM-SCID-hu mice for human cytokine mRNA gene expression demonstrated human leukemia inhibitory factor mRNA and interleukin 7 mRNA in nine of nine BM-SCID-hu mice and macrophage-colony-stimulating factor mRNA in seven of eight BM-SCID-hu mice. This was an intriguing observation because these cytokines regulate different stages of human hematopoiesis. Since engraftment occurs in the absence of exogenous cytokine treatment, the BM-SCID-hu mouse model described should provide a useful in vivo system for studying factors important in the maturation of human myeloid and lymphoid cells in the bone marrow and the behavior of the mature human cells after dissemination into the peripheral lymphoid tissue. Images PMID:7914701

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

    PubMed Central

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

    2013-01-01

    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

  15. Association of acute myeloid leukemia’s most immature phenotype with risk groups and outcomes

    PubMed Central

    Gerber, Jonathan M.; Zeidner, Joshua F.; Morse, Sarah; Blackford, Amanda L.; Perkins, Brandy; Yanagisawa, Breann; Zhang, Hao; Morsberger, Laura; Karp, Judith; Ning, Yi; Gocke, Christopher D.; Rosner, Gary L.; Smith, B. Douglas; Jones, Richard J.

    2016-01-01

    The precise phenotype and biology of acute myeloid leukemia stem cells remain controversial, in part because the “gold standard” immunodeficient mouse engraftment assay fails in a significant fraction of patients and identifies multiple cell-types in others. We sought to analyze the clinical utility of a novel assay for putative leukemia stem cells in a large prospective cohort. The leukemic clone’s most primitive hematopoietic cellular phenotype was prospectively identified in 109 newly-diagnosed acute myeloid leukemia patients, and analyzed against clinical risk groups and outcomes. Most (80/109) patients harbored CD34+CD38− leukemia cells. The CD34+CD38− leukemia cells in 47 of the 80 patients displayed intermediate aldehyde dehydrogenase expression, while normal CD34+CD38− hematopoietic stem cells expressed high levels of aldehyde dehydrogenase. In the other 33/80 patients, the CD34+CD38− leukemia cells exhibited high aldehyde dehydrogenase activity, and most (28/33, 85%) harbored poor-risk cytogenetics or FMS-like tyrosine kinase 3 internal tandem translocations. No CD34+ leukemia cells could be detected in 28/109 patients, including 14/21 patients with nucleophosmin-1 mutations and 6/7 acute promyelocytic leukemia patients. The patients with CD34+CD38− leukemia cells with high aldehyde dehydrogenase activity manifested a significantly lower complete remission rate, as well as poorer event-free and overall survivals. The leukemic clone’s most immature phenotype was heterogeneous with respect to CD34, CD38, and ALDH expression, but correlated with acute myeloid leukemia risk groups and outcomes. The strong clinical correlations suggest that the most immature phenotype detectable in the leukemia might serve as a biomarker for “clinically-relevant” leukemia stem cells. ClinicalTrials.gov: NCT01349972. PMID:26819054

  16. Targeted alpha-particle immunotherapy for acute myeloid leukemia.

    PubMed

    Jurcic, Joseph G; Rosenblat, Todd L

    2014-01-01

    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 μCi/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

  17. Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions

    PubMed Central

    Van de Walle, Inge; De Smet, Greet; Gärtner, Martina; De Smedt, Magda; Waegemans, Els; Vandekerckhove, Bart; Leclercq, Georges; Plum, Jean; Aster, Jon C.; Bernstein, Irwin D.; Guidos, Cynthia J.; Kyewski, Bruno

    2011-01-01

    Notch signaling critically mediates various hematopoietic lineage decisions and is induced in mammals by Notch ligands that are classified into 2 families, Delta-like (Delta-like-1, -3 and -4) and Jagged (Jagged1 and Jagged2), based on structural homology with both Drosophila ligands Delta and Serrate, respectively. Because the functional differences between mammalian Notch ligands were still unclear, we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1. OP9 coculture experiments revealed that Jagged2, like Delta-like ligands, induces T-lineage differentiation and inhibits B-cell and myeloid development. However, dose-dependent Notch activation studies, gene expression analysis, and promoter activation assays indicated that Jagged2 is a weaker Notch1-activator compared with the Delta-like ligands, revealing a Notch1 specific signal strength hierarchy for mammalian Notch ligands. Strikingly, Lunatic-Fringe– mediated glycosylation of Notch1 potentiated Notch signaling through Delta-like ligands and also Jagged2, in contrast to Jagged1. Thus, our results reveal a unique role for Jagged1 in preventing the induction of T-lineage differentiation in hematopoietic stem cells and show an unexpected functional similarity between Jagged2 and the Delta-like ligands. PMID:21372153

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

    PubMed Central

    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

    2014-01-01

    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 cebpα+) 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

  19. FOXP1 Expression in Normal and Neoplastic Erythroid and Myeloid Cells.

    PubMed

    Lovrić, Eva; Pavlov, Katarina Horvat; Korać, Petra; Dominis, Mara

    2015-09-01

    FOXP1 protein was firstly analyzed in normal tissues, and afterwards in different tumor tissues, mainly carcinoma and lymphoma. In B-cell malignancies, its role was well explored; its expression was shown to be connected with disease prognosis in certain B-non Hodgkin lymphomas. In this study, 16 bone marrow trephine samples from patients with no hematopoietic malignancies and 10 samples from peripheral blood of healthy individuals were immunostained with anti-FOXP1 antibody. Positive cells in bone marrows were not only lymphocytes, but also cells that are immunohistochemically positive for glycophorin C or myeloperoxidase. Peripheral blood samples showed no other positive cells, but small round lymphocytes. Additionally 60 samples from patients with myeloid lineage neoplasms were analyzed. 25 samples from patients with myelodysplastic syndrome (MDS) and 35 patients with myeloproliferative disease (MPD) were double immunostained with anti-FOXP1/anti-glycophorin C and anti-FOXP1/anti-myeloperoxidase antibodies. FOXP1 was found to be expressed in 22 cases of MDS and in none of MPD cases. Its expression in MDS was observed mostly in myeloperoxidase positive cells in contrast to gylcophorin C positive cells. Only two cases revealed both myeloperoxidase positive cells and gylcophorin C positive cells expressing FOXP1 transcription factor. Our results show that FOXP1 is present in normal cells of erythroid and myeloid linages and thus suggest its possible role in development of all hematopoetic cells as well as possible involvement in neoplasm development of myeloid disorders. PMID:26898077

  20. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse.

    PubMed

    Sportoletti, Paolo; Grisendi, Silvia; Majid, Samia M; Cheng, Ke; Clohessy, John G; Viale, Agnes; Teruya-Feldstein, Julie; Pandolfi, Pier Paolo

    2008-04-01

    Nucleophosmin (NPM1) gene has been heavily implicated in cancer pathogenesis both as a putative proto-oncogene and tumor suppressor gene. NPM1 is the most frequently mutated gene in acute myeloid leukemia (AML), while deletion of 5q, where NPM1 maps, is frequent in patients with myelodysplastic syndromes (MDS). We have previously shown that mice heterozygous for Npm1 (Npm1+/-) develop a hematologic syndrome with features of human MDS. Here we analyzed Npm1+/- mutants to determine their susceptibility to cancer. Npm1+/- mice displayed a greater propensity to develop malignancies compared with Npm1+/+ mice. The Npm1+/- cohort frequently developed hematologic malignancies of both myeloid and lymphoid origin with myeloid malignancies displaying the highest incidence. Malignant cells retained the wild-type allele with normal localization and expression of Npm1 at the protein level, suggesting that complete Npm1 loss is not a prerequisite for tumorigenesis. Our results conclusively demonstrate that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment.

  1. Aging-like Phenotype and Defective Lineage Specification in SIRT1-Deleted Hematopoietic Stem and Progenitor Cells

    PubMed Central

    Rimmelé, Pauline; Bigarella, Carolina L.; Liang, Raymond; Izac, Brigitte; Dieguez-Gonzalez, Rebeca; Barbet, Gaetan; Donovan, Michael; Brugnara, Carlo; Blander, Julie M.; Sinclair, David A.; Ghaffari, Saghi

    2014-01-01

    Summary Aging hematopoietic stem cells (HSCs) exhibit defective lineage specification that is thought to be central to increased incidence of myeloid malignancies and compromised immune competence in the elderly. Mechanisms underlying these age-related defects remain largely unknown. We show that the deacetylase Sirtuin (SIRT)1 is required for homeostatic HSC maintenance. Differentiation of young SIRT1-deleted HSCs is skewed toward myeloid lineage associated with a significant decline in the lymphoid compartment, anemia, and altered expression of associated genes. Combined with HSC accumulation of damaged DNA and expression patterns of age-linked molecules, these have striking overlaps with aged HSCs. We further show that SIRT1 controls HSC homeostasis via the longevity transcription factor FOXO3. These findings suggest that SIRT1 is essential for HSC homeostasis and lineage specification. They also indicate that SIRT1 might contribute to delaying HSC aging. PMID:25068121

  2. Cryopreserved Ex Vivo-Expanded Allogeneic Myeloid Progenitor Cell Product Protects Neutropenic Mice From a Lethal Fungal Infection.

    PubMed

    Domen, Jos; Christensen, Julie L; Gille, Daphne; Smith-Berdan, Stephanie; Fong, Timothy; Brown, Janice M Y; Sedello, Anna K

    2016-01-01

    Severe neutropenia induced by chemotherapy or conditioning for hematopoietic cell transplantation often results in morbidity and mortality due to infection by opportunistic pathogens. A system has been developed to generate ex vivo-expanded mouse myeloid progenitor cells (mMPCs) that produce functional neutrophils in vivo upon transplantation in a pathogen challenge model. It has previously been demonstrated that transplantation of large numbers of freshly isolated myeloid progenitors from a single donor provides survival benefit in radiation-induced neutropenic mice. In the present work, an ex vivo-expanded and cryopreserved mMPC product generated from an allogeneic donor pool retains protective activity in vivo in a lethal fungal infection model. Infusion of the allogeneic pooled mMPC product is effective in preventing death from invasive Aspergillus fumigatus in neutropenic animals, and protection is dose dependent. Cell progeny from the mMPC product is detected in the bone marrow, spleen, blood, and liver by flow cytometry 1 week postinfusion but is no longer evident in most animals 4 weeks posttransplant. In this model, the ex vivo-generated pooled allogeneic mMPC product (i) expands and differentiates in vivo; (ii) is functional and prevents death from invasive fungal infection; and (iii) does not permanently engraft or cause allosensitization. These data suggest that an analogous ex vivo-expanded human myeloid progenitor cell product may be an effective off-the-shelf bridging therapy for the infectious complications that develop during hematopoietic recovery following hematopoietic cell transplantation or intensive chemotherapy. PMID:25812169

  3. Plasticity of hematopoietic stem cells.

    PubMed

    Ogawa, Makio; LaRue, Amanda C; Mehrotra, Meenal

    2015-01-01

    Almost two decades ago, a number of cell culture and preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired by controversy and remained dormant. This chapter provides a brief review of evidence for HSC plasticity including our findings based on single HSC transplantation in mouse. These studies strongly support the concept that HSCs are pluripotent and may be the source for the majority, if not all, of the cell types in our body. PMID:26590762

  4. Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

    PubMed Central

    Morris, Valerie A.; Cummings, Carrie L.; Korb, Brendan; Boaglio, Sean

    2015-01-01

    Acute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression. PMID:26644403

  5. Olive leaf components apigenin 7-glucoside and luteolin 7-glucoside direct human hematopoietic stem cell differentiation towards erythroid lineage.

    PubMed

    Samet, Imen; Villareal, Myra O; Motojima, Hideko; Han, Junkyu; Sayadi, Sami; Isoda, Hiroko

    2015-06-01

    The generation of blood cellular components from hematopoietic stem cells is important for the therapy of a broad spectrum of hematological disorders. In recent years, several lines of evidence suggested that certain nutrients, vitamins and flavonoids may have important roles in controlling the stem cell fate decision by maintaining their self-renewal or stimulating the lineage-specific differentiation. In this study, main olive leaf phytochemicals oleuropein (Olp), apigenin 7-glucoside (Api7G) and luteolin 7-glucoside (Lut7G) were investigated for their potential effects on hematopoietic stem cell differentiation using both phenotypic and molecular analysis. Oleuropein and the combination of the three compounds enhanced the differentiation of CD34+ cells into myelomonocytic cells and lymphocytes progenitors and inhibited the commitment to megakaryocytic and erythroid lineages. Treatment with Lut7G stimulated both the erythroid and the myeloid differentiation, while treatment with Api7G specifically induced the differentiation of CD34+ cells towards the erythroid lineage and inhibited the myeloid differentiation. Erythroid differentiation induced by Api7G and Lut7G treatments was confirmed by the increase in hemoglobin genes expressions (α-hemoglobin, β-hemoglobin and γ-hemoglobin) and erythroid transcription factor GATA1 expression. As revealed by microarray analysis, the mechanisms underlying the erythroid differentiation-inducing effect of Api7G on hematopoietic stem cells involves the activation of JAK/STAT signaling pathway. These findings prove the differentiation-inducing effects of olive leaf compounds on hematopoietic stem cells and highlight their potential use in the ex vivo generation of blood cells.

  6. Olive leaf components apigenin 7-glucoside and luteolin 7-glucoside direct human hematopoietic stem cell differentiation towards erythroid lineage.

    PubMed

    Samet, Imen; Villareal, Myra O; Motojima, Hideko; Han, Junkyu; Sayadi, Sami; Isoda, Hiroko

    2015-06-01

    The generation of blood cellular components from hematopoietic stem cells is important for the therapy of a broad spectrum of hematological disorders. In recent years, several lines of evidence suggested that certain nutrients, vitamins and flavonoids may have important roles in controlling the stem cell fate decision by maintaining their self-renewal or stimulating the lineage-specific differentiation. In this study, main olive leaf phytochemicals oleuropein (Olp), apigenin 7-glucoside (Api7G) and luteolin 7-glucoside (Lut7G) were investigated for their potential effects on hematopoietic stem cell differentiation using both phenotypic and molecular analysis. Oleuropein and the combination of the three compounds enhanced the differentiation of CD34+ cells into myelomonocytic cells and lymphocytes progenitors and inhibited the commitment to megakaryocytic and erythroid lineages. Treatment with Lut7G stimulated both the erythroid and the myeloid differentiation, while treatment with Api7G specifically induced the differentiation of CD34+ cells towards the erythroid lineage and inhibited the myeloid differentiation. Erythroid differentiation induced by Api7G and Lut7G treatments was confirmed by the increase in hemoglobin genes expressions (α-hemoglobin, β-hemoglobin and γ-hemoglobin) and erythroid transcription factor GATA1 expression. As revealed by microarray analysis, the mechanisms underlying the erythroid differentiation-inducing effect of Api7G on hematopoietic stem cells involves the activation of JAK/STAT signaling pathway. These findings prove the differentiation-inducing effects of olive leaf compounds on hematopoietic stem cells and highlight their potential use in the ex vivo generation of blood cells. PMID:26299581

  7. Diagnosis of acute myeloid leukemia in a dental hospital; report of a case with severe gingival hypertrophy.

    PubMed

    Misirlioglu, M; Adisen, M Z; Yilmaz, S

    2015-01-01

    Acute myeloid leukemias (AMLs) are aggressive hematopoietic neoplasms that, if untreated, can lead to death within days. Owing to its high morbidity rate, early diagnosis and appropriate medical therapy is essential. Oral lesions may be the presenting feature of acute leukemias and are, therefore, important diagnostic indicators of the disease. Erythematous or cyanotic gingival hyperplasia with or without necrosis is reported to be the most consistent symptom leading to a diagnosis of acute leukemia that directs the patient to seek early dental consultation. This report refers to a patient with AML that was provisionally diagnosed in the dental hospital due to severe gingival enlargements.

  8. Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity.

    PubMed

    Torres, Juan Manuel; Martinez-Barricarte, Rubén; García-Gómez, Sonia; Mazariegos, Marina S; Itan, Yuval; Boisson, Bertrand; Rholvarez, Rita; Jiménez-Reinoso, Anaïs; del Pino, Lucia; Rodríguez-Pena, Rebeca; Ferreira, Antonio; Hernández-Jiménez, Enrique; Toledano, Victor; Cubillos-Zapata, Carolina; Díaz-Almirón, Mariana; López-Collazo, Eduardo; Unzueta-Roch, José L; Sánchez-Ramón, Silvia; Regueiro, Jose R; López-Granados, Eduardo; Casanova, Jean-Laurent; Pérez de Diego, Rebeca

    2014-12-01

    Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain-containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects. PMID:25365219

  9. Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

    PubMed Central

    Torres, Juan Manuel; Martinez-Barricarte, Rubén; García-Gómez, Sonia; Mazariegos, Marina S.; Itan, Yuval; Boisson, Bertrand; ρlvarez, Rita; Jiménez-Reinoso, Anaïs; del Pino, Lucia; Rodríguez-Pena, Rebeca; Ferreira, Antonio; Hernández-Jiménez, Enrique; Toledano, Victor; Cubillos-Zapata, Carolina; Díaz-Almirón, Mariana; López-Collazo, Eduardo; Unzueta-Roch, José L.; Sánchez-Ramón, Silvia; Regueiro, Jose R.; López-Granados, Eduardo; Casanova, Jean-Laurent; Pérez de Diego, Rebeca

    2014-01-01

    Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain–containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient’s myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB–mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects. PMID:25365219

  10. Productive persistent infection of hematopoietic cells by human foamy virus.

    PubMed Central

    Yu, S F; Stone, J; Linial, M L

    1996-01-01

    Human foamy virus can establish persistent infections in human hematopoietic cell lines, such as H92.1.7 (erythroblastoid cells), Jurkat (CD4+ T cells), and U937 (myeloid-monocytic cells). The infection is characterized by constant production of infectious viruses (for > 2 1/2 years) with no cytopathic effects on the host cells. Electron microscopy of the infected cells showed a viral morphology similar to that observed for particles produced after acute infection. We have detected, in addition to the full-length form of bel1, a previously described deletion in the bel1 gene of the proviral DNA in these cells. RNA containing this 301-bp deletion, which mapped to the splice donor and acceptor sites of the intron of the bet gene, was also found in encapsidated virion RNA. However, the presence of this defective provirus harboring the deletion in bel1 does not prevent productive persistence in these chronically infected cells, since the virus titer does not decrease during cultivation. PMID:8551590

  11. Mobilization of hematopoietic progenitor cells in patients with liver cirrhosis

    PubMed Central

    Gehling, Ursula M; Willems, Marc; Schlagner, Kathleen; Benndorf, Ralf A; Dandri, Maura; Petersen, Jörg; Sterneck, Martina; Pollok, Joerg-Matthias; Hossfeld, Dieter K; Rogiers, Xavier

    2010-01-01

    AIM: To test the hypothesis that liver cirrhosis is associated with mobilization of hematopoietic progenitor cells. METHODS: Peripheral blood samples from 72 patients with liver cirrhosis of varying etiology were analyzed by flow cytometry. Identified progenitor cell subsets were immunoselected and used for functional assays in vitro. Plasma levels of stromal cell-derived factor-1 (SDF-1) were measured using an enzyme linked immunosorbent assay. RESULTS: Progenitor cells with a CD133+/CD45+/CD14+ phenotype were observed in 61% of the patients. Between 1% and 26% of the peripheral blood mononuclear cells (MNCs) displayed this phenotype. Furthermore, a distinct population of c-kit+ progenitor cells (between 1% and 38 % of the MNCs) could be detected in 91% of the patients. Additionally, 18% of the patients showed a population of progenitor cells (between 1% and 68% of the MNCs) that was characterized by expression of breast cancer resistance protein-1. Further phenotypic analysis disclosed that the circulating precursors expressed CXC chemokine receptor 4, the receptor for SDF-1. In line with this finding, elevated plasma levels of SDF-1 were present in all patients and were found to correlate with the number of mobilized CD133+ progenitor cells. CONCLUSION: These data indicate that in humans, liver cirrhosis leads to recruitment of various populations of hematopoietic progenitor cells that display markers of intrahepatic progenitor cells. PMID:20066741

  12. Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-08

    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

  13. Human Olfactory Mucosa Multipotent Mesenchymal Stromal Cells Promote Survival, Proliferation, and Differentiation of Human Hematopoietic Cells

    PubMed Central

    Diaz-Solano, Dylana; Wittig, Olga; Ayala-Grosso, Carlos; Pieruzzini, Rosalinda

    2012-01-01

    Multipotent mesenchymal stromal cells (MSCs) from the human olfactory mucosa (OM) are cells that have been proposed as a niche for neural progenitors. OM-MSCs share phenotypic and functional properties with bone marrow (BM) MSCs, which constitute fundamental components of the hematopoietic niche. In this work, we investigated whether human OM-MSCs may promote the survival, proliferation, and differentiation of human hematopoietic stem cells (HSCs). For this purpose, human bone marrow cells (BMCs) were co-cultured with OM-MSCs in the absence of exogenous cytokines. At different intervals, nonadherent cells (NACs) were harvested from BMC/OM-MSC co-cultures, and examined for the expression of blood cell markers by flow cytometry. OM-MSCs supported the survival (cell viability >90%) and proliferation of BMCs, after 54 days of co-culture. At 20 days of co-culture, flow cytometric and microscopic analyses showed a high percentage (73%) of cells expressing the pan-leukocyte marker CD45, and the presence of cells of myeloid origin, including polymorphonuclear leukocytes, monocytes, basophils, eosinophils, erythroid cells, and megakaryocytes. Likewise, T (CD3), B (CD19), and NK (CD56/CD16) cells were detected in the NAC fraction. Colony-forming unit–granulocyte/macrophage (CFU-GM) progenitors and CD34+ cells were found, at 43 days of co-culture. Reverse transcriptase–polymerase chain reaction (RT-PCR) studies showed that OM-MSCs constitutively express early and late-acting hematopoietic cytokines (i.e., stem cell factor [SCF] and granulocyte- macrophage colony-stimulating factor [GM-CSF]). These results constitute the first evidence that OM-MSCs may provide an in vitro microenvironment for HSCs. The capacity of OM-MSCs to support the survival and differentiation of HSCs may be related with the capacity of OM-MSCs to produce hematopoietic cytokines. PMID:22471939

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

    PubMed

    Abraham, N G

    1996-12-01

    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 lowered 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 LTBMC 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 micrograms/g bw i.v. over 2 weeks for a total dose of 9 micrograms/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.

  15. The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function

    PubMed Central

    Gu, Yue; Jones, Amanda E.; Yang, Wei; Liu, Shanrun; Dai, Qian; Liu, Yudong; Swindle, C. Scott; Zhou, Dewang; Zhang, Zhuo; Ryan, Thomas M.; Townes, Tim M.; Klug, Christopher A.; Chen, Dongquan; Wang, Hengbin

    2016-01-01

    Epigenetic mechanisms play important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it is unclear which of the several counteracting H2A deubiquitinases functions along with PRC1 to control H2A ubiquitination (ubH2A) level and regulates hematopoiesis in vivo. Here we investigated the function of Usp16 in mouse hematopoiesis. Conditional deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and lethality. Usp16 deletion did not change HSC number but was associated with a dramatic reduction of mature and progenitor cell populations, revealing a role in governing HSC lineage commitment. ChIP- and RNA-sequencing studies in HSC and progenitor cells revealed that Usp16 bound to many important hematopoietic regulators and that Usp16 deletion altered the expression of genes in transcription/chromosome organization, immune response, hematopoietic/lymphoid organ development, and myeloid/leukocyte differentiation. The altered gene expression was partly rescued by knockdown of PRC1 subunits, suggesting that Usp16 and PRC1 counterbalance each other to regulate cellular ubH2A level and gene expression in the hematopoietic system. We further discovered that knocking down Cdkn1a (p21cip1), a Usp16 target and regulated gene, rescued the altered cell cycle profile and differentiation defect of Usp16-deleted HSCs. Collectively, these studies identified Usp16 as one of the histone H2A deubiquitinases, which coordinates with the H2A ubiquitin ligase PRC1 to regulate hematopoiesis, and revealed cell cycle regulation by Usp16 as key for HSC differentiation. PMID:26699484

  16. Human olfactory mucosa multipotent mesenchymal stromal cells promote survival, proliferation, and differentiation of human hematopoietic cells.

    PubMed

    Diaz-Solano, Dylana; Wittig, Olga; Ayala-Grosso, Carlos; Pieruzzini, Rosalinda; Cardier, Jose E

    2012-11-20

    Multipotent mesenchymal stromal cells (MSCs) from the human olfactory mucosa (OM) are cells that have been proposed as a niche for neural progenitors. OM-MSCs share phenotypic and functional properties with bone marrow (BM) MSCs, which constitute fundamental components of the hematopoietic niche. In this work, we investigated whether human OM-MSCs may promote the survival, proliferation, and differentiation of human hematopoietic stem cells (HSCs). For this purpose, human bone marrow cells (BMCs) were co-cultured with OM-MSCs in the absence of exogenous cytokines. At different intervals, nonadherent cells (NACs) were harvested from BMC/OM-MSC co-cultures, and examined for the expression of blood cell markers by flow cytometry. OM-MSCs supported the survival (cell viability >90%) and proliferation of BMCs, after 54 days of co-culture. At 20 days of co-culture, flow cytometric and microscopic analyses showed a high percentage (73%) of cells expressing the pan-leukocyte marker CD45, and the presence of cells of myeloid origin, including polymorphonuclear leukocytes, monocytes, basophils, eosinophils, erythroid cells, and megakaryocytes. Likewise, T (CD3), B (CD19), and NK (CD56/CD16) cells were detected in the NAC fraction. Colony-forming unit-granulocyte/macrophage (CFU-GM) progenitors and CD34(+) cells were found, at 43 days of co-culture. Reverse transcriptase-polymerase chain reaction (RT-PCR) studies showed that OM-MSCs constitutively express early and late-acting hematopoietic cytokines (i.e., stem cell factor [SCF] and granulocyte- macrophage colony-stimulating factor [GM-CSF]). These results constitute the first evidence that OM-MSCs may provide an in vitro microenvironment for HSCs. The capacity of OM-MSCs to support the survival and differentiation of HSCs may be related with the capacity of OM-MSCs to produce hematopoietic cytokines.

  17. Hematopoietic management in oncology practice. Part 2. Erythropoietic factors.

    PubMed

    Glaspy, John A

    2003-12-01

    As the major regulator of erythropoiesis in man, erythropoietin inhibits the programmed cell death of committed erythroid precursors. In cancer patients, a relative erythropoietin deficiency is coupled with a decreased responsiveness to the substance mediated by the effects of inflammatory cytokines on the marrow and on ferrokinetics, leading to a high incidence of anemia. Two recombinant human erythropoietin (rhEPO) preparations--epoetin alfa (Epogen, Procrit) and epoetin beta (Marogen)--as well as a modified erythropoietic compound (darbepoetin alfa [Aranesp]) are in clinical use. Part 2 of this two-part series on hematopoietic agents reviews the use of these erythropoietic factors and their effect on the anemia that develops in cancer patients. Thrombopoietic factors and progenitor cell-mobilizing factors are also briefly addressed. PMID:14723012

  18. Sex differences in the incidence of chronic myeloid leukemia

    PubMed Central

    Jankovic, Gradimir M.; Tiu, Ramon V.; Saunthararajah, Yogen; Jackson, Robert C.; Hlatky, Lynn R.; Gale, Robert Peter; Sachs, Rainer K.

    2014-01-01

    The incidence of chronic myeloid leukemia (CML), which is caused by BCR/ABL chimeric oncogene formation in a pluripotent hematopoietic stem cell (HSC), increases with age and exposure to ionizing radiation. CML is a comparatively well-characterized neoplasm, important for its own sake and useful for insights into other neoplasms. Here, Surveillance, Epidemiology and End Results (SEER) CML data are analyzed after considering possible misclassification of chronic myelo-monocytic leukemia as CML. For people older than 25 years, plots of male and female CML log incidences versus age at diagnosis are approximately parallel straight lines with males either above or to the left of females. This is consistent with males having a higher risk of developing CML or a shorter latency from initiation to diagnosis of CML. These distinct mechanisms cannot be distinguished using SEER data alone. Therefore, CML risks among male and female Japanese A-bomb survivors are also analyzed. The present analyses suggest that sex differences in CML incidence more likely result from differences in risk than in latency. The simplest but not the sole interpretation of this is that males have more target cells at risk to develop CML. Comprehensive mathematical models of CML could lead to a better understanding of the role of HSCs in CML and other preleukemias that can progress to acute leukemia. PMID:24337217

  19. Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells.

    PubMed

    Reinisch, Andreas; Chan, Steven M; Thomas, Daniel; Majeti, Ravindra

    2015-07-01

    Evidence for the cancer stem cell model was first demonstrated in xenotransplanted blood and bone marrow samples from patients with acute myeloid leukemia (AML) almost two decades ago, supporting the concept that a rare clonal and mutated leukemic stem cell (LSC) population is sufficient to drive leukemic growth. The inability to eliminate LSCs with conventional therapies is thought to be the primary cause of disease relapse in AML patients, and as such, novel therapies with the ability to target this population are required to improve patient outcomes. An important step towards this goal is the identification of common immunophenotypic surface markers and biological properties that distinguish LSCs from normal hematopoietic stem and progenitor cells (HSPCs) across AML patients. This work has resulted in the development of a large number of potential LSC-selective therapies that target cell surface molecules, intracellular signaling pathways, and the bone marrow microenvironment. Here, we will review the basic biology, immunophenotypic detection, and clinical relevance of LSCs, as well as emerging biological and small-molecule strategies that either directly target LSCs or indirectly target these cells through modulation of their microenvironment.

  20. Hsp90 Inhibitors for the Treatment of Chronic Myeloid Leukemia

    PubMed Central

    Khajapeer, Kalubai Vari; Baskaran, Rajasekaran

    2015-01-01

    Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5′ sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin-proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors. PMID:26770832

  1. Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype

    PubMed Central

    Akagi, Tadayuki; Ogawa, Seishi; Dugas, Martin; Kawamata, Norihiko; Yamamoto, Go; Nannya, Yasuhito; Sanada, Masashi; Miller, Carl W.; Yung, Amanda; Schnittger, Susanne; Haferlach, Torsten; Haferlach, Claudia; Koeffler, H. Phillip

    2009-01-01

    Background Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45–50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples. Design and Methods Thirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis. Results Eighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of either mutant FLT3 (2 cases), JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region. Conclusions This study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable. PMID:19144660

  2. Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-03-19

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

  3. Therapy-related Myeloid Leukemia

    PubMed Central

    Godley, Lucy A.; Larson, Richard A.

    2008-01-01

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

  4. Clostridium difficile infection in Chilean patients submitted to hematopoietic stem cell transplantation

    PubMed Central

    Pilcante, Javier; Rojas, Patricio; Ernst, Daniel; Sarmiento, Mauricio; Ocqueteau, Mauricio; Bertin, Pablo; García, Maria; Rodriguez, Maria; Jara, Veronica; Ajenjo, Maria; Ramirez, Pablo

    2015-01-01

    Introduction Patients submitted to hematopoietic stem cell transplantation have an increased risk of Clostridium difficile infection and multiple risk factors have been identified. Published reports have indicated an incidence from 9% to 30% of transplant patients however to date there is no information about infection in these patients in Chile. Methods A retrospective analysis was performed of patients who developed C. difficile infection after hematopoietic stem cell transplantations from 2000 to 2013. Statistical analysis used the Statistical Package for the Social Sciences software. Results Two hundred and fifty patients were studied (mean age: 39 years; range: 17–69), with 147 (59%) receiving allogeneic transplants and 103 (41%) receiving autologous transplants. One hundred and ninety-two (77%) patients had diarrhea, with 25 (10%) cases of C. difficile infection being confirmed. Twenty infected patients had undergone allogeneic transplants, of which ten had acute lymphoblastic leukemia, three had acute myeloid leukemia and seven had other diseases (myelodysplastic syndrome, chronic myeloid leukemia, severe aplastic anemia). In the autologous transplant group, five patients had C. difficile infection; two had multiple myeloma, one had amyloidosis, one had acute myeloid leukemia and one had germinal carcinoma. The overall incidence of C. difficile infection was 4% within the first week, 6.4% in the first month and 10% in one year, with no difference in overall survival between infected and non-infected groups (72.0% vs. 67.6%, respectively; p-value = 0.56). Patients infected after allogeneic transplants had a slower time to neutrophil engraftment compared to non-infected patients (17.5 vs. 14.9 days, respectively; p-value = 0.008). In the autologous transplant group there was no significant difference in the neutrophil engraftment time between infected and non-infected patients (12.5 days vs. 11.8 days, respectively; p-value = 0.71). In the allogeneic

  5. Age and stage dependency of estrogen receptor expression by lymphocyte precursors

    PubMed Central

    Igarashi, Hideya; Kouro, Taku; Yokota, Takafumi; Comp, Phillip C.; Kincade, Paul W.

    2001-01-01

    Sex steroids negatively regulate B lymphopoiesis in adult mice. Paradoxically, lymphocytes arise during fetal life, when estrogen levels are high and maternal lymphopoiesis is suppressed. Here we demonstrate that embryonic B lymphopoiesis was unaffected by estrogen, but sensitive to glucocorticoids. Both fetal and adult precursors contained glucocorticoid receptor transcripts, but only adult precursors expressed estrogen receptor α and β together with the androgen receptor. Fetal hematopoietic cells did not efficiently acquire functional estrogen receptors after transplantation to irradiated adult mice. Sex steroid receptors were also expressed in a stage- and developmental age-dependent fashion in human precursors. A developmental switch in responsiveness of hematopoietic cells to sex steroids may be essential for formation of the immune system. PMID:11752459

  6. Cytomegalovirus immune evasion of myeloid lineage cells.

    PubMed

    Brinkmann, Melanie M; Dağ, Franziska; Hengel, Hartmut; Messerle, Martin; Kalinke, Ulrich; Čičin-Šain, Luka

    2015-06-01

    Cytomegalovirus (CMV) evades the immune system in many different ways, allowing the virus to grow and its progeny to spread in the face of an adverse environment. Mounting evidence about the antiviral role of myeloid immune cells has prompted the research of CMV immune evasion mechanisms targeting these cells. Several cells of the myeloid lineage, such as monocytes, dendritic cells and macrophages, play a role in viral control, but are also permissive for CMV and are naturally infected by it. Therefore, CMV evasion of myeloid cells involves mechanisms that qualitatively differ from the evasion of non-CMV-permissive immune cells of the lymphoid lineage. The evasion of myeloid cells includes effects in cis, where the virus modulates the immune signaling pathways within the infected myeloid cell, and those in trans, where the virus affects somatic cells targeted by cytokines released from myeloid cells. This review presents an overview of CMV strategies to modulate and evade the antiviral activity of myeloid cells in cis and in trans.

  7. Molecular pathways: myeloid complicity in cancer.

    PubMed

    Stromnes, Ingunn M; Greenberg, Philip D; Hingorani, Sunil R

    2014-10-15

    Cancer-induced inflammation results in accumulation of myeloid cells. These myeloid cells include progenitors and progeny of monocytes, granulocytes, macrophages, and dendritic cells. It has become increasingly evident that tumor-dependent factors can condition myeloid cells toward an immunosuppressive and protumorigenic phenotype. Thus, myeloid cells are not simply bystanders in malignancy or barometers of disease burden. Reflecting their dynamic and plastic nature, myeloid cells manifest a continuum of cellular differentiation and are intimately involved at all stages of neoplastic progression. They can promote tumorigenesis through both immune-dependent and -independent mechanisms and can dictate response to therapies. A greater understanding of the inherent plasticity and relationships among myeloid subsets is needed to inform therapeutic targeting. New clinical trials are being designed to modulate the activities of myeloid cells in cancer, which may be essential to maximize the efficacy of both conventional cytotoxic and immune-based therapies for solid tumors. Clin Cancer Res; 20(20); 5157-70. ©2014 AACR.

  8. Molecular pathways: myeloid complicity in cancer.

    PubMed

    Stromnes, Ingunn M; Greenberg, Philip D; Hingorani, Sunil R

    2014-10-15

    Cancer-induced inflammation results in accumulation of myeloid cells. These myeloid cells include progenitors and progeny of monocytes, granulocytes, macrophages, and dendritic cells. It has become increasingly evident that tumor-dependent factors can condition myeloid cells toward an immunosuppressive and protumorigenic phenotype. Thus, myeloid cells are not simply bystanders in malignancy or barometers of disease burden. Reflecting their dynamic and plastic nature, myeloid cells manifest a continuum of cellular differentiation and are intimately involved at all stages of neoplastic progression. They can promote tumorigenesis through both immune-dependent and -independent mechanisms and can dictate response to therapies. A greater understanding of the inherent plasticity and relationships among myeloid subsets is needed to inform therapeutic targeting. New clinical trials are being designed to modulate the activities of myeloid cells in cancer, which may be essential to maximize the efficacy of both conventional cytotoxic and immune-based therapies for solid tumors. Clin Cancer Res; 20(20); 5157-70. ©2014 AACR. PMID:25047706

  9. Delineation of Natural Killer Cell Differentiation from Myeloid Progenitors in Human.

    PubMed

    Chen, Qingfeng; Ye, Weijian; Jian Tan, Wei; Mei Yong, Kylie Su; Liu, Min; Qi Tan, Shu; Loh, Eva; Te Chang, Kenneth; Chye Tan, Thiam; Preiser, Peter R; Chen, Jianzhu

    2015-01-01

    Understanding of natural killer (NK) cell development in human is incomplete partly because of limited access to appropriate human tissues. We have developed a cytokine-enhanced humanized mouse model with greatly improved reconstitution and function of human NK cells. Here we report the presence of a cell population in the bone marrow of the cytokine-treated humanized mice that express both NK cell marker CD56 and myeloid markers such as CD36 and CD33. The CD56(+)CD33(+)CD36(+) cells are also found in human cord blood, fetal and adult bone marrow. Although the CD56(+)CD33(+)CD36(+) cells do not express the common NK cell functional receptors and exhibit little cytotoxic and cytokine-producing activities, they readily differentiate into mature NK cells by acquiring expression of NK cell receptors and losing expression of the myeloid markers. Further studies show that CD33(+)CD36(+) myeloid NK precursors are derived from granulo-myelomonocytic progenitors. These results delineate the pathway of human NK cell differentiation from myeloid progenitors in the bone marrow and suggest the utility of humanized mice for studying human hematopoiesis. PMID:26456148

  10. Technical Advance: Transcription factor, promoter, and enhancer utilization in human myeloid cells

    PubMed Central

    Joshi, Anagha; Pooley, Christopher; Freeman, Tom C.; Lennartsson, Andreas; Babina, Magda; Schmidl, Christian; Geijtenbeek, Teunis; Michoel, Tom; Severin, Jessica; Itoh, Masayoshi; Lassmann, Timo; Kawaji, Hideya; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R. R.; Rehli, Michael; Hume, David A.

    2015-01-01

    The generation of myeloid cells from their progenitors is regulated at the level of transcription by combinatorial control of key transcription factors influencing cell-fate choice. To unravel the global dynamics of this process at the transcript level, we generated transcription profiles for 91 human cell types of myeloid origin by use of CAGE profiling. The CAGE sequencing of these samples has allowed us to investigate diverse aspects of transcription control during myelopoiesis, such as identification of novel transcription factors, miRNAs, and noncoding RNAs specific to the myeloid lineage. We further reconstructed a transcription regulatory network by clustering coexpressed transcripts and associating them with enriched cis-regulatory motifs. With the use of the bidirectional expression as a proxy for enhancers, we predicted over 2000 novel enhancers, including an enhancer 38 kb downstream of IRF8 and an intronic enhancer in the KIT gene locus. Finally, we highlighted relevance of these data to dissect transcription dynamics during progressive maturation of granulocyte precursors. A multifaceted analysis of the myeloid transcriptome is made available (www.myeloidome.roslin.ed.ac.uk). This high-quality dataset provides a powerful resource to study transcriptional regulation during myelopoiesis and to infer the likely functions of unannotated genes in human innate immunity. PMID:25717144

  11. Parasitic Infections in Hematopoietic Stem Cell Transplantation.

    PubMed

    Jarque, Isidro; Salavert, Miguel; Pemán, Javier

    2016-01-01

    Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients. PMID:27413527

  12. Parasitic Infections in Hematopoietic Stem Cell Transplantation

    PubMed Central

    Jarque, Isidro; Salavert, Miguel; Pemán, Javier

    2016-01-01

    Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients. PMID:27413527

  13. Hematopoietic toxicity of regional radiation therapy. Correlations for combined modality therapy with systemic chemotherapy

    SciTech Connect

    Abrams, R.A.; Lichter, A.S.; Bromer, R.H.; Minna, J.D.; Cohen, M.H.; Deisseroth, A.B.

    1985-04-01

    Using circulating granulocyte-monocyte precursor colony-forming units in culture (CFUc) numbers as a probe along with standard blood count (CBC), the authors have quantitatively examined the hematopoietic toxicity of conventionally fractionated radiation therapy (RT) when combined with concurrent systemic chemotherapy or when used alone. Among 20 patients with limited stage small cell lung cancer receiving systemic chemotherapy with cyclophosphamide, CCNU, and methotrexate, the addition of involved field chest RT resulted in increased hematopoietic toxicity as judged by increased need for platelet transfusion (P less than 0.05) and decreased frequency of measurable CFUc (P less than 0.04). Among 22 patients receiving regional radiotherapy alone consistent hematopoietic toxicity was also observed. This toxicity, although generally of only mild to moderate clinical significance, was detected earlier and to a greater degree in patients who required radiation to larger treatment volumes, who had significant amounts of bone marrow in the port, and who had a high percentage of cardiac output flowing through the port. These data suggest that the hematopoietic toxicity of regional radiotherapy may be additive to that of concurrent systemic chemotherapy and may occur more promptly and to a greater degree when treatment volumes are larger or incorporate increased amounts of marrow volume or cardiac output.

  14. Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B.

    PubMed

    Khoriaty, Rami; Vasievich, Matthew P; Jones, Morgan; Everett, Lesley; Chase, Jennifer; Tao, Jiayi; Siemieniak, David; Zhang, Bin; Maillard, Ivan; Ginsburg, David

    2014-10-01

    Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease of ineffective erythropoiesis characterized by increased bi/multinucleated erythroid precursors in the bone marrow. CDAII results from mutations in SEC23B. The SEC23 protein is a core component of coat protein complex II-coated vesicles, which transport secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Though the genetic defect underlying CDAII has been identified, the pathophysiology of this disease remains unknown. We previously reported that SEC23B-deficient mice die perinatally, exhibiting massive pancreatic degeneration, with this early mortality limiting evaluation of the adult hematopoietic compartment. We now report that mice with SEC23B deficiency restricted to the hematopoietic compartment survive normally and do not exhibit anemia or other CDAII characteristics. We also demonstrate that SEC23B-deficient hematopoietic stem cells (HSC) do not exhibit a disadvantage at reconstituting hematopoiesis when compared directly to wild-type HSC in a competitive repopulation assay. Secondary bone marrow transplants demonstrated continued equivalence of SEC23B-deficient and WT HSC in their hematopoietic reconstitution potential. The surprising discordance in phenotypes between SEC23B-deficient mice and humans may reflect an evolutionary shift in SEC23 paralog function and/or expression, or a change in a specific COPII cargo critical for erythropoiesis. PMID:25071156

  15. Thrombomucin, a Novel Cell Surface Protein that Defines Thrombocytes and Multipotent Hematopoietic Progenitors

    PubMed Central

    McNagny, Kelly M.; Pettersson, Inger; Rossi, Fabio; Flamme, Ingo; Shevchenko, Andrej; Mann, Matthias; Graf, Thomas

    1997-01-01

    MEP21 is an avian antigen specifically expressed on the surface of Myb-Ets–transformed multipotent hematopoietic precursors (MEPs) and of normal thrombocytes. Using nanoelectrospray tandem mass spectrometry, we have sequenced and subsequently cloned the MEP21 cDNA and named the gene thrombomucin as it encodes a 571–amino acid protein with an extracellular domain typical of the mucin family of proteoglycans. Thrombomucin is distantly related to CD34, the best characterized and most used human hematopoietic stem cell marker. It is also highly homologous in its transmembrane/intracellular domain to podocalyxinlike protein–1, a rabbit cell surface glycoprotein of kidney podocytes. Single cell analysis of yolk sac cells from 3-d-old chick embryos revealed that thrombomucin is expressed on the surface of both lineage-restricted and multipotent progenitors. In the bone marrow, thrombomucin is also expressed on mono- and multipotent progenitors, showing an overlapping but distinct expression pattern from that of the receptor-type stem cell marker c-kit. These observations strengthen the notion that the Myb-Ets oncoprotein can induce the proliferation of thrombomucin-positive hematopoietic progenitors that have retained the capacity to differentiate along multiple lineages. They also suggest that thrombomucin and CD34 form a family of stem cell–specific proteins with possibly overlapping functions in early hematopoietic progenitors. PMID:9298993

  16. Metalloproteinases: A functional pathway for myeloid cells

    PubMed Central

    Chou, Jonathan; Chan, Matilda F.; Werb, Zena

    2015-01-01

    Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix (ECM) turnover. To accomplish these tasks, myeloid cells carry an arsenal of metalloproteinases, which include the matrix metalloproteinases (MMPs) and the adamalysins. These enzymes have diverse substrate repertoires, and are thus involved in mediating proteolytic cascades, cell migration and cell signaling. Dysregulation of metalloproteinases contributes to pathogenic processes, including inflammation, fibrosis and cancer. Metalloproteinases also have important non-proteolytic functions in controlling cytoskeletal dynamics during macrophage fusion and enhancing transcription to promote anti-viral immunity. This review highlights the diverse contributions of metalloproteinases to myeloid cell functions. PMID:27227311

  17. The effect of smoking on myeloid-related protein-8 and myeloid-related protein-14.

    PubMed

    Ertugrul, Abdullah Seckin; Sahin, Hacer

    2016-05-20

    The aim of this study was to determine the myeloid-related protein-8 and myeloid-related protein-14 levels in the gingival crevicular fluid of smoker patients with generalized aggressive periodontitis (SAgP), smoker patients with chronic periodontitis (SCP), smoker patients with gingivitis (SG-smoker control), non-smoker patients with generalized aggressive periodontitis (AgP), non-smoker patients with chronic periodontitis (CP), and non-smoker patients with gingivitis (G-non-smoker control). The periodontal statuses of the patients were determined by periodontal clinical measurements and radiographical evaluations. The levels of myeloid-related protein-8 and myeloid-related protein-14 in the gingival crevicular fluid were assessed using enzyme-linked immuno sorbent assay. The myeloid-related protein-8 and myeloid-related protein-14 levels in the gingival crevicular fluid of patients with generalized aggressive periodontitis (non-smoker and smoker) were found to be statistically higher than patients with chronic periodontitis (non-smoker and smoker) and patients with gingivitis (non-smoker and smoker). Myeloid-related protein-8 and myeloid-related protein-14 levels of non-smokers were significantly higher than smokers in all types of periodontitis and gingivitis. The decreased myeloid-related protein-8 and myeloid-related protein-14 level could have prevented the haemostasis of calcium which plays a significant role in the migration of neutrophiles. Smoking affects myeloid-related protein-8 and myeloid-related protein-14 levels and may inhibit the antimicrobial efficiency against microorganisms. Due to these reasons smoker generalized aggressive periodontitis patients need to be treated in detail and their maintenance durations should be shortened. PMID:27223132

  18. mTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors

    PubMed Central

    Wu, Tingting; Zhao, Yang; Wang, Hao; Li, yang; Shao, Lijuan; Wang, Ruoyu; Lu, Jun; Yang, Zhongzhou; Wang, Junjie; Zhao, Yong

    2016-01-01

    CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) play critical roles in controlling the processes of tumors, infections, autoimmunity and graft rejection. Immunosuppressive drug rapamycin (RPM), targeting on the key cellular metabolism molecule mTOR, is currently used in clinics to treat patients with allo-grafts, autoimmune diseases and tumors. However, the effect of RPM on MDSCs has not been studied. RPM significantly decreases the cell number and the immunosuppressive ability on T cells of CD11b+ Ly6Chigh monocytic MDSCs (M-MDSCs) in both allo-grafts-transplanted and tumor-bearing mice respectively. Mice with a myeloid-specific deletion of mTOR have poor M-MDSCs after grafting with allo-skin tissue or a tumor. Grafting of allo-skin or tumors significantly activates glycolysis pathways in myeloid precursor cells in bone marrow, which is inhibited by RPM or mTOR deletion. 2-deoxyglucose (2-DG), an inhibitor of the glycolytic pathway, inhibits M-MDSC differentiation from precursors, while enhancing glycolysis by metformin significantly rescues the RPM-caused deficiency of M-MDSCs. Therefore, we offer evidence supporting that mTOR is an intrinsic factor essential for the differentiation and immunosuppressive function of M-MDSCs and that these metabolism-relevant medicines may impact MDSCs-mediated immunosuppression or immune tolerance induction, which is of considerable clinical importance in treating graft rejection, autoimmune diseases and cancers. PMID:26833095

  19. Radioimmunotherapy for hematopoietic cell transplantation.

    PubMed

    Jurcic, Joseph G

    2013-04-01

    Radioimmunotherapy (RIT) represents an attractive strategy to deliver radiation selectively to tumor and other target organs while minimizing toxicity to normal tissues. RIT with β-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. α-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

  20. Generation of axolotl hematopoietic chimeras

    PubMed Central

    Lopez, David; Scott, Edward W.

    2015-01-01

    Wound repair is an extremely complex process that requires precise coordination between various cell types including immune cells. Unfortunately, in mammals this usually results in scar formation instead of restoration of the original fully functional tissue, otherwise known as regeneration. Various animal models like frogs and salamanders are currently being studied to determine the intracellular and intercellular pathways, controlled by gene expression, that elicit cell proliferation, differentiation, and migration of cells during regenerative healing. Now, the necessary genetic tools to map regenerative pathways are becoming available for the axolotl salamander, thus allowing comparative studies between scarring and regeneration. Here, we describe in detail three methods to produce axolotl hematopoietic cell-tagged chimeras for the study of hematopoiesis and regeneration. PMID:26366424

  1. Polyimide Precursor Solid Residuum

    NASA Technical Reports Server (NTRS)

    Weiser, Erik S. (Inventor); St.Clair, Terry L. (Inventor); Echigo, Yoshiaki (Inventor); Kaneshiro, Hisayasu (Inventor)

    2001-01-01

    A polyimide precursor solid residuum is an admixture of an aromatic dianhydride or derivative thereof and an aromatic diamine or derivative thereof plus a complexing agent, which is complexed with the admixture by hydrogen bonding. The polyimide precursor solid residuum is effectively employed in the preparation of polyimide foam and the fabrication of polyimide foam structures.

  2. A retrospective cohort study of cause-specific mortality and incidence of hematopoietic malignancies in Chinese benzene-exposed workers.

    PubMed

    Linet, Martha S; Yin, Song-Nian; Gilbert, Ethel S; Dores, Graça M; Hayes, Richard B; Vermeulen, Roel; Tian, Hao-Yuan; Lan, Qing; Portengen, Lutzen; Ji, Bu-Tian; Li, Gui-Lan; Rothman, Nathaniel

    2015-11-01

    Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI = 1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI = 1.2, 2.3) and diseases of blood forming organs (RR = ∞, 95% CI = 3.4, ∞). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95%CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95%CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders.

  3. A retrospective cohort study of cause-specific mortality and incidence of hematopoietic malignancies in Chinese benzene-exposed workers.

    PubMed

    Linet, Martha S; Yin, Song-Nian; Gilbert, Ethel S; Dores, Graça M; Hayes, Richard B; Vermeulen, Roel; Tian, Hao-Yuan; Lan, Qing; Portengen, Lutzen; Ji, Bu-Tian; Li, Gui-Lan; Rothman, Nathaniel

    2015-11-01

    Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI = 1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI = 1.2, 2.3) and diseases of blood forming organs (RR = ∞, 95% CI = 3.4, ∞). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95%CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95%CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders. PMID:25944549

  4. Acute myeloid leukemia presenting as galactorrhea

    PubMed Central

    Nambiar, K. Rakul; Devi, R. Nandini

    2016-01-01

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

  5. Acute myeloid leukemia presenting as galactorrhea

    PubMed Central

    Nambiar, K. Rakul; Devi, R. Nandini

    2016-01-01

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

  6. Recognizing familial myeloid leukemia in adults

    PubMed Central

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

    2013-01-01

    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

  7. Rapid Inflammation in Mice Lacking Both SOCS1 and SOCS3 in Hematopoietic Cells.

    PubMed

    Ushiki, Takashi; Huntington, Nicholas D; Glaser, Stefan P; Kiu, Hiu; Georgiou, Angela; Zhang, Jian-Guo; Metcalf, Donald; Nicola, Nicos A; Roberts, Andrew W; Alexander, Warren S

    2016-01-01

    The Suppressors of Cytokine Signalling (SOCS) proteins are negative regulators of cytokine signalling required to prevent excess cellular responses. SOCS1 and SOCS3 are essential to prevent inflammatory disease, SOCS1 by attenuating responses to IFNγ and gamma-common (γc) cytokines, and SOCS3 via regulation of G-CSF and IL-6 signalling. SOCS1 and SOCS3 show significant sequence homology and are the only SOCS proteins to possess a KIR domain. The possibility of overlapping or redundant functions was investigated in inflammatory disease via generation of mice lacking both SOCS1 and SOCS3 in hematopoietic cells. Loss of SOCS3 significantly accelerated the pathology and inflammatory disease characteristic of SOCS1 deficiency. We propose a model in which SOCS1 and SOCS3 operate independently to control specific cytokine responses and together modulate the proliferation and activation of lymphoid and myeloid cells to prevent rapid inflammatory disease. PMID:27583437

  8. Rapid Inflammation in Mice Lacking Both SOCS1 and SOCS3 in Hematopoietic Cells

    PubMed Central

    Ushiki, Takashi; Huntington, Nicholas D.; Glaser, Stefan P.; Kiu, Hiu; Georgiou, Angela; Zhang, Jian-Guo; Nicola, Nicos A.; Roberts, Andrew W.; Alexander, Warren S.

    2016-01-01

    The Suppressors of Cytokine Signalling (SOCS) proteins are negative regulators of cytokine signalling required to prevent excess cellular responses. SOCS1 and SOCS3 are essential to prevent inflammatory disease, SOCS1 by attenuating responses to IFNγ and gamma-common (γc) cytokines, and SOCS3 via regulation of G-CSF and IL-6 signalling. SOCS1 and SOCS3 show significant sequence homology and are the only SOCS proteins to possess a KIR domain. The possibility of overlapping or redundant functions was investigated in inflammatory disease via generation of mice lacking both SOCS1 and SOCS3 in hematopoietic cells. Loss of SOCS3 significantly accelerated the pathology and inflammatory disease characteristic of SOCS1 deficiency. We propose a model in which SOCS1 and SOCS3 operate independently to control specific cytokine responses and together modulate the proliferation and activation of lymphoid and myeloid cells to prevent rapid inflammatory disease. PMID:27583437

  9. Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy.

    PubMed

    Chhabra, Akanksha; Ring, Aaron M; Weiskopf, Kipp; Schnorr, Peter John; Gordon, Sydney; Le, Alan C; Kwon, Hye-Sook; Ring, Nan Guo; Volkmer, Jens; Ho, Po Yi; Tseng, Serena; Weissman, Irving L; Shizuru, Judith A

    2016-08-10

    Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti-c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti-c-Kit conditioning to fully immunocompetent mice. The combined treatment leads to elimination of >99% of host HSCs and robust multilineage blood reconstitution after HSC transplantation. This targeted conditioning regimen that uses only biologic agents has the potential to transform the practice of HSC transplantation and enable its use in a wider spectrum of patients. PMID:27510901

  10. SNP Array in Hematopoietic Neoplasms: A Review

    PubMed Central

    Song, Jinming; Shao, Haipeng

    2015-01-01

    Cytogenetic analysis is essential for the diagnosis and prognosis of hematopoietic neoplasms in current clinical practice. Many hematopoietic malignancies are characterized by structural chromosomal abnormalities such as specific translocations, inversions, deletions and/or numerical abnormalities that can be identified by karyotype analysis or fluorescence in situ hybridization (FISH) studies. Single nucleotide polymorphism (SNP) arrays offer high-resolution identification of copy number variants (CNVs) and acquired copy-neutral loss of heterozygosity (LOH)/uniparental disomy (UPD) that are usually not identifiable by conventional cytogenetic analysis and FISH studies. As a result, SNP arrays have been increasingly applied to hematopoietic neoplasms to search for clinically-significant genetic abnormalities. A large numbers of CNVs and UPDs have been identified in a variety of hematopoietic neoplasms. CNVs detected by SNP array in some hematopoietic neoplasms are of prognostic significance. A few specific genes in the affected regions have been implicated in the pathogenesis and may be the targets for specific therapeutic agents in the future. In this review, we summarize the current findings of application of SNP arrays in a variety of hematopoietic malignancies with an emphasis on the clinically significant genetic variants. PMID:27600067

  11. SNP Array in Hematopoietic Neoplasms: A Review

    PubMed Central

    Song, Jinming; Shao, Haipeng

    2015-01-01

    Cytogenetic analysis is essential for the diagnosis and prognosis of hematopoietic neoplasms in current clinical practice. Many hematopoietic malignancies are characterized by structural chromosomal abnormalities such as specific translocations, inversions, deletions and/or numerical abnormalities that can be identified by karyotype analysis or fluorescence in situ hybridization (FISH) studies. Single nucleotide polymorphism (SNP) arrays offer high-resolution identification of copy number variants (CNVs) and acquired copy-neutral loss of heterozygosity (LOH)/uniparental disomy (UPD) that are usually not identifiable by conventional cytogenetic analysis and FISH studies. As a result, SNP arrays have been increasingly applied to hematopoietic neoplasms to search for clinically-significant genetic abnormalities. A large numbers of CNVs and UPDs have been identified in a variety of hematopoietic neoplasms. CNVs detected by SNP array in some hematopoietic neoplasms are of prognostic significance. A few specific genes in the affected regions have been implicated in the pathogenesis and may be the targets for specific therapeutic agents in the future. In this review, we summarize the current findings of application of SNP arrays in a variety of hematopoietic malignancies with an emphasis on the clinically significant genetic variants.

  12. Cell-intrinsic in vivo requirement for the E47-p21 pathway in long-term hematopoietic stem cells.

    PubMed

    Santos, Patricia M; Ding, Ying; Borghesi, Lisa

    2014-01-01

    Major regulators of long-term hematopoietic stem cell (LT-HSC) self-renewal and proliferation have been identified, but knowledge of their in vivo interaction in a linear pathway is lacking. In this study, we show a direct genetic link between the transcription factor E47 and the major cell cycle regulator p21 in controlling LT-HSC integrity in vivo under repopulation stress. Numerous studies have shown that E47 activates p21 transcription in hematopoietic subsets in vitro, and we now reveal the in vivo relevance of the E47-p21 pathway by reducing the gene dose of each factor individually (E47(het) or p21(het)) versus in tandem (E47(het)p21(het)). E47(het)p21(het) LT-HSCs and downstream short-term hematopoietic stem cells exhibit hyperproliferation and preferential susceptibility to mitotoxin compared to wild-type or single haploinsufficient controls. In serial adoptive transfers that rigorously challenge self-renewal, E47(het)p21(het) LT-HSCs dramatically and progressively decline, indicating the importance of cell-intrinsic E47-p21 in preserving LT-HSCs under stress. Transient numeric recovery of downstream short-term hematopoietic stem cells enabled the production of functionally competent myeloid but not lymphoid cells, as common lymphoid progenitors were decreased, and peripheral lymphocytes were virtually ablated. Thus, we demonstrate a developmental compartment-specific and lineage-specific requirement for the E47-p21 pathway in maintaining LT-HSCs, B cells, and T cells under hematopoietic repopulation stress in vivo.

  13. Measurement of myeloid cell immune suppressive activity.

    PubMed

    Dolcetti, Luigi; Peranzoni, Elisa; Bronte, Vincenzo

    2010-11-01

    This unit presents simple methods to assess the immunosuppressive properties of immunoregulatory cells of myeloid origin, such as myeloid-derived suppressor cells (MDSCs), both in vitro and in vivo. These methods are general and could be adapted to test the impact of different suppressive populations on T cell activation, proliferation, and cytotoxic activity; moreover they could be useful to assess the influence exerted on immune suppressive pathways by genetic modifications, chemical inhibitors, and drugs.

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

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri

    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

  15. Cutaneous myeloid sarcoma of the penile foreskin.

    PubMed

    Afrose, Ruquiya; Nebhnani, Deepa; Wadhwa, Neelam

    2015-01-01

    Myeloid sarcoma, considered to herald the onset of a blast crisis in the setting of chronic myeloproliferative neoplasm/dysplasia, typically presents during the course of the disorder. Cutaneous involvement is uncommon and lesions on genital skin are seldom seen. We present a case of a well-differentiated myeloid sarcoma in the penile foreskin in an apparently healthy 29-year-old male presenting with phimosis. The unusual composition of the inflammatory cell infiltrate, and characteristic sparing of dermal blood vessels, nerves and smooth muscle fibres led to the correct diagnosis. Absence of commonly observed changes in the circumcision skin like those of balanitis xerotica was also helpful. Detailed hematological work up revealed a previously undiagnosed chronic myeloid leukemia in chronic phase. The patient also had simultaneous priapism, another rare presentation of chronic myeloid leukemia. One year hence, the patient is in hematological remission with no evidence of extramedullary disease. Although priapism has been described as a rare presenting symptom in chronic myeloid leukemia, the present case is unique as this is the first time a cutaneous myeloid sarcoma has been documented in the penile foreskin. PMID:24913300

  16. IL-1β differently stimulates proliferation and multinucleation of distinct mouse bone marrow osteoclast precursor subsets.

    PubMed

    Cao, Yixuan; Jansen, Ineke D C; Sprangers, Sara; Stap, Jan; Leenen, Pieter J M; Everts, Vincent; de Vries, Teun J

    2016-09-01

    Osteoclasts are bone-resorbing cells and targets for treating bone diseases. Previously, we reported that distinct murine osteoclast precursor subsets, such as early blasts (CD31(hi) Ly-6C(-)), myeloid blasts (CD31(+) Ly-6C(+)), and monocytes (CD31(-) Ly-6C(hi)), respond differently to the osteoclastogenesis-inducing cytokines, macrophage colony-stimulating factor, and receptor activator for nuclear factor κB ligand. It is unknown, however, how these cell types respond to the osteoclast-stimulating inflammatory cytokine interleukin 1β. This study aims to investigate the effect of interleukin 1β on osteoclastogenesis derived from different mouse bone marrow precursors. Early blasts, myeloid blasts, and monocytes were sorted from mouse bone marrow cells using flow cytometry. Cells were cultured on plastic or on bone slices in the presence of macrophage colony-stimulating factor and receptor activator for nuclear factor κB ligand, without or with interleukin 1β (0.1-10 ng/ml). We found that interleukin 1β stimulated multinucleation and bone resorption of osteoclasts derived from the 3 precursors at different rates. The most large osteoclasts (>20 nuclei) and highest level of bone resorption (16.3%) was by myeloid blast-derived osteoclasts. Interleukin 1β particularly accelerated proliferation of early blasts and the most small osteoclasts (3-5 nuclei) formed on plastic. Life span varied among osteoclasts derived from different precursors: large osteoclasts (>2400 µm(2)) formed most rapidly (75 h) from myeloid blasts but had a short life span (30 h). Monocytes needed the longest time (95 h) for the generation of such large osteoclasts, but these cells had a longer life span (50 h). Our results indicate that the different bone marrow osteoclast precursors are differently stimulated by interleukin 1β with respect to proliferation, multinucleation, life span, and bone resorption. PMID:26957213

  17. Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality

    PubMed Central

    Alvarez, Silvia; Díaz, Marcos; Flach, Johanna; Rodriguez-Acebes, Sara; López-Contreras, Andrés J.; Martínez, Dolores; Cañamero, Marta; Fernández-Capetillo, Oscar; Isern, Joan; Passegué, Emmanuelle; Méndez, Juan

    2015-01-01

    Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These ‘dormant' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our results indicate that hematopoietic progenitors are particularly sensitive to replication stress, and full origin licensing ensures their correct differentiation and functionality. PMID:26456157

  18. Control of Both Myeloid Cell Infiltration and Angiogenesis by CCR1 Promotes Liver Cancer Metastasis Development in Mice12

    PubMed Central

    Rodero, Mathieu Paul; Auvynet, Constance; Poupel, Lucie; Combadière, Behazine; Combadière, Christophe

    2013-01-01

    Expression of the CC chemokine receptor 1 (CCR1) by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM) and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo) in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy. PMID:23730212

  19. Green tea polyphenol epigallocatechin-O-gallate induces cell death by acid sphingomyelinase activation in chronic myeloid leukemia cells

    PubMed Central

    HUANG, YUHUI; KUMAZOE, MOTOFUMI; BAE, JAEHOON; YAMADA, SHUHEI; TAKAI, MIKA; HIDAKA, SHIORI; YAMASHITA, SHUYA; KIM, YOONHEE; WON, YEONGSEON; MURATA, MOTOKI; TSUKAMOTO, SHUNTARO; TACHIBANA, HIROFUMI

    2015-01-01

    An epidemiological study showed that green tea consumption is associated with a reduced risk of hematopoietic malignancy. The major green tea polyphenol epigallocatechin-3-O-gallate (EGCG) is reported to have anticancer effects. Chronic myeloid leukemia (CML) is a major hematopoietic malignancy characterized by expansion of myeloid cells. In the present study, we showed EGCG-induced acid sphingomyelinase (ASM) activation and lipid raft clustering in CML cells. The ASM inhibitor desipramine significantly reduced EGCG-induced cell death. Protein kinase Cδ is a well-known kinase that plays an important role in ASM activation. We observed EGCG-induced phos-phorylation of protein kinase Cδ at Ser664. Importantly, EGCG-induced ASM activation was significantly reduced by pretreatment of CML cells with the soluble guanylate cyclase inhibitor NS2028, suggesting that EGCG induced ASM activation through the cyclic guanosine monophosphate (cGMP)-dependent pathway. Indeed, pharmacological inhibition of a cGMP-negative regulator enhanced the anti-CML effect of EGCG. These results indicate that EGCG-induced cell death via the cGMP/ASM pathway in CML cells. PMID:26135316

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

    SciTech Connect

    Perkins, S.; Fleischman, R.A.

    1988-04-01

    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 chimeras, and (b) fetal chimeras, produced by placental injection of bone marrow into genetically anemic Wx/Wv fetuses, a technique that essentially precludes engraftment of nonhematopoietic cells. Using two-color indirect immunofluorescence, the stromal cells in long-term bone marrow culture derived from these chimeras were analyzed for donor or host origin by strain-specific H-2 antigens, and for cell lineage by a variety of other specific markers. 75-95% of the stromal cells were shown to be hematopoietic cells of the monocyte-macrophage lineage, based upon donor origin, phagocytosis, and expression of specific hematopoietic surface antigens. The remaining 5-25% of the stromal cells were exclusively host in origin. Apart from occasional fat cells, these cells uniformly expressed collagen type IV, laminin, and a surface antigen associated with endothelial cells. Since these endothelial-like cells are not transplantable into radiation or fetal chimeras, they are not derived from hematopoietic stem cells. The contrast between our findings and human studies suggests either unexpected species differences in the origin of stromal lineages or limitations in the previous methodology used to detect nonhematopoietic stromal cells.

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

    PubMed

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

    2014-09-01

    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

  2. Invasive fungal infection of the central nervous system in a patient with acute myeloid leukaemia

    PubMed Central

    Janik-Moszant, Anna; Matyl, Aleksander; Rurańska, Iwona; Machowska-Majchrzak, Agnieszka; Kluczewska, Ewa; Szczepański, Tomasz

    2012-01-01

    Summary Background: Although the new intensive chemotherapeutic programs introduced recently into hematooncological therapies have led to a higher number of recoveries, persistent neutropenia favours the spread of severe infections, frequently fungal infections. Systemic fungal infections in patients treated for proliferative diseases of the hematopoietic system are characterised by a severe, progressing course and high morbidity. Case Reports: We present a case report that demonstrates the diagnostic problem of lesions in the central nervous system which developed following the fourth block of chemotherapy in an eight-year-old boy treated for acute myeloid leukaemia. The risk factors, high values of the inflammatory parameters and imaging results enabled us to diagnose a fungal infection of the central nervous system. Results: A fast improvement in the clinical condition of the patient after the applied antifungal therapy and the regression of lesions in the central nervous system shown in the imaging studies confirmed our final diagnosis. PMID:22802867

  3. Global proteomics dataset of miR-126 overexpression in acute myeloid leukemia.

    PubMed

    Schoof, Erwin M; Lechman, Eric R; Dick, John E

    2016-12-01

    A deep proteomics analysis was conducted on a primary acute myeloid leukemia culture system to identify potential protein targets regulated by miR-126. Leukemia cells were transduced either with an empty control lentivirus or one containing the sequence for miR-126, and resulting cells were analyzed using ultra-high performance liquid chromatography (UHPLC) coupled with high resolution mass spectrometry. The mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PRIDE: PXD001994. The proteomics data and statistical analysis described in this article is associated with a research article, "miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells" (Lechman et al., 2016) [1], and serves as a resource for researchers working in the field of microRNAs and their regulation of protein levels. PMID:27656662

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

    PubMed Central

    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

    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

  5. Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism.

    PubMed

    Li, Jing; Zhang, Jun; Tang, Minghui; Xin, Junping; Xu, Yan; Volk, Andrew; Hao, Caiqin; Hu, Chenglong; Sun, Jiewen; Wei, Wei; Cao, Quichan; Breslin, Peter; Zhang, Jiwang

    2016-08-01

    The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs, and multipotent progenitors (MPPs); however, the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of overexpression of p-Pten and nonphosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs. We found that overexpression of non-p-Pten enhances the LT-HRC of HSCs, whereas overexpression of p-Pten promotes myeloid differentiation and compromises the LT-HRC of HSCs. Such phosphorylation-regulated Pten functioning is mediated by repressing the cell:cell contact-induced activation of Fak/p38 signaling independent of Pten's lipid phosphatase activity because both p-Pten and non-p-Pten have comparable activity in repressing PI3K/Akt signaling. Our studies suggest that, in addition to repressing PI3K/Akt/mTor signaling, non-p-Pten maintains HSCs in bone marrow niches via a cell-contact inhibitory mechanism by inhibiting Fak/p38 signaling-mediated proliferation and differentiation. In contrast, p-Pten promotes the proliferation and differentiation of HSCs by enhancing the cell contact-dependent activation of Src/Fak/p38 signaling. Stem Cells 2016;34:2130-2144.

  6. Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism.

    PubMed

    Li, Jing; Zhang, Jun; Tang, Minghui; Xin, Junping; Xu, Yan; Volk, Andrew; Hao, Caiqin; Hu, Chenglong; Sun, Jiewen; Wei, Wei; Cao, Quichan; Breslin, Peter; Zhang, Jiwang

    2016-08-01

    The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs, and multipotent progenitors (MPPs); however, the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of overexpression of p-Pten and nonphosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs. We found that overexpression of non-p-Pten enhances the LT-HRC of HSCs, whereas overexpression of p-Pten promotes myeloid differentiation and compromises the LT-HRC of HSCs. Such phosphorylation-regulated Pten functioning is mediated by repressing the cell:cell contact-induced activation of Fak/p38 signaling independent of Pten's lipid phosphatase activity because both p-Pten and non-p-Pten have comparable activity in repressing PI3K/Akt signaling. Our studies suggest that, in addition to repressing PI3K/Akt/mTor signaling, non-p-Pten maintains HSCs in bone marrow niches via a cell-contact inhibitory mechanism by inhibiting Fak/p38 signaling-mediated proliferation and differentiation. In contrast, p-Pten promotes the proliferation and differentiation of HSCs by enhancing the cell contact-dependent activation of Src/Fak/p38 signaling. Stem Cells 2016;34:2130-2144. PMID:27096933

  7. Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-09-29

    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

  8. E2F4 modulates differentiation and gene expression in hematopoietic progenitor cells during commitment to the lymphoid lineage.

    PubMed

    Enos, Megan E; Bancos, Simona A; Bushnell, Timothy; Crispe, Ian N

    2008-03-15

    The E2F4 protein is involved in gene repression and cell cycle exit, and also has poorly understood effects in differentiation. We analyzed the impact of E2F4 deficiency on early steps in mouse hematopoietic development, and found defects in early hematopoietic progenitor cells that were propagated through common lymphoid precursors to the B and T lineages. In contrast, the defects in erythromyeloid precursor cells were self-correcting over time. This suggests that E2F4 is important in early stages of commitment to the lymphoid lineage. The E2F4-deficient progenitor cells showed reduced expression of several key lymphoid-lineage genes, and overexpression of two erythromyeloid lineage genes. However, we did not detect effects on cell proliferation. These findings emphasize the significance of E2F4 in controlling gene expression and cell fate.

  9. Decitabine, Cytarabine, and Daunorubicin Hydrochloride in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-20

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  10. Earthquakes: hydrogeochemical precursors

    USGS Publications Warehouse

    Ingebritsen, Steven E.; Manga, Michael

    2014-01-01

    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.

  11. Myeloid sarcomas of the head and neck in pediatric patients with myeloid leukemia.

    PubMed

    Cuthbertson, David W; Punia, Jyotinder Nain; Owczarzak, Vicki L

    2016-09-01

    Myeloid sarcoma is a rare extramedullary tumor composed of malignant myeloid cells that occur in the presence of myeloid leukemia. We report a case series of pediatric head and neck myeloid sarcomas representative of the epidemiology, symptomatology, laboratorial correlations, prognoses, and treatment of extramedullary leukemia. Presented are 3 cases involving patients ranging from 17 months to 11 years of age. Two patients were successfully treated with chemotherapy, and in the third patient, a large lytic lesion was treated palliatively with proton beam therapy. Knowledge and recognition of myeloid sarcomas is important as they can be locally invasive, and they may also be used as a diagnostic tool or a prognostic indicator for leukemia. PMID:27657319

  12. Economics of hematopoietic cell transplantation.

    PubMed

    Khera, Nandita; Zeliadt, Steven B; Lee, Stephanie J

    2012-08-23

    Given the rapidly rising healthcare costs, it is important to understand the economic costs of hematopoietic cell transplantation (HCT), a procedure that is being used more frequently in the treatment of various hematologic disorders. Studies have reported a wide range of costs for HCT, from $36 000 to $88 000 (USD) for a single autologous transplantation for the initial hospitalization, to $200 000 (USD) or more for a myeloablative allogeneic procedure involving an unrelated donor. Common posttransplantation complications, such as infections and GVHD, have been shown to be significant cost drivers. Comparisons across studies are limited by differences in patient populations, cost ascertainment methods, and length of follow-up. This article summarizes the current state of knowledge about costs and cost-effectiveness of HCT, highlighting the challenges in conducting these studies and identifying important areas for future research. We discuss the need for more value-based assessments of HCT using high-quality approaches to measuring costs and outcomes so that potential future efforts to contain costs are well informed and appropriate.

  13. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors

    PubMed Central

    Riddell, Jonah; Gazit, Roi; Garrison, Brian S.; Guo, Guoji; Saadatpour, Assieh; Mandal, Pankaj K.; Ebina, Wataru; Volchkov, Pavel; Yuan, Guo-Cheng; Orkin, Stuart H.; Rossi, Derrick J.

    2014-01-01

    Hematopoietic stem cells (HSCs) sustain blood formation throughout life and are the functional units of bone marrow transplantation. We show that transient expression of six transcription factors RUNX1T1, HLF, LMO2, PRDM5, PBX1, and ZFP37 imparts multi-lineage transplantation potential onto otherwise committed lymphoid and myeloid progenitors, and myeloid effector cells. Inclusion of MYC-N and MEIS1, and use of polycistronic viruses increase reprogramming efficacy. The reprogrammed cells, designated induced-HSCs (iHSCs), possess clonal multi-lineage differentiation potential, reconstitute stem/progenitor compartments, and are serially transplantable. Single-cell analysis revealed that iHSCs derived under optimal conditions exhibit a gene expression profile that is highly similar to endogenous HSCs. These findings demonstrate that expression of a set of defined factors is sufficient to activate the gene networks governing HSC functional identity in committed blood cells. Our results raise the prospect that blood cell reprogramming may be a strategy for derivation of transplantable stem cells for clinical application. PMID:24766805

  14. Modulation of homeobox gene expression alters the phenotype of human hematopoietic cell lines.

    PubMed

    Shen, W F; Detmer, K; Mathews, C H; Hack, F M; Morgan, D A; Largman, C; Lawrence, H J

    1992-03-01

    We have previously reported that certain genes of the HOX2 cluster of homeobox genes on human chromosome 17 are specifically expressed in human leukemic cell lines with erythroid potential, suggesting that these genes are involved in hematopoietic differentiation. We now show that the expression of the HOX 2.2 gene decreases during erythropoietin-induced differentiation of the erythroid cell line MB02. In order to study the role of the HOX 2.2 homeobox gene in hematopoiesis, vectors producing sense or antisense transcripts were introduced into K562 and HEL cells, pluripotent lines with erythroid and myeloid features. Overexpression of HOX 2.2 is associated with loss of erythroid features in both lines and an increase in certain myelomonocytic markers in K562 cells. Expression of antisense HOX 2.2 is associated with an increase in erythroid features in HEL cells and a mild decrease in myeloid characteristics in K562 cells. Overexpression of the adjacent HOX 2.1 gene in K562 cells does not produce similar phenotype changes. These data demonstrate that modulation of a specific HOX 2 homeobox gene can change the phenotype of somatic cells and suggest that certain HOX 2 genes play a role in blood cell differentiation.

  15. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells

    PubMed Central

    Olthof, Sandra; Schreuder, Jaring; Ritsema, Martha

    2011-01-01

    Hematopoietic stem cell (HSC) populations change with aging, but the extent to which this is caused by qualitative versus quantitative alterations in HSC subtypes is unclear. Using clonal assays, in this study we show that the aging HSC compartment undergoes both quantitative and qualitative changes. We observed a variable increase of HSC pool size with age, accompanied by the accumulation of predominantly myeloid-biased HSCs that regenerate substantially fewer mature progeny than young myeloid-biased HSCs and exhibit reduced self-renewal activity as measured by long-term secondary transplantation. Old HSCs had a twofold reduction in marrow-homing efficiency and a similar decrease in functional frequency as measured using long-term transplantation assays. Similarly, old HSCs had a twofold reduced seeding efficiency and a significantly delayed proliferative response compared with young HSCs in long-term stromal cell co-cultures but were indistinguishable in suspension cultures. We show that these functional defects are characteristics of most or all old HSCs and are not indicative of a nonfunctional subset of cells that express HSC markers. Furthermore, we demonstrate that cells with functional properties of old HSCs can be generated directly from young HSCs by extended serial transplantation, which is consistent with the possibility that they arise through a process of cellular aging. PMID:22110168

  16. DNMT3A and TET2 in the Pre-Leukemic Phase of Hematopoietic Disorders.

    PubMed

    Sato, Hanae; Wheat, Justin C; Steidl, Ulrich; Ito, Keisuke

    2016-01-01

    In recent years, advances in next-generation sequencing (NGS) technology have provided the opportunity to detect putative genetic drivers of disease, particularly cancers, with very high sensitivity. This knowledge has substantially improved our understanding of tumor pathogenesis. In hematological malignancies such as acute myeloid leukemia and myelodysplastic syndromes, pioneering work combining multi-parameter flow cytometry and targeted resequencing in leukemia have clearly shown that different classes of mutations appear to be acquired in particular sequences along the hematopoietic differentiation hierarchy. Moreover, as these mutations can be found in "normal" cells recovered during remission and can be detected at relapse, there is strong evidence for the existence of "pre-leukemic" stem cells (pre-LSC). These cells, while phenotypically normal by flow cytometry, morphology, and functional studies, are speculated to be molecularly poised to transform owing to a limited number of predisposing mutations. Identifying these "pre-leukemic" mutations and how they propagate a pre-malignant state has important implications for understanding the etiology of these disorders and for the development of novel therapeutics. NGS studies have found a substantial enrichment for mutations in epigenetic/chromatin remodeling regulators in pre-LSC, and elegant genetic models have confirmed that these mutations can predispose to a variety of hematological malignancies. In this review, we will discuss the current understanding of pre-leukemic biology in myeloid malignancies, and how mutations in two key epigenetic regulators, DNMT3A and TET2, may contribute to disease pathogenesis. PMID:27597933

  17. Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells.

    PubMed

    Poh, Ashleigh R; O'Donoghue, Robert J J; Ernst, Matthias

    2015-06-30

    The hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and bona fide oncogenic tyrosine kinases, excessive HCK activation can also reduce drug efficacy and contribute to chemo-resistance, while genetic ablation of HCK results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of cancer cells, and indirectly curb the source of tumor-promoting changes in the tumor microenvironment. PMID:26087188

  18. DNMT3A and TET2 in the Pre-Leukemic Phase of Hematopoietic Disorders

    PubMed Central

    Sato, Hanae; Wheat, Justin C.; Steidl, Ulrich; Ito, Keisuke

    2016-01-01

    In recent years, advances in next-generation sequencing (NGS) technology have provided the opportunity to detect putative genetic drivers of disease, particularly cancers, with very high sensitivity. This knowledge has substantially improved our understanding of tumor pathogenesis. In hematological malignancies such as acute myeloid leukemia and myelodysplastic syndromes, pioneering work combining multi-parameter flow cytometry and targeted resequencing in leukemia have clearly shown that different classes of mutations appear to be acquired in particular sequences along the hematopoietic differentiation hierarchy. Moreover, as these mutations can be found in “normal” cells recovered during remission and can be detected at relapse, there is strong evidence for the existence of “pre-leukemic” stem cells (pre-LSC). These cells, while phenotypically normal by flow cytometry, morphology, and functional studies, are speculated to be molecularly poised to transform owing to a limited number of predisposing mutations. Identifying these “pre-leukemic” mutations and how they propagate a pre-malignant state has important implications for understanding the etiology of these disorders and for the development of novel therapeutics. NGS studies have found a substantial enrichment for mutations in epigenetic/chromatin remodeling regulators in pre-LSC, and elegant genetic models have confirmed that these mutations can predispose to a variety of hematological malignancies. In this review, we will discuss the current understanding of pre-leukemic biology in myeloid malignancies, and how mutations in two key epigenetic regulators, DNMT3A and TET2, may contribute to disease pathogenesis.

  19. Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells.

    PubMed

    Poh, Ashleigh R; O'Donoghue, Robert J J; Ernst, Matthias

    2015-06-30

    The hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and bona fide oncogenic tyrosine kinases, excessive HCK activation can also reduce drug efficacy and contribute to chemo-resistance, while genetic ablation of HCK results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of cancer cells, and indirectly curb the source of tumor-promoting changes in the tumor microenvironment.

  20. DNMT3A and TET2 in the Pre-Leukemic Phase of Hematopoietic Disorders

    PubMed Central

    Sato, Hanae; Wheat, Justin C.; Steidl, Ulrich; Ito, Keisuke

    2016-01-01

    In recent years, advances in next-generation sequencing (NGS) technology have provided the opportunity to detect putative genetic drivers of disease, particularly cancers, with very high sensitivity. This knowledge has substantially improved our understanding of tumor pathogenesis. In hematological malignancies such as acute myeloid leukemia and myelodysplastic syndromes, pioneering work combining multi-parameter flow cytometry and targeted resequencing in leukemia have clearly shown that different classes of mutations appear to be acquired in particular sequences along the hematopoietic differentiation hierarchy. Moreover, as these mutations can be found in “normal” cells recovered during remission and can be detected at relapse, there is strong evidence for the existence of “pre-leukemic” stem cells (pre-LSC). These cells, while phenotypically normal by flow cytometry, morphology, and functional studies, are speculated to be molecularly poised to transform owing to a limited number of predisposing mutations. Identifying these “pre-leukemic” mutations and how they propagate a pre-malignant state has important implications for understanding the etiology of these disorders and for the development of novel therapeutics. NGS studies have found a substantial enrichment for mutations in epigenetic/chromatin remodeling regulators in pre-LSC, and elegant genetic models have confirmed that these mutations can predispose to a variety of hematological malignancies. In this review, we will discuss the current understanding of pre-leukemic biology in myeloid malignancies, and how mutations in two key epigenetic regulators, DNMT3A and TET2, may contribute to disease pathogenesis. PMID:27597933

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

    PubMed Central

    Zhang, Liping; Wang, Sa A

    2014-01-01

    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

  2. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors.

    PubMed

    Riddell, Jonah; Gazit, Roi; Garrison, Brian S; Guo, Guoji; Saadatpour, Assieh; Mandal, Pankaj K; Ebina, Wataru; Volchkov, Pavel; Yuan, Guo-Cheng; Orkin, Stuart H; Rossi, Derrick J

    2014-04-24

    Hematopoietic stem cells (HSCs) sustain blood formation throughout life and are the functional units of bone marrow transplantation. We show that transient expression of six transcription factors Run1t1, Hlf, Lmo2, Prdm5, Pbx1, and Zfp37 imparts multilineage transplantation potential onto otherwise committed lymphoid and myeloid progenitors and myeloid effector cells. Inclusion of Mycn and Meis1 and use of polycistronic viruses increase reprogramming efficacy. The reprogrammed cells, designated induced-HSCs (iHSCs), possess clonal multilineage differentiation potential, reconstitute stem/progenitor compartments, and are serially transplantable. Single-cell analysis revealed that iHSCs derived under optimal conditions exhibit a gene expression profile that is highly similar to endogenous HSCs. These findings demonstrate that expression of a set of defined factors is sufficient to activate the gene networks governing HSC functional identity in committed blood cells. Our results raise the prospect that blood cell reprogramming may be a strategy for derivation of transplantable stem cells for clinical application.

  3. Comparative Analysis of the Hematopoietic Progenitor Cells from Placenta, Cord Blood, and Fetal Liver, Based on Their Immunophenotype

    PubMed Central

    Kuchma, Maria D.; Kyryk, Vitaliy M.; Svitina, Hanna M.; Shablii, Yulia M.; Lukash, Lubov L.; Lobyntseva, Galina S.; Shablii, Volodymyr A.

    2015-01-01

    We have investigated the characteristics of human hematopoietic progenitor cells (HPCs) with the CD34+CD45lowSSClow phenotype from full-term placental tissue (FTPT) as compared to cord blood (CB) and fetal liver (FL) cells. We demonstrated the presence of cell subpopulations at various stages of the differentiation with such immunophenotypes as CD34+/lowCD45low/−, CD34++CD45low/−, CD34+++CD45low/−, CD34+/lowCD45hi, and CD34++CD45hi in both first trimester placental tissue (FiTPT) and FTPT which implies their higher phenotypic heterogeneity compared to CB. HPCs of the FTPT origin expressed the CD90 antigen at a higher level compared to its expression by the CB HPCs and the CD133 antigen expression being at the same level in both cases. The HPCs compartment of FTPT versus CB contained higher number of myeloid and erythroid committed cells but lower number of myeloid and lymphoid ones compared to FL HPCs. HPCs of the FTPT and CB origin possess similar potentials for the multilineage differentiation in vitro and similar ratios of myeloid and erythroid progenitors among the committed cells. This observation suggests that the active hematopoiesis occurs in the FTPT. We obtained viable HPCs from cryopreserved placental tissue fragments allowing us to develop procedures for banking and testing of placenta-derived HPCs for clinical use. PMID:26347038

  4. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases.

    PubMed Central

    Le Beau, M M; Espinosa, R; Neuman, W L; Stock, W; Roulston, D; Larson, R A; Keinanen, M; Westbrook, C A

    1993-01-01

    Loss of a whole chromosome 5 or a deletion of its long arm (5q) is a recurring abnormality in malignant myeloid neoplasms. To determine the location of genes on 5q that may be involved in leukemogenesis, we examined the deleted chromosome 5 homologs in a series of 135 patients with malignant myeloid diseases. By comparing the breakpoints, we identified a small segment of 5q, consisting of band 5q31, that was deleted in each patient. This segment has been termed the critical region. Distal 5q contains a number of genes encoding growth factors, hormone receptors, and proteins involved in signal transduction or transcriptional regulation. These include several genes that are good candidates for a tumor-suppressor gene, as well as the genes encoding five hematopoietic growth factors (CSF2, IL3, IL4, IL5, and IL9). By using fluorescence in situ hybridization, we have refined the localization of these genes to 5q31.1 and have determined the order of these genes and of other markers within 5q31. By hybridizing probes to metaphase cells with overlapping deletions involving 5q31, we have narrowed the critical region to a small segment of 5q31 containing the EGR1 gene. The five hematopoietic growth factor genes and seven other genes are excluded from this region. The EGR1 gene was not deleted in nine other patients with acute myeloid leukemia who did not have abnormalities of chromosome 5. By physical mapping, the minimum size of the critical region was estimated to be 2.8 megabases. This cytogenetic map of 5q31, together with the molecular characterization of the critical region, will facilitate the identification of a putative tumor-suppressor gene in this band. PMID:8516290

  5. Absence of WASp Enhances Hematopoietic and Megakaryocytic Differentiation in a Human Embryonic Stem Cell Model

    PubMed Central

    Toscano, Miguel G; Muñoz, Pilar; Sánchez-Gilabert, Almudena; Cobo, Marién; Benabdellah, Karim; Anderson, Per; Ramos-Mejía, Verónica; Real, Pedro J; Neth, Olaf; Molinos-Quintana, Agueda; Gregory, Philip D; Holmes, Michael C; Martin, Francisco

    2016-01-01

    The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene and characterized by severe thrombocytopenia. Although the role of WASp in terminally differentiated lymphocytes and myeloid cells is well characterized, its role in early hematopoietic differentiation and in platelets (Plts) biology is poorly understood. In the present manuscript, we have used zinc finger nucleases targeted to the WAS locus for the development of two isogenic WAS knockout (WASKO) human embryonic stem cell lines (hESCs). Upon hematopoietic differentiation, hESCs-WASKO generated increased ratios of CD34+CD45+ progenitors with altered responses to stem cell factor compared to hESCs-WT. When differentiated toward the megakaryocytic linage, hESCs-WASKO produced increased numbers of CD34+CD41+ progenitors, megakaryocytes (MKs), and Plts. hESCs-WASKO-derived MKs and Plts showed altered phenotype as well as defective responses to agonist, mimicking WAS patients MKs and Plts defects. Interestingly, the defects were more evident in WASp-deficient MKs than in WASp-deficient Plts. Importantly, ectopic WAS expression using lentiviral vectors restored normal Plts development and MKs responses. These data validate the AND-1_WASKO cell lines as a human cellular model for basic research and for preclinical studies for WAS. PMID:26502776

  6. Angiogenin Promotes Hematopoietic Regeneration by Dichotomously Regulating Quiescence of Stem and Progenitor Cells.

    PubMed

    Goncalves, Kevin A; Silberstein, Lev; Li, Shuping; Severe, Nicolas; Hu, Miaofen G; Yang, Hailing; Scadden, David T; Hu, Guo-Fu

    2016-08-11

    Regulation of stem and progenitor cell populations is critical in the development, maintenance, and regeneration of tissues. Here, we define a novel mechanism by which a niche-secreted RNase, angiogenin (ANG), distinctively alters the functional characteristics of primitive hematopoietic stem/progenitor cells (HSPCs) compared with lineage-committed myeloid-restricted progenitor (MyePro) cells. Specifically, ANG reduces the proliferative capacity of HSPC while simultaneously increasing proliferation of MyePro cells. Mechanistically, ANG induces cell-type-specific RNA-processing events: tRNA-derived stress-induced small RNA (tiRNA) generation in HSPCs and rRNA induction in MyePro cells, leading to respective reduction and increase in protein synthesis. Recombinant ANG protein improves survival of irradiated animals and enhances hematopoietic regeneration of mouse and human HSPCs in transplantation. Thus, ANG plays a non-cell-autonomous role in regulation of hematopoiesis by simultaneously preserving HSPC stemness and promoting MyePro proliferation. These cell-type-specific functions of ANG suggest considerable therapeutic potential. PMID:27518564

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

    PubMed Central

    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

    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

  8. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient. PMID:25674158

  9. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals.

    PubMed

    Yoder, Mervin C; Mead, Laura E; Prater, Daniel; Krier, Theresa R; Mroueh, Karim N; Li, Fang; Krasich, Rachel; Temm, Constance J; Prchal, Josef T; Ingram, David A

    2007-03-01

    The limited vessel-forming capacity of infused endothelial progenitor cells (EPCs) into patients with cardiovascular dysfunction may be related to a misunderstanding of the biologic potential of the cells. EPCs are generally identified by cell surface antigen expression or counting in a commercially available kit that identifies "endothelial cell colony-forming units" (CFU-ECs). However, the origin, proliferative potential, and differentiation capacity of CFU-ECs is controversial. In contrast, other EPCs with blood vessel-forming ability, termed endothelial colony-forming cells (ECFCs), have been isolated from human peripheral blood. We compared the function of CFU-ECs and ECFCs and determined that CFU-ECs are derived from the hematopoietic system using progenitor assays, and analysis of donor cells from polycythemia vera patients harboring a Janus kinase 2 V617F mutation in hematopoietic stem cell clones. Further, CFU-ECs possess myeloid progenitor cell activity, differentiate into phagocytic macrophages, and fail to form perfused vessels in vivo. In contrast, ECFCs are clonally distinct from CFU-ECs, display robust proliferative potential, and form perfused vessels in vivo. Thus, these studies establish that CFU-ECs are not EPCs and the role of these cells in angiogenesis must be re-examined prior to further clinical trials, whereas ECFCs may serve as a potential therapy for vascular regeneration. PMID:17053059

  10. Incomplete Splicing, Cell Division Defects and Hematopoietic Blockage in dhx8 Mutant Zebrafish

    PubMed Central

    English, Milton A.; Lei, Lin; Blake, Trevor; Wincovitch, Stephen M.; Sood, Raman; Azuma, Mizuki; Hickstein, Dennis; Liu, P. Paul

    2012-01-01

    Vertebrate hematopoiesis is a complex developmental process that is controlled by genes in diverse pathways. To identify novel genes involved in early hematopoiesis, we conducted an ENU (N-ethyl-N-nitrosourea) mutagenesis screen in zebrafish. The mummy (mmy) line was investigated because of its multiple hematopoietic defects. Homozygous mmy embryos lacked circulating blood cells types and were dead by 30 hours post-fertilization (hpf). The mmy mutants did not express myeloid markers and had significantly decreased expression of progenitor and erythroid markers in primitive hematopoiesis. Through positional cloning, we identified a truncation mutation in dhx8 in the mmy fish. dhx8 is the zebrafish ortholog of the yeast splicing factor prp22, which is a DEAH-box RNA helicase. Mmy mutants had splicing defects in many genes, including several hematopoietic genes. Mmy embryos also showed cell division defects as characterized by disorganized mitotic spindles and formation of multiple spindle poles in mitotic cells. These cell division defects were confirmed by DHX8 knockdown in HeLa cells. Together, our results confirm that dhx8 is involved in mRNA splicing and suggest that it is also important for cell division during mitosis. This is the first vertebrate model for dhx8, whose function is essential for primitive hematopoiesis in developing embryos. PMID:22411201

  11. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient.

  12. Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic/Erythroid Bias

    PubMed Central

    Rundberg Nilsson, Alexandra; Soneji, Shamit; Adolfsson, Sofia; Bryder, David; Pronk, Cornelis Jan

    2016-01-01

    Aging within the human hematopoietic system associates with various deficiencies and disease states, including anemia, myeloid neoplasms and reduced adaptive immune responses. Similar phenotypes are observed in mice and have been linked to alterations arising at the hematopoietic stem cell (HSC) level. Such an association is, however, less established in human hematopoiesis and prompted us here to detail characteristics of the most primitive human hematopoietic compartments throughout ontogeny. In addition, we also attempted to interrogate similarities between aging human and murine hematopoiesis. Coupled to the transition from human cord blood (CB) to young and aged bone marrow (BM), we observed a gradual increase in frequency of candidate HSCs. This was accompanied by functional impairments, including decreased lymphoid output and reduced proliferative potential. Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs. These findings were paralleled in mice. Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system. PMID:27368054

  13. Zebrafish embryonic stromal trunk (ZEST) cells support hematopoietic stem and progenitor cell (HSPC) proliferation, survival, and differentiation.

    PubMed

    Campbell, Clyde; Su, Tammy; Lau, Ryan P; Shah, Arpit; Laurie, Payton C; Avalos, Brenda; Aggio, Julian; Harris, Elena; Traver, David; Stachura, David L

    2015-12-01

    Forward genetic screens in zebrafish have been used to identify genes essential for the generation of primitive blood and the emergence of hematopoietic stem cells (HSCs), but have not elucidated the genes essential for hematopoietic stem and progenitor cell (HSPC) proliferation and differentiation because of the lack of methodologies to functionally assess these processes. We previously described techniques used to test the developmental potential of HSPCs by culturing them on zebrafish kidney stromal (ZKS) cells, derived from the main site of hematopoiesis in the adult teleost. Here we describe an additional primary stromal cell line we refer to as zebrafish embryonic stromal trunk (ZEST) cells, derived from tissue surrounding the embryonic dorsal aorta, the site of HSC emergence in developing fish. ZEST cells encouraged HSPC differentiation toward the myeloid, lymphoid, and erythroid pathways when assessed by morphologic and quantitative reverse transcription polymerase chain reaction analyses. Additionally, ZEST cells significantly expanded the number of cultured HSPCs in vitro, indicating that these stromal cells are supportive of both HSPC proliferation and multilineage differentiation. Examination of ZEST cells indicates that they express numerous cytokines and Notch ligands and possess endothelial characteristics. Further characterization of ZEST cells should prove to be invaluable in understanding the complex signaling cascades instigated by the embryonic hematopoietic niche required to expand and differentiate HSPCs. Elucidating these processes and identifying possibilities for the modulation of these molecular pathways should allow the in vitro expansion of HSPCs for a multitude of therapeutic uses.

  14. 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 ... benefit from current treatments. Researchers are studying many new chemo drugs for use in AML, including: Sapacitabine, ...

  15. What's New in Chronic Myeloid Leukemia Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for chronic myeloid leukemia What`s new in chronic myeloid leukemia research and treatment? Studies ... such as cyclosporine or hydroxychloroquine, with a TKI. New drugs for CML Because researchers now know the ...

  16. Genetics Home Reference: cytogenetically normal acute myeloid leukemia

    MedlinePlus

    ... one form of a cancer of the blood-forming tissue (bone marrow) called acute myeloid leukemia. In ... 1 link) PubMed Sources for This Page Döhner H. Implication of the molecular characterization of acute myeloid ...

  17. What Are the Risk Factors for Chronic Myeloid Leukemia?

    MedlinePlus

    ... of an atomic bomb blast or nuclear reactor accident) increases the risk of getting CML Age : The ... Myeloid (CML)? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treating Leukemia - Chronic Myeloid (CML) ...

  18. [Transfection efficiency of adenoviral vector AD5/F35 to malignant hematopoietic cells of different origins].

    PubMed

    Wabg, Kai; Peng, Jian-Qinag; Yuan, Zhen-Hua; Wu, Xiao-Bin

    2006-06-01

    This study was aimed to investigate the transfection efficiency of adenoviral vector AD5/F35 to hematopoietic malignant cells lines of various origins and AD5/F35 cytotoxicity. The hematologic malignant cell lines of various origins were transfected by AD5/F35-EGFP at different multiple of infection (MOI) and AD5-EGFP was used as control; the proportion of fluorescence positive cells was detected by flow cytometry; the killing effect of virus on infective target cells was assayed by MTT and observed by fluorescence microscopy. The results showed that the transfection efficiency of AD5/F35 vector to cell line of myeloid origin was > 99% at MOI = 30, the transfective efficiency of AD5 vector was 26.4% at MOI = 1,000; the transfection efficiency of AD5/F35 vector and AD5 vector to cell line of B cell origin were 11.7% and 5.7%, respectively, at MOI = 1,000. AD5/F35 and AD5 vectors could not effectively transfect cells of T cell origin, no fluorescence positive cells were detected at MOI = 1,000; no significant killing effect of AD5/F35 vector on infective target cells was observed at MOI = 1,000. It is concluded that AD5/F35 vector infection has definite selectivity to hematologic malignant cells of various origin, the infection ability of AD5/F35 vector to cells of myeloid origin is stronger than that to cells of B cell origin, the cytotoxicity of AD5/F35 vector to infective target cells is small. The AD5/F35 vector is preferable to AD5 vector in respect of infection ability and offers good prospects of application in gene therapy for myeloid leukemia cells as target cells.

  19. Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice

    PubMed Central

    Shing, Danielle C.; Trubia, Maurizio; Marchesi, Francesco; Radaelli, Enrico; Belloni, Elena; Tapinassi, Cinzia; Scanziani, Eugenio; Mecucci, Cristina; Crescenzi, Barbara; Lahortiga, Idoya; Odero, Maria D.; Zardo, Giuseppe; Gruszka, Alicja; Minucci, Saverio; Di Fiore, Pier Paolo; Pelicci, Pier Giuseppe

    2007-01-01

    Transgenic expression of the abnormal products of acute myeloid leukemia–associated (AML-associated) primary chromosomal translocations in hematopoietic stem/progenitor cells initiates leukemogenesis in mice, yet additional mutations are needed for leukemia development. We report here aberrant expression of PR domain containing 16 (PRDM16) in AML cells with either translocations of 1p36 or normal karyotype. These carried, respectively, relatively high prevalence of mutations in the TP53 tumor suppressor gene and in the nucleophosmin (NPM) gene, which regulates p53. Two protein isoforms are expressed from PRDM16, which differ in the presence or absence of the PR domain. Overexpression of the short isoform, sPRDM16, in mouse bone marrow induced AML with full penetrance, but only in the absence of p53. The mouse leukemias were characterized by multilineage cellular abnormalities and megakaryocyte dysplasia, a common feature of human AMLs with 1p36 translocations or NPM mutations. Overexpression of sPRDM16 increased the pool of HSCs in vivo, and in vitro blocked myeloid differentiation and prolonged progenitor life span. Loss of p53 augmented the effects of sPRDM16 on stem cell number and induced immortalization of progenitors. Thus, overexpression of sPRDM16 induces abnormal growth of stem cells and progenitors and cooperates with disruption of the p53 pathway in the induction of myeloid leukemia. PMID:18037989

  20. Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor–expressing T cells

    PubMed Central

    Lynn, Rachel C.; Poussin, Mathilde; Kalota, Anna; Feng, Yang; Low, Philip S.; Dimitrov, Dimiter S.

    2015-01-01

    T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate receptor β (FRβ) is a myeloid-lineage antigen expressed on 70% of acute myeloid leukemia (AML) patient samples. Here, we describe the development and evaluation of the first CARs specific for human FRβ (m909) in vitro and in vivo. m909 CAR T cells exhibited selective activation and lytic function against engineered C30-FRβ as well as endogenous FRβ+ AML cell lines in vitro. In mouse models of human AML, m909 CAR T cells mediated the regression of engrafted FRβ+ THP1 AML in vivo. In addition, we demonstrated that treatment of AML with all-trans retinoic acid (ATRA) enhanced FRβ expression, resulting in improved immune recognition by m909 CAR T cells. Because many cell surface markers are shared between AML blasts and healthy hematopoietic stem and progenitor cells (HSCs), we evaluated FRβ expression and recognition of HSCs by CAR T cells. m909 CAR T cells were not toxic against healthy human CD34+ HSCs in vitro. Our results indicate that FRβ is a promising target for CAR T-cell therapy of AML, which may be augmented by combination with ATRA. PMID:25887778

  1. Distal regulation of c-myb expression during IL-6-induced differentiation in murine myeloid progenitor M1 cells.

    PubMed

    Zhang, Junfang; Han, Bingshe; Li, Xiaoxia; Bies, Juraj; Jiang, Penglei; Koller, Richard P; Wolff, Linda

    2016-01-01

    The c-Myb transcription factor is a major regulator that controls differentiation and proliferation of hematopoietic progenitor cells, which is frequently deregulated in hematological diseases, such as lymphoma and leukemia. Understanding of the mechanisms regulating the transcription of c-myb gene is challenging as it lacks a typical promoter and multiple factors are involved. Our previous studies identified some distal regulatory elements in the upstream regions of c-myb gene in murine myeloid progenitor M1 cells, but the detailed mechanisms still remain unclear. In the present study, we found that a cell differentiation-related DNase1 hypersensitive site is located at a -28k region upstream of c-myb gene and that transcription factors Hoxa9, Meis1 and PU.1 bind to the -28k region. Circular chromosome conformation capture (4C) assay confirmed the interaction between the -28k region and the c-myb promoter, which is supported by the enrichment of CTCF and Cohesin. Our analysis also points to a critical role for Hoxa9 and PU.1 in distal regulation of c-myb expression in murine myeloid cells and cell differentiation. Overexpression of Hoxa9 disrupted the IL-6-induced differentiation of M1 cells and upregulated c-myb expression through binding of the -28k region. Taken together, our results provide an evidence for critical role of the -28k region in distal regulatory mechanism for c-myb gene expression during differentiation of myeloid progenitor M1 cells. PMID:27607579

  2. FES/FER kinase signaling in hematopoietic cells and leukemias.

    PubMed

    Craig, Andrew W B

    2012-01-01

    FES and FES-related (FER) comprise a unique subfamily of protein-tyrosine kinases (PTKs) that signal downstream of several classes of receptors involved in regulating hematopoietic cell development, survival, migration, and inflammatory mediator release. Activated alleles of FES are potent inducers of myeloid differentiation, however FES-deficient mice have only subtle differences in hematopoiesis. This may reflect overlapping function of other kinases such as FER. Studies of FES- and FER-deficient mice have revealed more prominent roles in regulating the activation of mature innate immune cells, including macrophages and mast cells. Recently, new insights into regulation of FES/FER kinases has emerged with the characterization of their N-terminal phospholipid-binding and membrane targeting FER/CIP4 homology-Bin/Amphyphysin/Rvs (F-BAR) and F-BAR extension (FX) domains. The F-BAR/FX domains regulate subcellular localization and FES/FER kinase activation. FES kinase activity is also enhanced upon ligand binding to its SH2 domain, which may lead to further phosphorylation of the same ligand, or other ligand-associated proteins. In mast cells, SH2 ligands of FES/FER include KIT receptor PTK, and the high affinity IgE receptor (FceRI) that trigger rapid activation of FES/FER and signaling to regulators of the actin cytoskeleton and membrane trafficking. Recently, FES/FER have also been implicated in growth and survival signaling in leukemias driven by oncogenic KIT and FLT3 receptors. With further definition of their roles in immune cells and their progenitors, FES/FER may emerge as relevant therapeutic targets in inflammatory diseases and leukemias.

  3. Immune Reconstitution After Antithymocyte Globulin-Conditioned Hematopoietic Cell Transplantation

    PubMed Central

    Bosch, Mark; Dhadda, Manveer; Hoegh-Petersen, Mette; Liu, Yiping; Hagel, Laura M; Podgorny, Peter; Ugarte-Torres, Alejandra; Khan, Faisal M.; Luider, Joanne; Auer-Grzesiak, Iwona; Mansoor, Adnan; Russell, James A; Daly, Andrew; Stewart, Douglas A.; Maloney, David; Boeckh, Michael; Storek, Jan

    2013-01-01

    Background Antithymocyte globulin (ATG) has been increasingly used to prevent graft-vs-host disease (GVHD), however, its impact on immune reconstitution is relatively unknown. Here we studied (1) immune reconstitution after ATG-conditioned hematopoietic cell transplantation (HCT), (2) determined factors influencing the reconstitution, and (3) compared it to non-ATG-conditioned HCT. Methods Immune cell subset counts were determined at 1–24 months posttransplant in 125 HCT recipients who received ATG during conditioning. The subset counts were also determined in 46 non-ATG-conditioned patients (similarly treated). Results (1) Reconstitution after ATG-conditioned HCT was fast for innate immune cells, intermediate for B cells and CD8 T cells, and very slow for CD4 T cells and invariant NKT (iNKT) cells. (2) Faster reconstitution after ATG-conditioned HCT was associated with higher number of cells of the same subset transferred with the graft in case of memory B cells, naïve CD4 T cells, naïve CD8 T cells, iNKT cells and myeloid dendritic cells; lower recipient age in case of naïve CD4 T cells and naïve CD8 T cells; cytomegalovirus recipient seropositivity in case of memory/effector T cells; absence of GVHD in case of naïve B cells; lower ATG serum levels in case of most T cell subsets including iNKT cells, and higher ATG levels in case of NK cells and B cells. (3) Compared to non-ATG-conditioned HCT, reconstitution after ATG-conditioned HCT was slower for CD4 T cells, and faster for NK cells and B cells. Conclusions ATG worsens reconstitution of CD4 T cells but improves reconstitution of NK and B cells. PMID:22985195

  4. Hypoxia and Metabolic Properties of Hematopoietic Stem Cells

    PubMed Central

    2014-01-01

    Abstract Significance: The effect of redox signaling on hematopoietic stem cell (HSC) function is not clearly understood. Recent Advances: A growing body of evidence suggests that adult HSCs reside in the hypoxic bone marrow microenvironment or niche during homeostasis. It was recently shown that primitive HSCs in the bone marrow prefer to utilize anaerobic glycolysis to meet their energy demands and have lower rates of oxygen consumption and lower ATP levels. Hypoxia-inducible factor-α (Hif-1α) is a master regulator of cellular metabolism. With hundreds of downstream target genes and crosstalk with other signaling pathways, it regulates various aspects of metabolism from the oxidative stress response to glycolysis and mitochondrial respiration. Hif-1α is highly expressed in HSCs, where it regulates their function and metabolic phenotype. However, the regulation of Hif-1α in HSCs is not entirely understood. The homeobox transcription factor myeloid ecotropic viral integration site 1 (Meis1) is expressed in the most primitive HSCs populations, and it is required for primitive hematopoiesis. Recent reports suggest that Meis1 is required for normal adult HSC function by regulating the metabolism and redox state of HSCs transcriptionally through Hif-1α and Hif-2α. Critical Issues: Given the profound effect of redox status on HSC function, it is critical to fully characterize the intrinsic, and microenvironment-related mechanisms of metabolic and redox regulation in HSCs. Future Directions: Future studies will be needed to elucidate the link between HSC metabolism and HSC fates, including quiescence, self-renewal, differentiation, apoptosis, and migration. Antioxid. Redox Signal. 20, 1891–1901. PMID:23621582

  5. Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.

    PubMed

    Yun, Haiyang; Damm, Frederik; Yap, Damian; Schwarzer, Adrian; Chaturvedi, Anuhar; Jyotsana, Nidhi; Lübbert, Michael; Bullinger, Lars; Döhner, Konstanze; Geffers, Robert; Aparicio, Samuel; Humphries, R Keith; Ganser, Arnold; Heuser, Michael

    2014-09-01

    Hypomethylating agents are widely used in patients with myelodysplastic syndromes and unfit patients with acute myeloid leukemia. However, it is not well understood why only some patients respond to hypomethylating agents. We found previously that the effect of decitabine on hematopoietic stem cell viability differed between Mll5 wild-type and null cells. We, therefore, investigated the role of MLL5 expression levels on outcome of acute myeloid leukemia patients who were treated with decitabine. MLL5 above the median expression level predicted longer overall survival independent of DNMT3A mutation status in bivariate analysis (median overall survival for high vs. low MLL5 expression 292 vs. 167 days; P=0.026). In patients who received three or more courses decitabine, high MLL5 expression and wild-type DNMT3A independently predicted improved overall survival (median overall survival for high vs. low MLL5 expression 468 vs. 243 days; P=0.012). In transformed murine cells, loss of Mll5 was associated with resistance to low-dose decitabine, less global DNA methylation in promoter regions, and reduced DNA demethylation upon decitabine treatment. Together, these data support our clinical observation of improved outcome in decitabine-treated patients who express MLL5 at high levels, and suggest a mechanistic role of MLL5 in the regulation of DNA methylation.

  6. ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia

    PubMed Central

    Weisberg, Stuart P.; Smith-Raska, Matthew R.; Esquilin, Jose M.; Zhang, Ji; Arenzana, Teresita L.; Lau, Colleen M.; Churchill, Michael; Pan, Haiyan; Klinakis, Apostolos; Dixon, Jack E.; Mirny, Leonid A.; Mukherjee, Siddhartha; Reizis, Boris

    2014-01-01

    Summary Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem cell-related genetic regulator. PMID:24485662

  7. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia

    PubMed Central

    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

    2014-01-01

    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

  8. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia.

    PubMed

    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

    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.

  9. MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

    PubMed Central

    Riedel, Simone S.; Haladyna, Jessica N.; Bezzant, Matthew; Stevens, Brett; Pollyea, Daniel A.; Sinha, Amit U.; Armstrong, Scott A.; Wei, Qi; Pollock, Roy M.; Daigle, Scott R.; Jordan, Craig T.; Ernst, Patricia; Bernt, Kathrin M.

    2016-01-01

    Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mll1 or Dot1l in MN1-expressing cells abrogated the cell of origin–derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1hi leukemia, and human MN1hi/HOXA9hi leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1hi AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML. PMID:26927674

  10. DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

    PubMed Central

    Alvarez, Sara; Suela, Javier; Valencia, Ana; Fernández, Agustín; Wunderlich, Mark; Agirre, Xabier; Prósper, Felipe; Martín-Subero, José Ignacio; Maiques, Alba; Acquadro, Francesco; Rodriguez Perales, Sandra; Calasanz, María José; Roman-Gómez, Jose; Siebert, Reiner; Mulloy, James C.; Cervera, José; Sanz, Miguel Angel; Esteller, Manel; Cigudosa, Juan C.

    2010-01-01

    Background Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required. Methodology/Principal Findings We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients. Conclusions/Significance Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature. PMID:20808941

  11. Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a

    PubMed Central

    Shields, Benjamin J.; Jackson, Jacob T.; Metcalf, Donald; Shi, Wei; Huang, Qiutong; Garnham, Alexandra L.; Glaser, Stefan P.; Beck, Dominik; Pimanda, John E.; Bogue, Clifford W.; Smyth, Gordon K.; Alexander, Warren S.; McCormack, Matthew P.

    2016-01-01

    Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a-encoded tumor suppressors p16INK4a and p19ARF, which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal. PMID:26728554

  12. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

    PubMed

    Arber, Daniel A; Orazi, Attilio; Hasserjian, Robert; Thiele, Jürgen; Borowitz, Michael J; Le Beau, Michelle M; Bloomfield, Clara D; Cazzola, Mario; Vardiman, James W

    2016-05-19

    The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.

  13. Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia.

    PubMed

    Will, Britta; Vogler, Thomas O; Narayanagari, Swathi; Bartholdy, Boris; Todorova, Tihomira I; da Silva Ferreira, Mariana; Chen, Jiahao; Yu, Yiting; Mayer, Jillian; Barreyro, Laura; Carvajal, Luis; Neriah, Daniela Ben; Roth, Michael; van Oers, Johanna; Schaetzlein, Sonja; McMahon, Christine; Edelmann, Winfried; Verma, Amit; Steidl, Ulrich

    2015-10-01

    Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in a 35% reduction of PU.1 expression, was sufficient to induce myeloid-biased preleukemic stem cells and their subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1-cooperating transcription factor, Irf8. Notably, we found marked molecular similarities between the disease in these mice and human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor, which commonly occurs in human disease, is sufficient to initiate cancer development, and it provides mechanistic insight into the formation and progression of preleukemic stem cells in AML.

  14. Myeloid leukemia factor is a conserved regulator of RUNX transcription factor activity involved in hematopoiesis.

    PubMed

    Bras, Stéphanie; Martin-Lannerée, Séverine; Gobert, Vanessa; Augé, Benoît; Breig, Osman; Sanial, Matthieu; Yamaguchi, Masamitsu; Haenlin, Marc; Plessis, Anne; Waltzer, Lucas

    2012-03-27

    Defining the function of the genes that, like RUNX1, are deregulated in blood cell malignancies represents an important challenge. Myeloid leukemia factors (MLFs) constitute a poorly characterized family of conserved proteins whose founding member, MLF1, has been associated with acute myeloid leukemia in humans. To gain insight into the functions of this family, we investigated the role of the Drosophila MLF homolog during blood cell development. Here we report that mlf controls the homeostasis of the Drosophila hematopoietic system. Notably, mlf participates in a positive feedback loop to fine tune the activity of the RUNX transcription factor Lozenge (LZ) during development of the crystal cells, one of the two main blood cell lineages in Drosophila. At the molecular level, our data in cell cultures and in vivo strongly suggest that MLF controls the number of crystal cells by protecting LZ from degradation. Remarkably, it appears that the human MLF1 protein can substitute for MLF in the crystal cell lineage. In addition, MLF stabilizes the human oncogenic fusion protein RUNX1-ETO and is required for RUNX1-ETO-induced blood cell disorders in a Drosophila model of leukemia. Finally, using the human leukemic blood cell line Kasumi-1, we show that MLF1 depletion impairs RUNX1-ETO accumulation and reduces RUNX1-ETO-dependent proliferation. Thus, we propose that the regulation of RUNX protein levels is a conserved feature of MLF family members that could be critical for normal and pathological blood cell development. PMID:22411814

  15. Noncoding RNAs in Acute Myeloid Leukemia: From Key Regulators to Clinical Players.

    PubMed

    Fatica, Alessandro

    2012-01-01

    Recent analyses have shown that human cells transcribe almost their entire genomes, implying the existence of a huge mass of ncRNAs. At the present, microRNAs are the most investigated regulative non-coding RNAs. Several studies have demonstrated that microRNAs play a crucial role in hematopoietic differentiation and hematological malignancies, including acute myeloid leukemia (AML). Aberrant expression of microRNAs has been associated with specific genetic abnormalities and clinical outcome of patients with AML. In addition, since microRNAs can function as either oncogenes or tumor suppressor genes, the potential of using these molecules as therapeutic targets opens up new opportunities in the future of AML therapy. The recent demonstration that other regulatory ncRNAs, in addition to microRNAs, are involved in hematopoietic cell differentiation and diseases, suggests that they may also have a biological relevance in AML. This paper will describe the role of ncRNAs in AML and discuss the expectations for the use of ncRNAs in diagnosis, prognosis, and therapy of AML.

  16. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

    PubMed Central

    Gori, Jennifer L.; Butler, Jason M.; Chan, Yan-Yi; Chandrasekaran, Devikha; Poulos, Michael G.; Ginsberg, Michael; Nolan, Daniel J.; Elemento, Olivier; Wood, Brent L.; Adair, Jennifer E.; Rafii, Shahin; Kiem, Hans-Peter

    2015-01-01

    Pluripotent stem cells (PSCs) represent an alternative hematopoietic stem cell (HSC) source for treating hematopoietic disease. The limited engraftment of human PSC–derived (hPSC-derived) multipotent progenitor cells (MPP) has hampered the clinical application of these cells and suggests that MPP require additional cues for definitive hematopoiesis. We hypothesized that the presence of a vascular niche that produces Notch ligands jagged-1 (JAG1) and delta-like ligand-4 (DLL4) drives definitive hematopoiesis. We differentiated hes2 human embryonic stem cells (hESC) and Macaca nemestrina–induced PSC (iPSC) line-7 with cytokines in the presence or absence of endothelial cells (ECs) that express JAG1 and DLL4. Cells cocultured with ECs generated substantially more CD34+CD45+ hematopoietic progenitors compared with cells cocultured without ECs or with ECs lacking JAG1 or DLL4. EC-induced cells exhibited Notch activation and expressed HSC-specific Notch targets RUNX1 and GATA2. EC-induced PSC-MPP engrafted at a markedly higher level in NOD/SCID/IL-2 receptor γ chain–null (NSG) mice compared with cytokine-induced cells, and low-dose chemotherapy-based selection further increased engraftment. Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction were similar to levels achieved for cord blood–derived MPP and up to 20-fold higher than those achieved with hPSC-derived MPP engraftment. Our findings indicate that endothelial Notch ligands promote PSC-definitive hematopoiesis and production of long-term engrafting CD34+ cells, suggesting these ligands are critical for HSC emergence. PMID:25664855

  17. Molecular Pathology: Prognostic and Diagnostic Genomic Markers for Myeloid Neoplasms.

    PubMed

    Kuo, Frank C

    2016-09-01

    Application of next-generation sequencing (NGS) on myeloid neoplasms has expanded our knowledge of genomic alterations in this group of diseases. Genomic alterations in myeloid neoplasms are complex, heterogeneous, and not specific to a disease entity. NGS-based panel testing of myeloid neoplasms can complement existing diagnostic modalities and is gaining acceptance in the clinics and diagnostic laboratories. Prospective, randomized trials to evaluate the prognostic significance of genomic markers in myeloid neoplasms are under way in academic medical centers. PMID:27523973

  18. Identification of Desirable Precursor Properties for Solution Precursor Plasma Spray

    NASA Astrophysics Data System (ADS)

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

    2011-06-01

    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.

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

    ClinicalTrials.gov

    2016-07-04

    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

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

    ClinicalTrials.gov

    2016-04-21

    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

  1. Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

    PubMed

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin G; Eggert, Tobias; Hawk, Nga; Kleiner, David E; Korangy, Firouzeh; Greten, Tim F

    2015-05-01

    Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2(-/-), Cd40(-/-), and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b(+)Gr-1(+) immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14(+)HLA-DR(low) peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. PMID:25637366

  2. Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

    PubMed

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin G; Eggert, Tobias; Hawk, Nga; Kleiner, David E; Korangy, Firouzeh; Greten, Tim F

    2015-05-01

    Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2(-/-), Cd40(-/-), and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b(+)Gr-1(+) immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14(+)HLA-DR(low) peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC.

  3. Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo.

    PubMed Central

    Feuer, G; Fraser, J K; Zack, J A; Lee, F; Feuer, R; Chen, I S

    1996-01-01

    Human T-cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T-cell leukemia and lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. We examined whether HTLV could productively infect human hematopoietic progenitor cells. CD34+ cells were enriched from human fetal liver cells and cocultivated with cell lines transformed with HTLV-1 and -2. HTLV-1 infection was established in between 10 and >95% of the enriched CD34+ cell population, as demonstrated by quantitative PCR analysis. HTLV-1 p19 Gag expression was also detected in infected hematopoietic progenitor cells. HTLV-1-infected hematopoietic progenitor cells were cultured in semisolid medium permissive for the development of erythbroid (BFU-E), myeloid (CFU-GM), and primitive progenitor (CFU-GEMM, HPP-CFC, or CFU-A) colonies. HTLV-1 sequences were detected in colonies of all hematopoietic lineages; furthermore, the ratio of HTLV genomes to the number of human cells in each infected colony was 1:1, consistent with each colony arising from a single infected hematopoietic progenitor cell. Severe combined immunodeficient mice engrafted with human fetal thymus and liver tissues (SCID-hu) develop a conjoint organ which supports human thymocyte differentiation and maturation. Inoculation of SCID-hu mice with HTLV-1-infected T cells or enriched populations of CD34+ cells established viral infection of thymocytes 4 to 6 weeks postreconstitution. Thymocytes from two mice with the greatest HTLV-1 proviral burdens showed increased expression of the CD25 marker and the interleukin 2 receptor alpha chain and perturbation of CD4+ and CD8+ thymocyte subset distribution profiles. Hematopoietic progenitor cells and thymuses may be targets for HTLV infection in humans, and these events may play a role in the pathogenesis associated with infection. PMID:8648741

  4. Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia.

    PubMed

    Gallipoli, Paolo; Giotopoulos, George; Huntly, Brian J P

    2015-06-01

    Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is an aggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. As a result, clinical outcome remains poor for the majority of patients, with overall long-term survival in the region of 20-30%. Recent successes in characterizing the genetic landscape of AML have highlighted that, despite its heterogeneity, many cases of AML carry recurrent mutations in genes encoding epigenetic regulators. Transcriptional dysregulation and altered epigenetic function have therefore emerged as exciting areas in AML research and it is becoming increasingly clear that epigenetic dysfunction is central to leukemogenesis in AML. This has subsequently paved the way for the development of epigenetically targeted therapies. In this review, we will discuss the most recent advances in our understanding of the role of epigenetic dysregulation in AML pathobiology. We will particularly focus on those altered epigenetic programs that have been shown to be central to the development and maintenance of AML in preclinical models. We will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that these novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.

  5. Chronic Myeloid Leukemia (CML) Mouse Model in Translational Research.

    PubMed

    Peng, Cong; Li, Shaoguang

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of granulocytic cells without the loss of their capability to differentiate. CML is a clonal disease, originated at the level of Hematopoietic Stem Cells with the Philadelphia chromosome resulting from a reciprocal translocation between the chromosomes 9 and 22t(9;22)-(q34;q11). This translocation produces a fusion gene known as BCR-ABL which acquires uncontrolled tyrosine kinase activity, constantly turning on its downstream signaling molecules/pathways, and promoting proliferation of leukemia cell through anti-apoptosis and acquisition of additional mutations. To evaluate the role of each critical downstream signaling molecule of BCR-ABL and test therapeutic drugs in vivo, it is important to use physiological mouse disease models. Here, we describe a mouse model of CML induced by BCR-ABL retrovirus (MSCV-BCR-ABL-GFP; MIG-BCR-ABL) and how to use this model in translational research.Moreover, to expand the application of this retrovirus induced CML model in a lot of conditional knockout mouse strain, we modified this vector to a triple gene coexpression vector in which we can co-express BCR-ABL, GFP, and a third gene which will be tested in different systems. To apply this triple gene system in conditional gene knockout strains, we can validate the CML development in the knockout mice and trace the leukemia cell following the GFP marker. In this protocol, we also describe how we utilize this triple gene system to prove the function of Pten as a tumor suppressor in leukemogenesis. Overall, this triple gene system expands our research spectrum in current conditional gene knockout strains and benefits our CML translational research. PMID:27150093

  6. Effect of Decitabine Combined with Unrelated Cord Blood Transplantation in an Adult Patient with -7/EVI1+ Acute Myeloid Leukemia: a Case Report and Literature Review.

    PubMed

    Jiang, Yi-Zhi; Su, Gui-Ping; Dai, Yan; He, He-Sheng; Huang, Lai-Quan; Sun, Zi-Min; Huang, Dong-Ping

    2015-01-01

    Patients with relapsed or refractory acute myeloid leukemia (rAML) have a poor prognosis if they do not undergo hematopoietic stem cell transplantation (HSCT). We describe a case herein of acute myeloid leukemia (AML) with monosomy 7 and EVI1(+)(-7/EVI1(+)) in a patient who failed to achieve a complete remission (CR) after two cycles of standard induction chemotherapy. He subsequently received decitabine (DAC) as "bridge therapy" and directly underwent unrelated cord blood transplantation (UCBT) due to the absence of an available sibling donor. Although DAC treatment did not induce CR, it did produce hematologic improvement and control disease progression with acceptable side effects, thus effectively bridging the time of donor search. Following UCBT, the marrow showed complete hematologic and cytogenetic remission. At present, 18 months after the transplantation, the patient's general condition is still good.

  7. A New Triggering Receptor Expressed on Myeloid Cells (TREM) Family Member, TLT-6, is Involved in Activation and Proliferation of Macrophages

    PubMed Central

    Won, Kyung-Jong; Park, Sung-Won; Lee, Seunghoon; Kong, Il-Keun; Chae, Jung-Il; Kim, Bokyung; Lee, Eun-Jong

    2015-01-01

    The triggering receptor expressed on myeloid cells (TREM) family, which is abundantly expressed in myeloid lineage cells, plays a pivotal role in innate and adaptive immune response. In this study, we aimed to identify a novel receptor expressed on hematopoietic stem cells (HSCs) by using in silico bioinformatics and to characterize the identified receptor. We thus found the TREM-like transcript (TLT)-6, a new member of TREM family. TLT-6 has a single immunoglobulin domain in the extracellular region and a long cytoplasmic region containing 2 immunoreceptor tyrosine-based inhibitory motif-like domains. TLT-6 transcript was expressed in HSCs, monocytes and macrophages. TLT-6 protein was up-regulated on the surface of bone marrow-derived and peritoneal macrophages by lipopolysaccharide stimulation. TLT-6 exerted anti-proliferative effects in macrophages. Our results demonstrate that TLT-6 may regulate the activation and proliferation of macrophages. PMID:26557807

  8. Oral squamous cell carcinoma arising in a patient after hematopoietic stem cell transplantation with bisphosphonate-related osteonecrosis of the jaws.

    PubMed

    Arduino, Paolo G; Scully, Crispian; Chiusa, Luigi; Broccoletti, Roberto

    2015-01-01

    A 55-year-old man with a history of acute myeloid leukaemia treated with hematopoietic stem cell transplantation and with a 5-year history of bisphosphonate-related osteonecrosis of the jaws, following 12 cycles of intravenous zoledronic acid therapy, presented in December 2009 with a history of increasingly severe unilateral lower jaw pain. Oral examination revealed, as previously, exposed bone in the left mandible, but also a new exophytic mass on the lower-left buccal mucosa. Biopsy confirmed a diagnosis of oral squamous cell carcinoma. To the best of our knowledge, this is the first report of an oral squamous cell carcinoma that appeared adjacent to an area of osteochemonecrosis.

  9. Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies

    PubMed Central

    Mirantes, Cristina; Dosil, Maria Alba; Hills, David; Yang, Jian; Eritja, Núria; Santacana, Maria; Gatius, Sònia; Vilardell, Felip; Medvinsky, Alexander; Matias-Guiu, Xavier

    2016-01-01

    Since its discovery in the late 1990s, Pten has turned out to be one of the most important tumor suppressor genes. Pten loss results in increased activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which is associated with increased proliferation, survival, and neoplastic growth. Here, we have addressed the effects of conditional deletion of Pten in hematopoietic cells by crossing Pten conditional knockout mice with a knock-in mouse expressing the Cre recombinase in the CD45 locus. CD45 is also known as leukocyte common antigen, and it is expressed in virtually all white cells and in hematopoietic stem cells. Using a reporter mouse, we demonstrate that CD45:Cre mouse displays recombinase activity in both myeloid and lymphoid cells. However, deletion of Pten in CD45-expressing cells induces development of T-cell acute lymphoblastic leukemia and lymphoma, but not other hematologic malignancies. PMID:26773036

  10. Tet2 facilitates the de-repression of myeloid target genes during C/EBPa induced transdifferentiation of pre-B cells

    PubMed Central

    Kallin, Eric M.; Rodríguez-Ubreva, Javier; Christensen, J esper; Cimmino, Luisa; Aifantis, Iannis; Helin, Kristian; Ballestar, Esteban; Graf, Thomas

    2013-01-01

    SUMMARY The methylcytosine hydroxylase Tet2 has been implicated in hematopoietic differentiation and the formation of myeloid malignancies when mutated. An ideal system to study the role of Tet2 in myelopoeisis is C/EBPa induced transdifferentiation of pre-B cells into macrophages. Here we found that C/EBPa binds to upstream regions of Tet2 and that the gene becomes activated. Tet2 knockdowns impaired the upregulation of macrophage markers as well as phagocytic capacity, suggesting that the enzyme is required for both early and late stage myeloid differentiation. A slightly weaker effect was seen in primary cells with a Tet2 ablation. Expression arrays of transdifferentiating cells with Tet2 knockdowns permitted the identification of a small subset of myeloid genes whose upregulation was blunted. Activation of these target genes was accompanied by rapid increases of promoter hydroxy-methylation. Our observations indicate that Tet2 helps C/EBPa rapidly de-repress myeloid genes during the conversion of pre-B cells into macrophages. PMID:22981865

  11. Newly recruited CD11b+, GR-1+, Ly6C(high) myeloid cells augment tumor-associated immunosuppression immediately following the therapeutic administration of oncolytic reovirus.

    PubMed

    Clements, Derek R; Sterea, Andra M; Kim, Youra; Helson, Erin; Dean, Cheryl A; Nunokawa, Anna; Coyle, Krysta Mila; Sharif, Tanveer; Marcato, Paola; Gujar, Shashi A; Lee, Patrick W K

    2015-05-01

    Tumor-associated immunosuppression aids cancer cells to escape immune-mediated attack and subsequent elimination. Recently, however, many oncolytic viruses, including reovirus, have been reported to overturn such immunosuppression and promote the development of a clinically desired antitumor immunity, which is known to promote favorable patient outcomes. Contrary to this existing paradigm, in this article we demonstrate that reovirus augments tumor-associated immunosuppression immediately following its therapeutic administration. Our data show that reovirus induces preferential differentiation of highly suppressive CD11b(+), Gr-1(+), Ly6C(high) myeloid cells from bone marrow hematopoietic progenitor cells. Furthermore, reovirus administration in tumor-bearing hosts drives time-dependent recruitment of CD11b(+), Gr-1(+), Ly6C(high) myeloid cells in the tumor milieu, which is further supported by virus-induced increased expression of numerous immune factors involved in myeloid-derived suppressor cell survival and trafficking. Most importantly, CD11b(+), Gr-1(+), Ly6C(high) myeloid cells specifically potentiate the suppression of T cell proliferation and are associated with the absence of IFN-γ response in the tumor microenvironment early during oncotherapy. Considering that the qualitative traits of a specific antitumor immunity are largely dictated by the immunological events that precede its development, our findings are of critical importance and must be considered while devising complementary interventions aimed at promoting the optimum efficacy of oncolytic virus-based anticancer immunotherapies. PMID:25825443

  12. A Case of Myeloid Sarcoma of Intestine.

    PubMed

    Lim, Sung Won; Lee, Hang Lak; Lee, Kang Nyeong; Jun, Dae Won; Kim, In Young; Kim, Eunjin; Ahn, Hyein; Park, Chan Kum

    2016-09-25

    Myeloid sarcoma (MS) is an extramedullary involvement of immature myeloid proliferation. An isolated MS is defined as a myeloblastic tumor when it arises without any concomitant circulating disease. A diagnosis of MS is established using pathologic features including infiltration of myeloblasts and strong myeloperoxidase expression with negative cytokeratin immunohistochemical staining. We report a rare case of colonic MS without any peripheral blood abnormality. If the affected patient were left untreated, the MS could evolve into acute myeloid leukemia (AML) within one year. Several studies recommend the same regimens of chemotherapy as used for circulating AML to treat isolated MS. We focused on the diagnosis of MS in this study. The correct diagnosis of MS is important for adequate treatment. In conclusion, MS should be considered in the differential diagnosis of intestinal tumor. PMID:27646584

  13. Novel drug therapies in myeloid leukemia.

    PubMed

    Horne, Gillian A; Kinstrie, Ross; Copland, Mhairi

    2015-01-01

    Both acute myeloid leukemia and chronic myeloid leukemia are thought to arise from a subpopulation of primitive cells, termed leukemic stem cells that share properties with somatic stem cells. Leukemic stem cells are capable of continued self-renewal, and are resistant to conventional chemotherapy and are considered to be responsible for disease relapse. In recent years, improved understanding of the underlying mechanisms of myeloid leukemia biology has led to the development of novel and targeted therapies. This review focuses on clinically relevant patent applications and their relevance within the known literature in two areas of prevailing therapeutic interest, namely monoclonal antibody therapy and small molecule inhibitors in disease-relevant signaling pathways. PMID:26030080

  14. Myelopoiesis and Myeloid Leukaemogenesis in the Zebrafish

    PubMed Central

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

    2012-01-01

    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

  15. Challenges in Consolidated Reporting of Hematopoietic Neoplasms.

    PubMed

    Ohgami, Robert S; Arber, Daniel A

    2013-12-01

    This article focuses on the challenges of generating comprehensive diagnostic reports in hematopathology. In particular, two main challenges that diagnosticians face are (1) interpreting and understanding the rapid advances in molecular and genetic pathology, which have gained increasing importance in classifications of hematopoietic neoplasms, and (2) managing the logistics of reporting ancillary studies and incorporating them effectively into a final synthesized report. This article summarizes many important genetic findings in hematopoietic neoplasms, which are required for accurate diagnoses, and discusses practical issues to generating accurate and complete hematopathology reports.

  16. In utero hematopoietic cell transplantation for hemoglobinopathies

    PubMed Central

    Derderian, S. Christopher; Jeanty, Cerine; Walters, Mark C.; Vichinsky, Elliott; MacKenzie, Tippi C.

    2014-01-01

    In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC) transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor–specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application. PMID:25628564

  17. Signal, Transduction, and the Hematopoietic Stem Cell

    PubMed Central

    Louria-Hayon, Igal

    2014-01-01

    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

  18. MicroRNA-126-mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors.

    PubMed

    Okuyama, Kazuki; Ikawa, Tomokatsu; Gentner, Bernhard; Hozumi, Katsuto; Harnprasopwat, Ratanakanit; Lu, Jun; Yamashita, Riu; Ha, Daon; Toyoshima, Takae; Chanda, Bidisha; Kawamata, Toyotaka; Yokoyama, Kazuaki; Wang, Shusheng; Ando, Kiyoshi; Lodish, Harvey F; Tojo, Arinobu; Kawamoto, Hiroshi; Kotani, Ai

    2013-08-13

    Lineage specification is thought to be largely regulated at the level of transcription, where lineage-specific transcription factors drive specific cell fates. MicroRNAs (miR), vital to many cell functions, act posttranscriptionally to decrease the expression of target mRNAs. MLL-AF4 acute lymphocytic leukemia exhibits both myeloid and B-cell surface markers, suggesting that the transformed cells are B-cell myeloid progenitor cells. Through gain- and loss-of-function experiments, we demonstrated that microRNA 126 (miR-126) drives B-cell myeloid biphenotypic leukemia differentiation toward B cells without changing expression of E2A immunoglobulin enhancer-binding factor E12/E47 (E2A), early B-cell factor 1 (EBF1), or paired box protein 5, which are critical transcription factors in B-lymphopoiesis. Similar induction of B-cell differentiation by miR-126 was observed in normal hematopoietic cells in vitro and in vivo in uncommitted murine c-Kit(+)Sca1(+)Lineage(-) cells, with insulin regulatory subunit-1 acting as a target of miR-126. Importantly, in EBF1-deficient hematopoietic progenitor cells, which fail to differentiate into B cells, miR-126 significantly up-regulated B220, and induced the expression of B-cell genes, including recombination activating genes-1/2 and CD79a/b. These data suggest that miR-126 can at least partly rescue B-cell development independently of EBF1. These experiments show that miR-126 regulates myeloid vs. B-cell fate through an alternative machinery, establishing the critical role of miRNAs in the lineage specification of multipotent mammalian cells.

  19. Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome.

    PubMed

    Deschler, Barbara; Ihorst, Gabriele; Platzbecker, Uwe; Germing, Ulrich; März, Eva; de Figuerido, Marcelo; Fritzsche, Kurt; Haas, Peter; Salih, Helmut R; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; de Witte, Theo; Wijermans, Pierre; Lübbert, Michael

    2013-02-01

    Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and

  20. Frozen cord blood hematopoietic stem cells differentiate into higher numbers of functional natural killer cells in vitro than mobilized hematopoietic stem cells or freshly isolated cord blood hematopoietic stem cells.

    PubMed

    Luevano, Martha; Domogala, Anna; Blundell, Michael; Jackson, Nicola; Pedroza-Pacheco, Isabela; Derniame, Sophie; Escobedo-Cousin, Michelle; Querol, Sergio; Thrasher, Adrian; Madrigal, Alejandro; Saudemont, Aurore

    2014-01-01

    Adoptive natural killer (NK) cell therapy relies on the acquisition of large numbers of NK cells that are cytotoxic but not exhausted. NK cell differentiation from hematopoietic stem cells (HSC) has become an alluring option for NK cell therapy, with umbilical cord blood (UCB) and mobilized peripheral blood (PBCD34(+)) being the most accessible HSC sources as collection procedures are less invasive. In this study we compared the capacity of frozen or freshly isolated UCB hematopoietic stem cells (CBCD34(+)) and frozen PBCD34(+) to generate NK cells in vitro. By modifying a previously published protocol, we showed that frozen CBCD34(+) cultures generated higher NK cell numbers without loss of function compared to fresh CBCD34(+) cultures. NK cells generated from CBCD34(+) and PBCD34(+) expressed low levels of killer-cell immunoglobulin-like receptors but high levels of activating receptors and of the myeloid marker CD33. However, blocking studies showed that CD33 expression did not impact on the functions of the generated cells. CBCD34(+)-NK cells exhibited increased capacity to secrete IFN-γ and kill K562 in vitro and in vivo as compared to PBCD34(+)-NK cells. Moreover, K562 killing by the generated NK cells could be further enhanced by IL-12 stimulation. Our data indicate that the use of frozen CBCD34(+) for the production of NK cells in vitro results in higher cell numbers than PBCD34(+), without jeopardizing their functionality, rendering them suitable for NK cell immunotherapy. The results presented here provide an optimal strategy to generate NK cells in vitro for immunotherapy that exhibit enhanced effector function when compared to alternate sources of HSC.

  1. Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-05-05

    Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  2. Vaccine Therapy and Basiliximab in Treating Patients With Acute Myeloid Leukemia in Complete Remission

    ClinicalTrials.gov

    2016-06-27

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

  3. CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-26

    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

  4. Clofarabine and Cytarabine in Treating Patients With Acute Myeloid Leukemia With Minimal Residual Disease

    ClinicalTrials.gov

    2013-05-07

    Adult Acute Myeloid Leukemia in Remission; 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); Recurrent Adult Acute Myeloid Leukemia

  5. Romidepsin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-12-03

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

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

    ClinicalTrials.gov

    2016-03-14

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

  7. CTCF depletion alters chromatin structure and transcription of myeloid-specific factors.

    PubMed

    Ouboussad, Lylia; Kreuz, Sarah; Lefevre, Pascal F

    2013-10-01

    Differentiation is a multistep process tightly regulated and controlled by complex transcription factor networks. Here, we show that the rate of differentiation of common myeloid precursor cells increases after depletion of CTCF, a protein emerging as a potential key factor regulating higher-order chromatin structure. We identified CTCF binding in the vicinity of important transcription factors regulating myeloid differentiation and showed that CTCF depletion impacts on the expression of these genes in concordance with the observed acceleration of the myeloid commitment. Furthermore, we observed a loss of the histone variant H2A.Z within the selected promoter regions and an increase in non-coding RNA transcription upstream of these genes. Both abnormalities suggest a global chromatin structure destabilization and an associated increase of non-productive transcription in response to CTCF depletion but do not drive the CTCF-mediated transcription alterations of the neighbouring genes. Finally, we detected a transient eviction of CTCF at the Egr1 locus in correlation with Egr1 peak of expression in response to lipopolysaccharide (LPS) treatment in macrophages. This eviction is also correlated with the expression of an antisense non-coding RNA transcribing through the CTCF-binding region indicating that non-coding RNA transcription could be the cause and the consequence of CTCF eviction.

  8. Case Report: Myelodysplastic syndrome- associated myeloid sarcoma: an unusual clinical presentation of a rare disease.

    PubMed

    Horvath, Emoke; Demian, Smaranda; Nagy, Elod

    2016-01-01

    Myeloid sarcoma results from the extramedullary homing and proliferation of immature myeloid precursors. We present the timeline, events and diagnostic pitfalls related to a 66 year-old male patient's case, admitted to the Hematology Clinic for pancytopenia, fever, weight loss and fatigue. The severe cytopenia and the few blasts observed in his blood smear indicated a bone marrow biopsy. The bone marrow showed hypercellularity and multilineage dysplasia with the presence of 15% myeloblasts. After the biopsy, he promptly developed paraplegia and nuclear magnetic resonance revealed an epidural tumour which was then resected.In the epidural tumour mass blast-like, round cells were observed with a complex immunophenotype, characterized by myeloperoxidase, CD117, CD15, CD99, leucocyte common antigen positivity and a high Ki-67 proliferation index. Considering the main differential diagnostic issues, the final diagnosis was stated as myelodysplastic syndrome-associated myeloid sarcoma. The prognosis was unfavourable, the bone marrow was quickly invaded by proliferating blast cells, and despite chemotherapy attempts, the patient died.

  9. Case Report: Myelodysplastic syndrome- associated myeloid sarcoma: an unusual clinical presentation of a rare disease

    PubMed Central

    Horvath, Emoke; Demian, Smaranda; Nagy, Elod

    2016-01-01

    Myeloid sarcoma results from the extramedullary homing and proliferation of immature myeloid precursors. We present the timeline, events and diagnostic pitfalls related to a 66 year-old male patient’s case, admitted to the Hematology Clinic for pancytopenia, fever, weight loss and fatigue. The severe cytopenia and the few blasts observed in his blood smear indicated a bone marrow biopsy. The bone marrow showed hypercellularity and multilineage dysplasia with the presence of 15% myeloblasts. After the biopsy, he promptly developed paraplegia and nuclear magnetic resonance revealed an epidural tumour which was then resected.In the epidural tumour mass blast-like, round cells were observed with a complex immunophenotype, characterized by myeloperoxidase, CD117, CD15, CD99, leucocyte common antigen positivity and a high Ki-67 proliferation index. Considering the main differential diagnostic issues, the final diagnosis was stated as myelodysplastic syndrome-associated myeloid sarcoma. The prognosis was unfavourable, the bone marrow was quickly invaded by proliferating blast cells, and despite chemotherapy attempts, the patient died. PMID:27019694

  10. Case Report: Myelodysplastic syndrome- associated myeloid sarcoma: an unusual clinical presentation of a rare disease.

    PubMed

    Horvath, Emoke; Demian, Smaranda; Nagy, Elod

    2016-01-01

    Myeloid sarcoma results from the extramedullary homing and proliferation of immature myeloid precursors. We present the timeline, events and diagnostic pitfalls related to a 66 year-old male patient's case, admitted to the Hematology Clinic for pancytopenia, fever, weight loss and fatigue. The severe cytopenia and the few blasts observed in his blood smear indicated a bone marrow biopsy. The bone marrow showed hypercellularity and multilineage dysplasia with the presence of 15% myeloblasts. After the biopsy, he promptly developed paraplegia and nuclear magnetic resonance revealed an epidural tumour which was then resected.In the epidural tumour mass blast-like, round cells were observed with a complex immunophenotype, characterized by myeloperoxidase, CD117, CD15, CD99, leucocyte common antigen positivity and a high Ki-67 proliferation index. Considering the main differential diagnostic issues, the final diagnosis was stated as myelodysplastic syndrome-associated myeloid sarcoma. The prognosis was unfavourable, the bone marrow was quickly invaded by proliferating blast cells, and despite chemotherapy attempts, the patient died. PMID:27019694

  11. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer

    PubMed Central

    Sawant, Anandi; Deshane, Jessy; Jules, Joel; Lee, Carnella M.; Harris, Brittney A.; Feng, Xu; Ponnazhagan, Selvarangan

    2012-01-01

    Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth but the factors contributing to aggressive bone destruction are not well understood. In this study, we demonstrate the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Since MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression. PMID:23243021

  12. A rare case of myeloid sarcoma presenting as anal fissure

    PubMed Central

    VECCHIO, R.; INTAGLIATA, E.; FIUMARA, P.F.; VILLARI, L.; MARCHESE, S.; CACCIOLA, E.

    2015-01-01

    Myeloid sarcoma is a tumor composed of myeloblasts occurring at an extramedullary site. It may develop in patients with acute myeloid leukemia, myeloproliferative or myelodysplastic syndrome, sometimes preceding onset of the systemic disease. Frequent sites of myeloid sarcoma are bones or various soft tissues. Gastrointestinal involvement is very rare. We report a unique case of myeloid sarcoma presenting as a painful anal fissure, in a patient with a history of acute myeloid leukemia. The diagnosis was achieved by a surgical excisional biopsy and immunoistochemical staining. PMID:26712260

  13. Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders.

    PubMed

    Persons, Derek A

    2009-01-01

    Hematopoietic stem cell (HSC)-targeted gene transfer is an attractive approach for the treatment of a number of hematopoietic disorders caused by single gene defects. Indeed, in a series of gene transfer trials for two different primary immunodeficiencies beginning early in this decade, outstanding success has been achieved. Despite generally low levels of engrafted, genetically modified HSCs, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors that allowed reconstitution of the immune system. Unlike the immunodeficiencies, this robust level of in vivo selection is not available to hematopoietic repopulating cells or early progenitor cells following gene transfer of a therapeutic globin gene in the setting of beta-thalassemia and sickle cell disease. Both preclinical and clinical transplant studies involving bone marrow chimeras suggest that 20% or higher levels of engraftment of genetically modified HSCs will be needed for clinical success in the most severe of these disorders. Encouragingly, gene transfer levels in this range have recently been reported in a lentiviral vector gene transfer clinical trial for children with adrenoleukodystrophy. A clinical gene transfer trial for beta-thalassemia has begun in France, and one patient with transfusion-dependent HbE/beta-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD34(+) cells genetically modified with a beta-globin lentiviral vector. Here, the development and recent progress of gene therapy for the hemoglobin disorders is reviewed.

  14. Disseminated prostate cancer cells can instruct hematopoietic stem and progenitor cells to regulate bone phenotype.

    PubMed

    Joseph, Jeena; Shiozawa, Yusuke; Jung, Younghun; Kim, Jin Koo; Pedersen, Elisabeth; Mishra, Anjali; Zalucha, Janet Linn; Wang, Jingcheng; Keller, Evan T; Pienta, Kenneth J; Taichman, Russell S

    2012-03-01

    Prostate cancer metastases and hematopoietic stem cells (HSC) frequently home to the bone marrow, where they compete to occupy the same HSC niche. We have also shown that under conditions of hematopoietic stress, HSCs secrete the bone morphogenetic proteins (BMP)-2 and BMP-6 that drives osteoblastic differentiation from mesenchymal precursors. As it is not known, we examined whether metastatic prostate cancer cells can alter regulation of normal bone formation by HSCs and hematopoietic progenitor cells (HPC). HSC/HPCs isolated from mice bearing nonmetastatic and metastatic tumor cells were isolated and their ability to influence osteoblastic and osteoclastic differentiation was evaluated. When the animals were inoculated with the LNCaP C4-2B cell line, which produces mixed osteoblastic and osteolytic lesions in bone, HPCs, but not HSCs, were able to induced stromal cells to differentiate down an osteoblastic phenotype. Part of the mechanism responsible for this activity was the production of BMP-2. On the other hand, when the animals were implanted with PC3 cells that exhibits predominantly osteolytic lesions in bone, HSCs derived from these animals were capable of directly differentiating into tartrate-resistant acid phosphatase-positive osteoclasts through an interleukin-6-mediated pathway. These studies for the first time identify HSC/HPCs as novel targets for future therapy involved in the bone abnormalities of prostate cancer.

  15. Contrasting Roles for C/EBPα and Notch in Irradiation-Induced Multipotent Hematopoietic Progenitor Cell Defects

    PubMed Central

    Fleenor, Courtney Jo; Rozhok, Andrii Ivan; Zaberezhnyy, Vadym; Mathew, Divij; Kim, Jihye; Tan, Aik-Choon; Bernstein, Irwin David; DeGregori, James

    2014-01-01

    Ionizing radiation (IR) is associated with reduced hematopoietic function and increased risk of hematopoietic malignancies, although the mechanisms behind these relationships remain poorly understood. Both effects of IR have been commonly attributed to the direct induction of DNA mutations, but evidence supporting these hypotheses is largely lacking. Here we demonstrate that IR causes long-term, somatically heritable, cell-intrinsic reductions in hematopoietic stem cell (HSC) and multipotent hematopoietic progenitor cell (mHPC) self-renewal that are mediated by C/EBPα and reversed by Notch. mHPC from previously irradiated (>9 weeks prior), homeostatically restored mice exhibit gene expression profiles consistent with their precocious differentiation phenotype, including decreased expression of HSC-specific genes and increased expression of myeloid program genes (including C/EBPα). These gene expression changes are reversed by ligand-mediated activation of Notch. Loss of C/EBPα expression is selected for within previously irradiated HSC and mHPC pools, and is associated with reversal of IR-dependent precocious differentiation and restoration of self-renewal. Remarkably, restoration of mHPC self-renewal by ligand-mediated activation of Notch prevents selection for C/EBPα loss of function in previously irradiated mHPC pools. We propose that environmental insults prompt HSC to initiate a program limiting their self-renewal, leading to loss of the damaged HSC from the pool while allowing this HSC to temporarily contribute to differentiated cell pools. This “programmed mediocrity” is advantageous for the sporadic genotoxic insults animals have evolved to deal with, but becomes tumor promoting when the entire HSC compartment is damaged, such as during total body irradiation, by increasing selective pressure for adaptive oncogenic mutations. PMID:25546133

  16. Lenalidomide in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-07-25

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  17. Hematopoiesis and hematopoietic organs in arthropods.

    PubMed

    Grigorian, Melina; Hartenstein, Volker

    2013-03-01

    Hemocytes (blood cells) are motile cells that move throughout the extracellular space and that exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and the body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self-renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review, we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species.

  18. Proteoglycan synthesis by hematopoietic progenitor cells

    SciTech Connect

    Minguell, J.J.; Tavassoli, M. )

    1989-05-15

    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.

  19. Supportive Care of Hematopoietic Cell Transplant Patients

    PubMed Central

    Jim, Heather S. L.; Syrjala, Karen L.; Rizzo, Doug

    2012-01-01

    Hematopoietic cell transplant survivors face a number of challenges including low energy and stamina, “chemo-brain” and emotional distress, and late effects that can compromise functioning or lead to early mortality. This session will review the most recent interventions and recommendations to avoid or mitigate these complications. PMID:22226095

  20. NMR-Based Metabolomic Analysis of the Molecular Pathogenesis of Therapy-Related Myelodysplasia/Acute Myeloid Leukemia

    PubMed Central

    Cano, Kristin E.; Li, Liang; Bhatia, Smita; Bhatia, Ravi; Forman, Stephen J.; Chen, Yuan

    2012-01-01

    Hematopoietic stem cell transplantation is the oldest and successful form of stem cell therapy. High dose therapy (HDT) followed by hematopoietic stem cell transplantation allows physicians to administer increased amounts of chemotherapy and/or radiation while minimizing negative side effects such as damage to blood-producing bone marrow cells. Although HDT is successful in treating a wide range of cancers, it leads to lethal therapy-related myelodysplasia syndrome or acute myeloid leukemia (t-MDS/AML) in 5–10% of patients undergoing autologous hematopoietic cell transplantation for Hodgkin lymphoma and non-Hodgkin lymphoma. In this study, we carried out metabolomic analysis of peripheral blood stem cell samples collected in a cohort of patients before hematopoietic cell transplantation in order to gain insights into the molecular and cellular pathogenesis of t-MDS. Nonparametric tests and multivariate analyses were used to compare the metabolite concentrations in samples from patients that developed t-MDS within 5 years of transplantation and the patients that did not. The results suggest that the development of t-MDS is associated with dysfunctions in cellular metabolic pathways. The top canonical pathways suggested by the metabolomic analysis include alanine and aspartate metabolism, glyoxylate and dicarboxylate metabolism, phenylalanine metabolism, citrate acid cycle, and aminoacyl-t-RNA biosynthesis. Dysfunctions in these pathways indicate mitochondrial dysfunction that would result in decreased ability to detoxify reactive oxygen species generated by chemo and radiation therapy, therefore leading to cancer causing mutations. These observations suggest predisposing factors for the development of t-MDS. PMID:21510650

  1. Inhibition of growth by p205: a nuclear protein and putative tumor suppressor expressed during myeloid cell differentiation.

    PubMed

    Dermott, Jonathan M; Gooya, John M; Asefa, Benyam; Weiler, Sarah R; Smith, Mark; Keller, Jonathan R

    2004-01-01

    p205 belongs to a family of interferon-inducible proteins called the IFI-200 family, which have been implicated in the regulation of cell growth and differentiation. While p205 is induced in hematopoietic stem cells during myeloid cell differentiation, its function is not known. Therefore, the aim of this study was to determine the role of p205 in regulating proliferation in hematopoietic progenitor cells and in nonhematopoietic cell lines. We found that p205 localizes to the nucleus in hematopoietic and nonhematopoietic cell lines. Transient expression of p205 in murine IL-3-dependent BaF3 and 32D-C123 progenitor cell lines inhibited IL-3-induced growth and proliferation. The closely related IFI-200 family members, p204 and p202, similarly inhibited IL-3-dependent progenitor cell proliferation. p205 also inhibited the proliferation and growth of normal hematopoietic progenitor cells. In nonhematopoietic cell lines, p205 and p204 expression inhibited NIH3T3 cell colony formation in vitro, and microinjection of p205 expression vectors into NIH3T3 fibroblasts inhibited serum-induced proliferation. We have determined the functional domains of p205 necessary for activity, which were identified as the N-terminal domain in apoptosis and interferon response (DAPIN)/PYRIN domain, and the C-terminal retinoblastoma protein (Rb)-binding motif. In addition, we have demonstrated that a putative ataxia telangiectasia, mutated (ATM) kinase phosphorylation site specifically regulates the activity of p205. Taken together, these data suggest that p205 is a potent cell growth regulator whose activity is mediated by its protein-binding domains. We propose that during myelomonocytic cell differentiation, induction of p205 expression contributes to cell growth arrest, thus allowing progenitor cells to differentiate. PMID:15342947

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

    PubMed

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

    2014-07-01

    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.

  3. Chronic myeloid leukemia: reminiscences and dreams

    PubMed Central

    Mughal, Tariq I.; Radich, Jerald P.; Deininger, Michael W.; Apperley, Jane F.; Hughes, Timothy P.; Harrison, Christine J.; Gambacorti-Passerini, Carlo; Saglio, Giuseppe; Cortes, Jorge; Daley, George Q.

    2016-01-01

    With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people’s lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman. PMID:27132280

  4. Calcineurin/NFAT signalling inhibits myeloid haematopoiesis.

    PubMed

    Fric, Jan; Lim, Clarice X F; Koh, Esther G L; Hofmann, Benjamin; Chen, Jinmiao; Tay, Hock Soon; Mohammad Isa, Siti Aminah Bte; Mortellaro, Alessandra; Ruedl, Christiane; Ricciardi-Castagnoli, Paola

    2012-04-01

    Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signalling can also mediate granulocyte and dendritic cell (DC) activation, but it is unknown whether NFAT influences their development from progenitors. Here, we report a novel role for calcineurin/NFAT signalling as a negative regulator of myeloid haematopoiesis. Reconstituting lethally irradiated mice with haematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells in media supplemented with Flt3-L in the presence of the calcineurin/NFAT inhibitor Cyclosporin A increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. In conclusion, these results provide evidence that calcineurin/NFAT signalling negatively regulates myeloid lineage development. The finding that inhibition of NFAT enhances myeloid development provides a novel insight into understanding how the treatment with drugs targeting calcineurin/NFAT signalling influence the homeostasis of the innate immune system.

  5. Chronic myeloid leukemia: reminiscences and dreams.

    PubMed

    Mughal, Tariq I; Radich, Jerald P; Deininger, Michael W; Apperley, Jane F; Hughes, Timothy P; Harrison, Christine J; Gambacorti-Passerini, Carlo; Saglio, Giuseppe; Cortes, Jorge; Daley, George Q

    2016-05-01

    With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people's lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman.

  6. BCOR regulates myeloid cell proliferation and differentiation.

    PubMed

    Cao, Q; Gearhart, M D; Gery, S; Shojaee, S; Yang, H; Sun, H; Lin, D-C; Bai, J-W; Mead, M; Zhao, Z; Chen, Q; Chien, W-W; Alkan, S; Alpermann, T; Haferlach, T; Müschen, M; Bardwell, V J; Koeffler, H P

    2016-05-01

    BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1). Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukemia (AML). However, the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with upregulated expression of Hox genes. Mutation of Bcor reduced protein levels of RING1B, an H2A ubiquitin ligase subunit of PRC1 family complexes and reduced H2AK119ub upstream of upregulated HoxA genes. Global RNA expression profiling in murine cells and AML patient samples with BCOR loss-of-function mutation suggested that loss of BCOR expression is associated with enhanced cell proliferation and myeloid differentiation. Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. PMID:26847029

  7. Myeloid Cells in Cutaneous Wound Repair.

    PubMed

    Cash, Jenna L; Martin, Paul

    2016-06-01

    Cutaneous wound repair is a complex, dynamic process with the goal of rapidly sealing any breach in the skin's protective barrier. Myeloid cells compose a significant proportion of the inflammatory cells recruited to a wound site and play important roles in decontaminating the injured tissue of any invading microorganisms. Subsequently, myeloid cells are able to influence many aspects of the healing response, in part through their capacity to release a large array of signaling molecules that allow them to communicate with and regulate the behavior of other wound cells and in turn, be themselves exquisitely regulated by the wound microenvironment. Macrophages, for example, appear to play important, temporally changing roles in the initiation of scarring and subsequently in matrix remodeling to resolve fibrosis. In this way, myeloid cells seem to play both positive (e.g., pathogen killing and matrix remodeling) and negative (e.g., scarring) roles in wound repair. Further research is of course needed to elucidate the precise temporal and spatial myeloid cell phenotypes and behaviors and ultimately to design effective strategies to optimize the beneficial functions of these cells while minimizing their detrimental contributions to improve wound healing in the clinic. PMID:27337466

  8. Chronic myeloid leukemia: reminiscences and dreams.

    PubMed

    Mughal, Tariq I; Radich, Jerald P; Deininger, Michael W; Apperley, Jane F; Hughes, Timothy P; Harrison, Christine J; Gambacorti-Passerini, Carlo; Saglio, Giuseppe; Cortes, Jorge; Daley, George Q

    2016-05-01

    With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people's lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman. PMID:27132280

  9. Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-18

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

  10. Chimerism of bone marrow mesenchymal stem/stromal cells in allogeneic hematopoietic cell transplantation: is it clinically relevant?

    PubMed

    Miura, Yasuo; Yoshioka, Satoshi; Yao, Hisayuki; Takaori-Kondo, Akifumi; Maekawa, Taira; Ichinohe, Tatsuo

    2013-01-01

    Multipotent mesenchymal stem/stromal cells (MSCs) have been extensively used as a transplantable cell source for regenerative medicine and immunomodulatory therapy. Specifically in allogeneic hematopoietic stem cell transplantation (HSCT), co-transplantation or post-transplant infusion of MSCs derived from bone marrow (BM) of non-self donors has been implicated in accelerating hematopoietic recovery, ameliorating graft-vs.-host disease, and promoting tissue regeneration. However, irrespective of the use of MSC co-administration, post-transplant chimerism of BM-derived MSCs after allogeneic HSCT has been reported to remain of host origin, suggesting that the infused donor MSCs are immunologically rejected or not capable of long-term engraftment in the host microenvironment. Also, hematopoietic cell allografts currently used for HSCT do not seem to contain sufficient amount of MSCs or their precursors to reconstitute host BM microenvironment. Since the toxic conditioning employed in allo-HSCT may impair the function of host MSCs to maintain hematopoietic/regenerative stem cell niches and to provide a local immunomodulatory milieu, we propose that new directions for enhancing immunohematopoietic reconstitution and tissue repair after allogeneic HSCT include the development of strategies to support functional replenishment of residual host MSCs or to support more efficient engraftment of infused donor MSCs. Future areas of research should include in vivo tracking of infused MSCs and detection of their microchimeric presence in extra-marrow sites as well as in BM.

  11. Decitabine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-09-27

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); 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

  12. Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study

    PubMed Central

    Ferreira, Érika Elias; Guerra, Daiane Cristina; Baluz, Kátia; de Resende Furtado, Wander; da Silva Bouzas, Luis Fernando

    2014-01-01

    Objective This study aimed to describe and compare the nutritional status of adult patients submitted to allogeneic hematopoietic stem cell transplantation at two different time points (admission and discharge). Methods A retrospective, descriptive and quantitative study was performed based on clinical, laboratory and nutritional data obtained from medical records of adult patients of both genders submitted to allogeneic hematopoietic stem cell transplantation in a bone marrow transplantation reference center in Rio de Janeiro in the period from 2010 to 2013. Statistical analysis was performed using the SPSS software (version 22.0). Results Sixty-four patients were evaluated. The mean age was 42.1 ± 3.2 years and the most prevalent disease was acute myeloid leukemia (39%). There was a high prevalence of gastrointestinal symptoms including nausea (100%), vomiting (97%) and mucositis (93%). Between admission and discharge there was a significant decrease in the median weight (−2.5 kg; 71.5 vs. 68.75 kg; p-value < 0.001), body mass index (−0.9 kg/m2; 24.8 vs. 24.4 kg/m2; p-value < 0.001), and serum albumin levels (−0.2 g/dL; 3.7 vs. 3.6 g/dL; p-value = 0.024). The survival time after hematopoietic stem cell transplantation correlated negatively with C-reactive protein at discharge (CC = −0.72; p-value < 0.001) and positively with serum albumin levels (CC = 0.56; p-value = 0.004) and with high total protein level at discharge (CC = 0.53; p-value = 0.006). Conclusion Our results suggest that patients submitted to allogeneic hematopoietic stem cell transplantation have compromised nutritional status during the hospital stay for transplantation. PMID:25453651

  13. PECAM-1, apoptosis and CD34+ precursors.

    PubMed

    Zocchi, Maria R; Poggi, A

    2004-11-01

    Apoptosis is a physiological process that controls tissue homeostasis, in combination with survival signals delivered by distinct receptors that bind hormones, growth factors or extracellular matrix components. The extrinsic pathway of apoptosis is due to the triggering of death receptors and the activation of the caspase cascade; the intrinsic pathway is due to withdrawal of growth factors and mainly related to mitochondrial metabolism. The choice between survival or apoptosis, which is the result of such different integrated environmental signals, is crucial for the maintainance of bone marrow reservoir of hematopoietic precursors (HPC). CD34+ HPC can receive multiple survival signals during homing and maturation, due to different interactions with adhesion molecules expressed on endothelial and bone marrow stromal cells, proteins of the extracellular matrix and chemokines or growth factors. Among them, the signal delivered via platelet endothelial cell adhesion molecule-1 (PECAM-1) seems to contribute to the resistance of this cell population to starvation, and it is related to the maintainance of mitochondrial metabolism. Indeed, this molecule, originally described as an adhesion receptor belonging to the immunoglobulin superfamily, capable of homophilic and heterophilic interactions, turned out to be a signalling molecule, containing an immunoreceptor tyrosine-based inhibitory motifs (ITIM) within its cytoplasmic domain. In particular, it has been shown that PECAM-1 binds to different kinases and phosphatases, including the phosphatidylinositide-3-kinase that phosphorylates Akt, which, in turn can upregulate transcription and function of antiapoptotic proteins, such as Bcl-2 and Bcl-x or A1, responsible for the rescue from mitochondrial apoptosis. The possible role of PECAM-1 engagement in the prevention of starvation-induced apoptosis of HPC precursors and in the maintainance of their survival is discussed. PMID:15512808

  14. The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3(+) lymphocyte-primed multipotent precursors.

    PubMed

    Xiao, Jing; Zhou, Haibo; Wu, Ning; Wu, Li

    2016-09-01

    The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a(-)CD8α(+)conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3(+) lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging.

  15. The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3+ lymphocyte-primed multipotent precursors

    PubMed Central

    Xiao, Jing; Zhou, Haibo; Wu, Ning; Wu, Li

    2016-01-01

    The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a−CD8α+conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3+ lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging. PMID:26051474

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

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri

    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

  17. Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors

    PubMed Central

    Arai, Fumio; Miyamoto, Takeshi; Ohneda, Osamu; Inada, Tomohisa; Sudo, Tetsuo; Brasel, Kenneth; Miyata, Takashi; Anderson, Dirk M.; Suda, Toshio

    1999-01-01

    Osteoclasts are terminally differentiated cells derived from hematopoietic stem cells. However, how their precursor cells diverge from macrophagic lineages is not known. We have identified early and late stages of osteoclastogenesis, in which precursor cells sequentially express c-Fms followed by receptor activator of nuclear factor κB (RANK), and have demonstrated that RANK expression in early-stage of precursor cells (c-Fms+RANK−) was stimulated by macrophage colony-stimulating factor (M-CSF). Although M-CSF and RANKL (ligand) induced commitment of late-stage precursor cells (c-Fms+RANK+) into osteoclasts, even late-stage precursors have the potential to differentiate into macrophages without RANKL. Pretreatment of precursors with M-CSF and delayed addition of RANKL showed that timing of RANK expression and subsequent binding of RANKL are critical for osteoclastogenesis. Thus, the RANK–RANKL system determines the osteoclast differentiation of bipotential precursors in the default pathway of macrophagic differentiation. PMID:10601350

  18. The EM Earthquake Precursor

    NASA Astrophysics Data System (ADS)

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

    2013-12-01

    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

  19. ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation.

    PubMed

    Alemdehy, Mir Farshid; Haanstra, Jurgen R; de Looper, Hans W J; van Strien, Paulina M H; Verhagen-Oldenampsen, Judith; Caljouw, Yvette; Sanders, Mathijs A; Hoogenboezem, Remco; de Ru, Arnoud H; Janssen, George M C; Smetsers, Stephanie E; Bierings, Marc B; van Veelen, Peter A; von Lindern, Marieke; Touw, Ivo P; Erkeland, Stefan J

    2015-06-18

    Interstrand crosslinks (ICLs) are toxic DNA lesions that cause severe genomic damage during replication, especially in Fanconi anemia pathway-deficient cells. This results in progressive bone marrow failure and predisposes to acute myeloid leukemia (AML). The molecular mechanisms responsible for these defects are largely unknown. Using Ercc1-deficient mice, we show that Trp53 is responsible for ICL-induced bone marrow failure and that loss of Trp53 is leukemogenic in this model. In addition, Ercc1-deficient myeloid progenitors gain elevated levels of miR-139-3p and miR-199a-3p with age. These microRNAs exert opposite effects on hematopoiesis. Ectopic expression of miR-139-3p strongly inhibited proliferation of myeloid progenitors, whereas inhibition of miR-139-3p activity restored defective proliferation of Ercc1-deficient progenitors. Conversely, the inhibition of miR-199a-3p functions aggravated the myeloid proliferation defect in the Ercc1-deficient model, whereas its enforced expression enhanced proliferation of progenitors. Importantly, miR-199a-3p caused AML in a pre-leukemic mouse model, supporting its role as an onco-microRNA. Target genes include HuR for miR-139-3p and Prdx6, Runx1, and Suz12 for miR-199a-3p. The latter genes have previously been implicated as tumor suppressors in de novo and secondary AML. These findings show that, in addition to TRP53-controlled mechanisms, miR-139-3p and miR-199a-3p are involved in the defective hematopoietic function of ICL-repair deficient myeloid progenitors. PMID:25778535

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

    PubMed Central

    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

    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

  1. Midostaurin and Decitabine in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia and FLT3 Mutation

    ClinicalTrials.gov

    2016-10-10

    Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Gene Mutations; FLT3 Tyrosine Kinase Domain Point Mutation; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  2. miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells

    PubMed Central

    Lechman, Eric R.; Gentner, Bernhard; Ng, Stanley W.K.; Schoof, Erwin M.; van Galen, Peter; Kennedy, James A.; Nucera, Silvia; Ciceri, Fabio; Kaufmann, Kerstin B.; Takayama, Naoya; Dobson, Stephanie M.; Trotman-Grant, Aaron; Krivdova, Gabriela; Elzinga, Janneke; Mitchell, Amanda; Nilsson, Björn; Hermans, Karin G.; Eppert, Kolja; Marke, Rene; Isserlin, Ruth; Voisin, Veronique; Bader, Gary D.; Zandstra, Peter W.; Golub, Todd R.; Ebert, Benjamin L.; Lu, Jun; Minden, Mark; Wang, Jean C.Y.; Naldini, Luigi; Dick, John E.

    2016-01-01

    Summary To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance. PMID:26832662

  3. CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation.

    PubMed

    Kumar, Vinit; Cheng, Pingyan; Condamine, Thomas; Mony, Sridevi; Languino, Lucia R; McCaffrey, Judith C; Hockstein, Neil; Guarino, Michael; Masters, Gregory; Penman, Emily; Denstman, Fred; Xu, Xiaowei; Altieri, Dario C; Du, Hong; Yan, Cong; Gabrilovich, Dmitry I

    2016-02-16

    Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy. PMID:26885857

  4. JAK2 V617F in myeloid disorders: molecular diagnostic techniques and their clinical utility: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology.

    PubMed

    Steensma, David P

    2006-09-01

    In early 2005, several groups of investigators studying myeloid malignancies described a novel somatic point mutation (V617F) in the conserved autoinhibitory pseudokinase domain of the Janus kinase 2 (JAK2) protein, which plays an important role in normal hematopoietic growth factor signaling. The V617F mutation is present in blood and marrow from a large proportion of patients with classic BCR/ABL-negative chronic myeloproliferative disorders and of a few patients with other clonal hematological diseases such as myelodysplastic syndrome, atypical myeloproliferative disorders, and acute myeloid leukemia. The JAK2 V617F mutation causes constitutive activation of the kinase, with deregulated intracellular signaling that mimics continuous hematopoietic growth factor stimulation. Within 7 months of the first electronic publication describing this new mutation, clinical molecular diagnostic laboratories in the United States and Europe began offering JAK2 mutation testing on a fee-for-service basis. Here, I review the various techniques used by research groups and clinical laboratories to detect the genetic mutation underlying JAK2 V617F, including fluorescent dye chemistry sequencing, allele-specific polymerase chain reaction (PCR), real-time PCR, DNA-melting curve analysis, pyrosequencing, and others. I also discuss diagnostic sensitivity, performance, and other practical concerns relevant to the clinical laboratorian in addition to the potential diagnostic utility of JAK2 mutation tests.

  5. Hematopoietic stem cell transplantation for HIV cure.

    PubMed

    Kuritzkes, Daniel R

    2016-02-01

    The apparent cure of an HIV-infected person following hematopoietic stem cell transplantation (HSCT) from an allogeneic donor homozygous for the ccr5Δ32 mutation has stimulated the search for strategies to eradicate HIV or to induce long-term remission without requiring ongoing antiretroviral therapy. A variety of approaches, including allogeneic HSCT from CCR5-deficient donors and autologous transplantation of genetically modified hematopoietic stem cells, are currently under investigation. This Review covers the experience with HSCT in HIV infection to date and provides a survey of ongoing work in the field. The challenges of developing HSCT for HIV cure in the context of safe, effective, and convenient once-daily antiretroviral therapy are also discussed.

  6. Hematopoietic progenitor migration to the adult thymus

    PubMed Central

    Zlotoff, Daniel A.; Bhandoola, Avinash

    2010-01-01

    While most hematopoietic lineages develop in the bone marrow (BM), T cells uniquely complete their development in the specialized environment of the thymus. Hematopoietic stem cells with long-term self-renewal capacity are not present in the thymus. As a result, continuous T cell development requires that BM-derived progenitors be imported into the thymus throughout adult life. The process of thymic homing begins with the mobilization of progenitors out of the bone marrow, continues with their circulation in the bloodstream, and concludes with their settling in the thymus. This review will discuss each of these steps as they occur in the unirradiated and post-irradiation scenarios, focusing on the molecular mechanisms of regulation. Improved knowledge about these early steps in T cell generation may accelerate the development of new therapeutic options in patients with impaired T cell number or function. PMID:21251013

  7. Hematopoietic stem cell origin of connective tissues.

    PubMed

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications.

  8. Epigenomics in hematopoietic transplantation: novel treatment strategies.

    PubMed

    Engel, Nicole; Rank, Andreas

    2011-10-01

    Allogeneic hematopoietic stem cell transplantation is a high risk but curative treatment option for leukemia, myelodysplasia and other hematological malignancies. After high dose radio- or chemo-therapy, recipient's hematopoiesis is replaced by a new immunosystem and residual malignant cells are eliminated by the graft-versus-leukemia reaction. The benefit of this immunological effect is limited by the most frequent complication of hematopoietic stem cell transplantation: graft-versus-host disease. In addition to their well-known anti-tumor activity, epigenetic drugs mediate immunotolerance without reducing alloreactivity or even enhance graft-versus-leukemia effect without inducing graft-versus-host disease by regulating cytokine release, increasing the circulating number of regulatory T cells and interacting with natural killer cells. We focus on the use of epigenetic drugs in the allogeneic transplantation setting in relation to their anti-tumor and immunomodulatory potential.

  9. Making sense of hematopoietic stem cell niches

    PubMed Central

    Boulais, Philip E.

    2015-01-01

    The hematopoietic stem cell (HSC) niche commonly refers to the pairing of hematopoietic and mesenchymal cell populations that regulate HSC self-renewal, differentiation, and proliferation. Anatomic localization of the niche is a dynamic unit from the developmental stage that allows proliferating HSCs to expand before they reach the bone marrow where they adopt a quiescent phenotype that protects their integrity and functions. Recent studies have sought to clarify the complexity behind the HSC niche by assessing the contributions of specific cell populations to HSC maintenance. In particular, perivascular microenvironments in the bone marrow confer distinct vascular niches that regulate HSC quiescence and the supply of lineage-committed progenitors. Here, we review recent data on the cellular constituents and molecular mechanisms involved in the communication between HSCs and putative niches. PMID:25762174

  10. Hematopoietic stem cell engineering at a crossroads.

    PubMed

    Rivière, Isabelle; Dunbar, Cynthia E; Sadelain, Michel

    2012-02-01

    The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead.

  11. Hematopoietic stem cell engineering at a crossroads

    PubMed Central

    Rivière, Isabelle; Dunbar, Cynthia E.

    2012-01-01

    The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead. PMID:22096239

  12. Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies

    ClinicalTrials.gov

    2016-05-25

    Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Essential Thrombocythemia; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm; Polycythemia Vera; Previously Treated Myelodysplastic Syndrome; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  13. Effects of the bone marrow microenvironment on hematopoietic malignancy.

    PubMed

    Askmyr, Maria; Quach, Julie; Purton, Louise E

    2011-01-01

    The bone marrow (BM) is contained within the bone cavity and is the main site of hematopoiesis, the continuous development of blood cells from immature hematopoietic stem and progenitor cells. The bone marrow consists of developing hematopoietic cells and non-hematopoietic cells, the latter collectively termed the bone marrow microenvironment. These non-hematopoietic cells include cells of the osteoblast lineage, adipocytes and endothelial cells. For many years these bone marrow microenvironment cells were predicted to play active roles in regulating hematopoiesis, and recent studies have confirmed such roles. Importantly, more recent data has indicated that cells of the BM microenvironment may also contribute to hematopoietic diseases. In this review we provide an overview of the roles of the data suggesting that the cells of the bone marrow microenvironment may play an active role in the initiation and progression of hematopoietic malignancy.

  14. Acute Myeloid Leukaemia Diagnosed by Intra-Oral Myeloid Sarcoma. A Case Report

    PubMed Central

    Papamanthos, Mattheos K.; Skulakis, Haralampos E.; Fericean, Angela-Monika A.; Zorba, Matina T.; Matiakis, Apostolos T.

    2010-01-01

    Myeloid sarcoma (MS) is a rare extramedullary malignant tumor composed of immature myeloid cells. It is strongly associated with a well known or covert acute myeloid leukaemia, chronic myeloproliferative diseases or myelodysplastic syndromes. Intraoral MS scarcely occurs. An unusual case of acute myeloid leukaemia, which was diagnosed by mandibular MS that was developed in the alveolar socket after a dental extraction, is reported. The histological examination (including immunohistochemical analysis) of a subsequent biopsy showed infiltration of the oral mucosa by neoplastic cells. This lesion was therefore classified as acute myeloid leukaemia. The patient was referred to oncologists that confirmed the initial diagnosis. The patient underwent chemotherapy and the mandibular tumor disappeared. Forty days later, a relapse of the disease, which appeared as a great-ulcerated lesion, was developed in the hard palate. Thirty days after the second chemotherapy had finished, a new intraoral tumor was developed in the vestibular maxillary gingiva. Review of the literature shows no report of intraoral relapse and particularly multiple relapse of a MS that involves the oral cavity. Even though MS is encountered infrequently in the oral cavity, it should be considered in the differential diagnosis of conditions (especially tumors) with a similar clinical appearance. PMID:20512638

  15. Myeloid-derived cells are key targets of tumor immunotherapy

    PubMed Central

    Medina-Echeverz, José; Aranda, Fernando; Berraondo, Pedro

    2014-01-01

    Tumors are composed of heterogeneous cell populations recruited by cancer cells to promote growth and metastasis. Among cells comprising the tumor stroma, myeloid-derived cells play pleiotropic roles in supporting tumorigenesis at distinct stages of tumor development. The tumor-infiltrating myeloid cell contingent is composed of mast cells, neutrophils, dendritic cells, macrophages, and myeloid-derived suppressor cells. Such cells are capable of evading the hostile tumor environment typically prone to immune cell destruction and can even promote angiogenesis, chronic inflammation, and invasion. This paper briefly summarizes the different myeloid-derived subsets that promote tumor development and the strategies that have been used to counteract the protumorigenic activity of these cells. These strategies include myeloid cell depletion, reduction of recruitment, and inactivation or remodeling of cell phenotype. Combining drugs designed to target tumor myeloid cells with immunotherapies that effectively trigger antitumor adaptive immune responses holds great promise in the development of novel cancer treatments. PMID:25050208

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

    ClinicalTrials.gov

    2016-01-07

    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

  17. Phase I Trial of AZD1775 and Belinostat in Treating Patients With Relapsed or Refractory Myeloid Malignancies or Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-20

    Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  18. Chronic variable stress activates hematopoietic stem cells

    PubMed Central

    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

    2014-01-01

    Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis1,2. While incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known crosstalk 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 reflex3,4. It remains unknown however if chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive 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. Sympathetic nerve fibers release surplus noradrenaline, which uses the β3 adrenergic receptor to signal bone marrow niche cells to decrease CXCL12 levels. Consequently, elevated hematopoietic stem cell proliferation increases output of neutrophils and inflammatory monocytes. When atherosclerosis–prone ApoE−/− mice encounter chronic stress, accelerated hematopoiesis promotes plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans. PMID:24952646

  19. Response of human hematopoietic precursor cells (CFUc) to hyperthermia and radiation

    SciTech Connect

    Bromer, R.H.; Mitchell, J.B.; Soares, N.

    1982-04-01

    Currently, whole-body and local hyperthermia is being evaluated in clinical studies as a potential method of cancer treatment. Since the hyperthermic sensitivity of normal human bone marrow cells is not known, we have studied the in vitro response of these cells to two anticancer modalities when administered alone or in combination. Cell survival following various treatment schedules was determined by colony formation of bone marrow cells (CFUc) in soft agar suspensions. Within the survival range studied, a thermal tolerant plateau on the cell survival was not observed for temperatures of 42 degrees or less. However, thermotolerance induction could not be ruled out. In addition, when hyperthermia (42.5 degrees for 1 hr) and radiation (100 rads) were sequenced, the human CFUc survival remained the same regardless of whether the radiation was administered before, during, or after the hyperthermic exposure. Under our experimental conditions, we found the human CFUc to be more radiosensitive (D0 . 84 rads) than what has been reported previously. The radiation survival response of human CFUc was similar for cells irradiated either in vitro or in vivo. The possible clinical implications for these data are discussed.

  20. Myeloid derived suppressor cells and autoimmunity.

    PubMed

    Boros, Peter; Ochando, Jordi; Zeher, Margit

    2016-08-01

    Myeloid-derived suppressor cells are a heterogeneous group of immature myeloid cells with immunoregulatory function. When activated and expanded, these cells can suppress T cell functions via cell-to cell interactions as well as soluble mediators. Recent studies investigated the involvement of MDSC in autoimmune diseases. Some papers have described beneficial effect of MDSC during the course of autoimmune diseases, and suggest a potential role as a treatment option, while others failed to detect these effects. Their contributions to autoimmune diseases are not fully understood, and many questions and some controversies remain as to the expansion, activation, and inhibitory functions of MDSC. This review aims to summarize current knowledge of MDSC in autoimmune disorders. PMID:27240453

  1. Combination Chemotherapy and Dasatinib in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-19

    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; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  2. Megakaryocyte growth and development factor is a potent growth factor for primitive hematopoietic progenitors in the human fetus.

    PubMed

    Muench, Marcus O; Bárcena, Alicia

    2004-06-01

    Megakaryocyte growth and development factor (MGDF), or thrombopoietin, has received considerable attention as a therapeutic agent for treating thrombocytopenia or for its use in the ex vivo culture of hematopoietic stem cells. MGDF is known to support the growth of a broad spectrum of hematopoietic precursors obtained from adult or neonatal tissues, but its effects on the growth of fetal progenitors and stem cells has not been studied. Human CD38(+)CD34(2+) progenitors and CD38(-)CD34(2+) cells, a population that contains stem cells, were isolated from midgestation liver and grown under defined conditions with MGDF and various cytokines known to support the growth of primitive hematopoietic precursors. In clonal assays of colony-forming cells (CFCs), MGDF supported the growth of 15-25% of candidate stem cells when combined with granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), flk-2/flt3 ligand, or stem cell factor. MGDF was observed to strongly support the early stages of hematopoiesis and expansion of high proliferative potential CFCs. More mature progenitors were expanded nearly 78-fold in 1 wk of culture with MGDF+SCF+GM-CSF. MGDF alone was also found to support the short-term (2 d) survival of CD38(-)CD34(2+) high proliferative potential CFCs. The effects of MGDF were more modest on CD38(+)CD34(2+) progenitors with only additive increases in colony formation being observed. These findings suggest that MGDF administration in fetuses and neonates may strongly affect the growth and mobilization of primitive hematopoietic progenitors and that MGDF may find use in the ex vivo growth and expansion of fetal stem cells.

  3. Development of the definitive hematopoietic hierarchy in the mouse.

    PubMed

    Medvinsky, A L; Dzierzak, E A

    1998-01-01

    Recent research on the ontogeny of the hematopoietic system in mammals has shown that a simple textbook steady-state hematopoietic hierarchy can not be strictly applied to the hematopoietic cells found within the embryo. During embryonic development, hematopoietic cells originate, migrate and differentiate in a number of distinct anatomical sites such as the yolk sac AGM region and liver and thus represent various classes of cells within diverse microenvironments. In this manuscript we review both cellular and molecular aspects of developmental hematopoiesis and present our current views on the numerous complex mechanisms underlying the establishment of definitive hematopoiesis. PMID:9700459

  4. Precursors of prostate cancer.

    PubMed

    Bostwick, David G; Cheng, Liang

    2012-01-01

    High-grade prostatic intraepithelial neoplasia (PIN) is the only accepted precursor of prostatic adenocarcinoma, according to numerous studies of animal models and man; other proposed precursors include atrophy and malignancy-associated changes (with no morphologic changes). PIN is characterized by progressive abnormalities of phenotype and genotype that are intermediate between benign prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. The only method of detection of PIN is biopsy because it does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultrasonography. The mean incidence of PIN in biopsies is 9% (range, 4%-16%), representing about 115,000 new cases of isolated PIN diagnosed each year in the United States. The clinical importance of PIN is its high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent carcinoma, especially when multifocal or observed in association with atypical small acinar proliferation (ASAP). Carcinoma develops in most patients with PIN within 10 years. Androgen deprivation therapy and radiation therapy decrease the prevalence and extent of PIN, suggesting that these forms of treatment may play a role in prevention of subsequent cancer. Multiple clinical trials to date of men with PIN have had modest success in delaying or preventing subsequent cancer. PMID:22212075

  5. Bortezomib in Treating Patients With High-Risk Acute Myeloid Leukemia in Remission

    ClinicalTrials.gov

    2014-10-30

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia

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

    ClinicalTrials.gov

    2016-07-26

    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

  7. RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation

    PubMed Central

    Palanichamy, Jayanth Kumar; Tran, Tiffany M.; Howard, Jonathan M.; Contreras, Jorge R.; Fernando, Thilini R.; Sterne-Weiler, Timothy; Katzman, Sol; Toloue, Masoud; Yan, Weihong; Sanford, Jeremy R.; Rao, Dinesh S.

    2016-01-01

    Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia–rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3′ untranslated regions (3′UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease. PMID:26974154

  8. Lineage-restricted expression of homeobox-containing genes in human hematopoietic cell lines.

    PubMed

    Shen, W F; Largman, C; Lowney, P; Corral, J C; Detmer, K; Hauser, C A; Simonitch, T A; Hack, F M; Lawrence, H J

    1989-11-01

    We investigated the role of homeobox-containing genes in human hematopoiesis because homeobox genes (i) control cell fate in the Drosophila embryo, (ii) are expressed in specific patterns in human embryos, and (iii) appear to function as transcription factors that control cell phenotype in other mammalian organs. Using four homeobox probes from the HOX2 locus and a previously undescribed homeobox cDNA (PL1), we screened mRNAs from 18 human leukemic cell lines representing erythroid, myeloid, and T- and B-cell lineages. Complex patterns of lineage-restricted expression are observed: some are restricted to a single lineage, while others are expressed in multiple lineages. No single homeobox gene is expressed in all types of hematopoietic cells, but each cell type exhibits homeobox gene expression. HOX2.2 and -2.3 homeobox-containing cDNAs were cloned from an erythroleukemia cell (HEL) cDNA library, while the homeobox cDNA PL1 was isolated from a monocytic cell (U-937) library. Differentiation of HEL and K-562 cells with various inducers results in modulation of specific homeobox transcripts. In addition, HOX2.2 is expressed in normal bone marrow cells. We have demonstrated (i) lineage-restricted expression of five homeobox genes in erythroid and monocytic cell lines; (ii) expression of additional homeobox genes in other cell lineages (HL-60 and lymphoid cells); (iii) expression of one homeobox gene in normal marrow cells; and (iv) modulation of expression during differentiation. These data suggest that these genes play a role in human hematopoietic development and lineage commitment.

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

    PubMed Central

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

    2012-01-01

    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 α-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

  10. Lineage-restricted expression of homeobox-containing genes in human hematopoietic cell lines.

    PubMed Central

    Shen, W F; Largman, C; Lowney, P; Corral, J C; Detmer, K; Hauser, C A; Simonitch, T A; Hack, F M; Lawrence, H J

    1989-01-01

    We investigated the role of homeobox-containing genes in human hematopoiesis because homeobox genes (i) control cell fate in the Drosophila embryo, (ii) are expressed in specific patterns in human embryos, and (iii) appear to function as transcription factors that control cell phenotype in other mammalian organs. Using four homeobox probes from the HOX2 locus and a previously undescribed homeobox cDNA (PL1), we screened mRNAs from 18 human leukemic cell lines representing erythroid, myeloid, and T- and B-cell lineages. Complex patterns of lineage-restricted expression are observed: some are restricted to a single lineage, while others are expressed in multiple lineages. No single homeobox gene is expressed in all types of hematopoietic cells, but each cell type exhibits homeobox gene expression. HOX2.2 and -2.3 homeobox-containing cDNAs were cloned from an erythroleukemia cell (HEL) cDNA library, while the homeobox cDNA PL1 was isolated from a monocytic cell (U-937) library. Differentiation of HEL and K-562 cells with various inducers results in modulation of specific homeobox transcripts. In addition, HOX2.2 is expressed in normal bone marrow cells. We have demonstrated (i) lineage-restricted expression of five homeobox genes in erythroid and monocytic cell lines; (ii) expression of additional homeobox genes in other cell lineages (HL-60 and lymphoid cells); (iii) expression of one homeobox gene in normal marrow cells; and (iv) modulation of expression during differentiation. These data suggest that these genes play a role in human hematopoietic development and lineage commitment. Images PMID:2573064

  11. RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation.

    PubMed

    Palanichamy, Jayanth Kumar; Tran, Tiffany M; Howard, Jonathan M; Contreras, Jorge R; Fernando, Thilini R; Sterne-Weiler, Timothy; Katzman, Sol; Toloue, Masoud; Yan, Weihong; Basso, Giuseppe; Pigazzi, Martina; Sanford, Jeremy R; Rao, Dinesh S

    2016-04-01

    Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.

  12. Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells.

    PubMed

    Slukvin, Igor I

    2013-12-12

    Significant advances in cellular reprogramming technologies and hematopoietic differentiation from human pluripotent stem cells (hPSCs) have already enabled the routine production of multiple lineages of blood cells in vitro and opened novel opportunities to study hematopoietic development, model genetic blood diseases, and manufacture immunologically matched cells for transfusion and cancer immunotherapy. However, the generation of hematopoietic cells with robust and sustained multilineage engraftment has not been achieved. Here, we highlight the recent advances in understanding the molecular and cellular pathways leading to blood development from hPSCs and discuss potential approaches that can be taken to facilitate the development of technologies for de novo production of hematopoietic stem cells.

  13. Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status.

    PubMed

    Liu, Na; Ning, Hong-Mei; Hu, Liang-Ding; Jiang, Min; Xu, Chen; Hu, Jiang-Wei; Wang, Jun; Li, Yu-Hang; Li, Bo-Tao; Lou, Xiao; Yang, Fan; Chen, Jian-Lin; Su, Yong-Feng; Li, Meng; Wang, Hong-Ye; Ren, Jing; Feng, Yue-Qian; Zhang, Bin; Wang, Dan-Hong; Chen, Hu

    2015-12-01

    To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group. PMID:26530539

  14. Haploidentical hematopoietic stem cell transplantation without total body irradiation for pediatric acute leukemia: a single-center experience

    PubMed Central

    Mu, Yanshun; Qin, Maoquan; Wang, Bin; Li, Sidan; Zhu, Guanghua; Zhou, Xuan; Yang, Jun; Wang, Kai; Lin, Wei; Zheng, Huyong

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is a promising method for therapy of pediatric patients with acute leukemia. However, less availability of matched donors limited its wide application. Recently, haploidentical HSCT has become a great resource. Here, we have retrospectively reported our experience of 20 pediatric patients with acute leukemia who underwent haploidentical HSCT without total body irradiation (TBI) myeloablative regimen in our center from November 2007 to June 2014. All the patients attained successful HSCT engraftment in terms of myeloid and platelet recovery. Thirteen patients developed grade I–IV acute graft-versus-host disease (a-GVHD). The incidence of grade I–II a-GVHD, grade III–IV a-GVHD, and chronic GVHD (c-GVHD) was 45%, 20%, and 25%, respectively. The mean myeloid and platelet recovery time was 13.20±2.41 and 19.10±8.37 days. The median follow-up time was 43.95±29.26 months. During the follow-up, three patients died. The overall survival (OS) rate was 85%. The present study indicated that haploidentical HSCT without TBI myeloablative regimen significantly improved the OS rate of pediatric patients with acute leukemia. PMID:27217774

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

    PubMed Central

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

    2015-01-01

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

  16. MDS: a stem cell disorder--but what exactly is wrong with the primitive hematopoietic cells in this disease?

    PubMed

    Nimer, Stephen D

    2008-01-01

    Despite the various abnormalities identified in the immune system or the bone marrow microenvironment in patients with myelodysplastic syndrome (MDS), most of the investigation of this disorder has centered on the hematopoietic stem/progenitor compartment. It is generally written that MDS is a stem cell disorder, and there is certainly evidence supporting this view. However, whether it occurs in a cell with only myeloid multipotentiality (i.e., that involves megakaryocytic, erythroid and granulocytic/monocytic lineages) or occurs in a true stem cell is open to debate. The absence of an assay for human stem cells necessitates the use of surrogate markers for such cells, such as gene expression profiles, or the identification of specific genetic or epigenetic abnormalities that are found in multiple lineages. Clearly, the common cytogenetic and genetic abnormalities found in MDS are most indicative of a clonal myeloid disease similar to AML, rather than a lymphoid disease, and the often tri-lineage ineffective hematopoiesis and dysplasia are generally not found within the lymphoid compartment. Recent studies, using modern molecular detection techniques, have identified new recurring molecular lesions in these disorders but have not really unraveled its pathogenesis.

  17. VSTM-v1, a potential myeloid differentiation antigen that is downregulated in bone marrow cells from myeloid leukemia patients.

    PubMed

    Xie, Min; Li, Ting; Li, Ning; Li, Jinlan; Yao, Qiumei; Han, Wenling; Ruan, Guorui

    2015-01-01

    Leukocyte differentiation antigens often represent important markers for the diagnosis, classification, prognosis, and therapeutic targeting of myeloid leukemia. Herein, we report a potential leukocyte differentiation antigen gene VSTM1 (V-set and transmembrane domain-containing 1) that was downregulated in bone marrow cells from leukemia patients and exhibited a higher degree of promoter methylation. The expression level of its predominant encoded product, VSTM1-v1, was positively correlated with myeloid cell maturation state. Restoration of VSTM1-v1 expression inhibited myeloid leukemia cells' growth. Therefore, VSTM1-v1 might represent an important myeloid leukocyte differentiation antigen and provide a potential target for the diagnosis and treatment of leukemia.

  18. [Transformation of secondary myelodysplastic syndrome to atypical chronic myeloid leukemia in a female patient with acute myeloid leukemia].

    PubMed

    Gritsaev, S V; Kostroma, I I; Zapreeva, I M; Shmidt, A V; Tiranova, S A; Balashova, V A; Martynkevich, I S; Chubukina, Zh V; Semenova, N Yu; Chechetkin, A V

    2016-01-01

    Secondary myeloid neoplasia may be a complication of intensive cytostatic therapy. The most common types of secondary neoplasias are acute myeloid leukemia and myelodysplastic syndrome. The development of secondary atypical chronic myeloid leukemia (aCML) is an extremely rare phenomenon. The paper describes transformation of secondary myelodysplastic syndrome to aCML 6 months after its diagnosis. The development of aCML was accompanied by additional chromosomal aberration as monosomy of chromosome 17. No mutations in the JAK2, MPL, and CalR genes were detected. It is concluded that the clinical course of secondary myeloid neoplasias is variable.

  19. Mathematical modeling reveals differential effects of erythropoietin on proliferation and lineage commitment of human hematopoietic progenitors in early erythroid culture

    PubMed Central

    Ward, Daniel; Carter, Deborah; Homer, Martin; Marucci, Lucia; Gampel, Alexandra

    2016-01-01

    Erythropoietin is essential for the production of mature erythroid cells, promoting both proliferation and survival. Whether erythropoietin and other cytokines can influence lineage commitment of hematopoietic stem and progenitor cells is of significant interest. To study lineage restriction of the common myeloid progenitor to the megakaryocyte/erythroid progenitor of peripheral blood CD34+ cells, we have shown that the cell surface protein CD36 identifies the earliest lineage restricted megakaryocyte/erythroid progenitor. Using this marker and carboxyfluorescein succinimidyl ester to track cell divisions in vitro, we have developed a mathematical model that accurately predicts population dynamics of erythroid culture. Parameters derived from the modeling of cultures without added erythropoietin indicate that the rate of lineage restriction is not affected by erythropoietin. By contrast, megakaryocyte/erythroid progenitor proliferation is sensitive to erythropoietin from the time that CD36 first appears at the cell surface. These results shed new light on the role of erythropoietin in erythropoiesis and provide a powerful tool for further study of hematopoietic progenitor lineage restriction and erythropoiesis. PMID:26589912

  20. Lymphoid and Myeloid Recovery in Rhesus Macaques Following Total Body X-Irradiation.

    PubMed

    Farese, Ann M; Hankey, Kim G; Cohen, Melanie Veirs; MacVittie, Thomas J

    2015-11-01

    Recovery from severe immunosuppression requires hematopoietic stem cell reconstitution and effective thymopoiesis to restore a functional immune cell repertoire. Herein, a model of immune cell reconstitution consequent to potentially lethal doses of irradiation is described, which may be valuable in evaluating potential medical countermeasures. Male rhesus macaques were total body irradiated by exposure to 6.00 Gy 250 kVp x-radiation (midline tissue dose, 0.13 Gy min), resulting in an approximate LD10/60 (n = 5/59). Animals received medical management, and hematopoietic and immune cell recovery was assessed (n ≤ 14) through 370 d post exposure. A subset of animals (n ≤ 8) was examined through 700 d. Myeloid recovery was assessed by neutrophil and platelet-related parameters. Lymphoid recovery was assessed by the absolute lymphocyte count and FACS-based phenotyping of B- and T-cell subsets. Recent thymic emigrants were identified by T cell receptor excision circle quantification. Severe neutropenia, lymphopenia, and thrombocytopenia resolved within 30 d. Total CD3+ cells μL required 60 d to reach values 60% of normal, followed by subsequent slow recovery to approximately normal by 180 d post irradiation. Recovery of CD3+4+ and CD3+8+ cell memory and naïve subsets were markedly different. Memory populations were ≥ 100% of normal by day 60, whereas naïve populations were only 57% normal at 180 d and never fully recovered to baseline post irradiation. Total (CD20+) B cells μL were within normal levels by 77 d post exposure. This animal model elucidates the variable T- and B-cell subset recovery kinetics after a potentially lethal dose of total-body irradiation that are dependent on marrow-derived stem and progenitor cell recovery, peripheral homeostatic expansion, and thymopoiesis.

  1. The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases

    PubMed Central

    Shizuru, Judith A.

    2008-01-01

    Advances in the understanding of the cells of the hematopoietic system have provided a rich basis for improving clinical hematopoietic cell transplants; finding and using proteins and molecules to amplify or suppress particular blood cell types; understanding the stepwise progression of preleukemic stages leading first to chronic myeloid disorders, then the emergence of acute blastic leukemias; and treating malignant and nonmalignant diseases with cell subsets. As a result of intense scientific investigation, hematopoietic stem cells (HSCs) have been isolated and their key functional characteristics revealed—self-renewal and multilineage differentiation. These characteristics are now found to be present in all tissue/organ stem cell studies, and even in the analysis of pluripotent embryonic, nuclear transfer, and induced pluripotent stem cells. Studies on HSC have identified hematopoiesis as one of the best systems for studying developmental cell lineages and as the best for understanding molecular changes in cell fate decision-making and for finding preclinical and clinical platforms for tissue and organ replacement, regeneration, and oncogenesis. Here we review the steps, from our viewpoint, that led to HSC isolation and its importance in self-nonself immune recognition. PMID:18948588

  2. Effect of The Receptor Activator of Nuclear Factor кB and RANK Ligand on In Vitro Differentiation of Cord Blood CD133+ Hematopoietic Stem Cells to Osteoclasts

    PubMed Central

    Kalantari, Nasim; Abroun, Saeid; Soleimani, Masoud; Kaviani, Saeid; Azad, Mehdi; Eskandari, Fatemeh; Habibi, Hossein

    2016-01-01

    Objective Receptor activator of nuclear factor-kappa B ligand (RANKL) appears to be an osteoclast-activating factor, bearing an important role in the pathogenesis of multiple myeloma. Some studies demonstrated that U-266 myeloma cell line and primary myeloma cells expressed RANK and RANKL. It had been reported that the expression of myeloid and monocytoid markers was increased by co-culturing myeloma cells with hematopoietic stem cells (HSCs). This study also attempted to show the molecular mechanism of RANK and RANKL on differentiation capability of human cord blood HSC to osteoclast, as well as expression of calcitonin receptor (CTR) on cord blood HSC surface. Materials and Methods In this experimental study, CD133+ hematopoietic stem cells were isolated from umbilical cord blood and cultured in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL. Osteoclast differentiation was characterized by using tartrate-resistant acid phosphatase (TRAP) staining, giemsa staining, immunophenotyping, and reverse transcription-polymerase chain reaction (RT-PCR) assay for specific genes. Results Hematopoietic stem cells expressed RANK before and after differentiation into osteoclast. Compared to control group, flow cytometric results showed an increased expression of RANK after differentiation. Expression of CTR mRNA showed TRAP reaction was positive in some differentiated cells, including osteoclast cells. Conclusion Presence of RANKL and M-CSF in bone marrow could induce HSCs differentiation into osteoclast.

  3. Effect of The Receptor Activator of Nuclear Factor кB and RANK Ligand on In Vitro Differentiation of Cord Blood CD133+ Hematopoietic Stem Cells to Osteoclasts

    PubMed Central

    Kalantari, Nasim; Abroun, Saeid; Soleimani, Masoud; Kaviani, Saeid; Azad, Mehdi; Eskandari, Fatemeh; Habibi, Hossein

    2016-01-01

    Objective Receptor activator of nuclear factor-kappa B ligand (RANKL) appears to be an osteoclast-activating factor, bearing an important role in the pathogenesis of multiple myeloma. Some studies demonstrated that U-266 myeloma cell line and primary myeloma cells expressed RANK and RANKL. It had been reported that the expression of myeloid and monocytoid markers was increased by co-culturing myeloma cells with hematopoietic stem cells (HSCs). This study also attempted to show the molecular mechanism of RANK and RANKL on differentiation capability of human cord blood HSC to osteoclast, as well as expression of calcitonin receptor (CTR) on cord blood HSC surface. Materials and Methods In this experimental study, CD133+ hematopoietic stem cells were isolated from umbilical cord blood and cultured in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL. Osteoclast differentiation was characterized by using tartrate-resistant acid phosphatase (TRAP) staining, giemsa staining, immunophenotyping, and reverse transcription-polymerase chain reaction (RT-PCR) assay for specific genes. Results Hematopoietic stem cells expressed RANK before and after differentiation into osteoclast. Compared to control group, flow cytometric results showed an increased expression of RANK after differentiation. Expression of CTR mRNA showed TRAP reaction was positive in some differentiated cells, including osteoclast cells. Conclusion Presence of RANKL and M-CSF in bone marrow could induce HSCs differentiation into osteoclast. PMID:27602313

  4. An interstellar precursor mission

    NASA Technical Reports Server (NTRS)

    Jaffe, L. D.; Ivie, C.; Lewis, J. C.; Lipes, R. G.; Norton, H. N.; Stearns, J. W.; Stimpson, L.; Weissman, P.

    1977-01-01

    A mission out of the planetary system, with launch about the year 2000, could provide valuable scientific data as well as test some of the technology for a later mission to another star. Primary scientific objectives for the precursor mission concern characteristics of the heliopause, the interstellar medium, stellar distances (by parallax measurements), low energy cosmic rays, interplanetary gas distribution, and mass of the solar system. Secondary objectives include investigation of Pluto. Candidate science instruments are suggested. Individual spacecraft systems for the mission were considered, technology requirements and problem areas noted, and a number of recommendations made for technology study and advanced development. The most critical technology needs include attainment of 50-yr spacecraft lifetime and development of a long-life NEP system.

  5. Identified EM Earthquake Precursors

    NASA Astrophysics Data System (ADS)

    Jones, Kenneth, II; Saxton, Patrick

    2014-05-01

    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

  6. Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors

    PubMed Central

    Canli, Özge; Alankuş, Yasemin B.; Grootjans, Sasker; Vegi, Naidu; Hültner, Lothar; Hoppe, Philipp S.; Schroeder, Timm; Vandenabeele, Peter; Bornkamm, Georg W.

    2016-01-01

    Maintaining cellular redox balance is vital for cell survival and tissue homoeostasis because imbalanced production of reactive oxygen species (ROS) may lead to oxidative stress and cell death. The antioxidant enzyme glutathione peroxidase 4 (Gpx4) is a key regulator of oxidative stress–induced cell death. We show that mice with deletion of Gpx4 in hematopoietic cells develop anemia and that Gpx4 is essential for preventing receptor-interacting protein 3 (RIP3)-dependent necroptosis in erythroid precursor cells. Absence of Gpx4 leads to functional inactivation of caspase 8 by glutathionylation, resulting in necroptosis, which occurs independently of tumor necrosis factor α activation. Although genetic ablation of Rip3 normalizes reticulocyte maturation and prevents anemia, ROS accumulation and lipid peroxidation in Gpx4-deficient cells remain high. Our results demonstrate that ROS and lipid hydroperoxides function as not-yet-recognized unconventional upstream signaling activators of RIP3-dependent necroptosis. PMID:26463424

  7. Mast cell-deficient Kit(W-sh) "Sash" mutant mice display aberrant myelopoiesis leading to the accumulation of splenocytes that act as myeloid-derived suppressor cells.

    PubMed

    Michel, Anastasija; Schüler, Andrea; Friedrich, Pamela; Döner, Fatma; Bopp, Tobias; Radsak, Markus; Hoffmann, Markus; Relle, Manfred; Distler, Ute; Kuharev, Jörg; Tenzer, Stefan; Feyerabend, Thorsten B; Rodewald, Hans-Reimer; Schild, Hansjörg; Schmitt, Edgar; Becker, Marc; Stassen, Michael

    2013-06-01

    Mast cell-deficient Kit(W-sh) "sash" mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that Kit(W-sh) causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumor-bearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell-independent phenomenon. Thus, the Kit(W-sh) mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research. PMID:23636054

  8. Efficient retroviral transduction of human B-lymphoid and myeloid progenitors: marked inhibition of their growth by the Pax5 transgene

    PubMed Central

    Sekine, Rieko; Kitamura, Toshio; Tsuji, Takashi

    2008-01-01

    We applied a coculture system for the genetic manipulation of human B-lymphoid and myeloid progenitor cells using murine bone marrow stromal cell support, and investigated the effects of forced Pax5 expression in both cell types. Cytokine-stimulated cord blood CD34+ cells could be transduced at 85% efficiency and 95% cell viability by a single 24-h infection with RD114-pseudotyped retroviral vectors, produced by the packaging cell line Plat-F and bicistronic vector plasmids pMXs-Ig, pMYs-Ig, or pMCs-Ig, encoding EGFP. Infected CD34+ cells were seeded onto HESS-5 cells in the presence of stem cell factor and granulocyte colony-stimulating factor, allowing the extensive production of B progenitors and granulocytic cells. We examined the cell number and CD34, CD33, CD19, and CD20 lambda and kappa expressions by flow cytometry. Ectopic expression of Pax5 in CD34+ cells resulted in small myeloid progenitors coexpressing CD33 and CD19 and inhibited myeloid differentiation. After 6 weeks, the number of Pax5-transduced CD19+ cells was 40-fold lower than that of control cells. However, the expression of CD20 and the κ/λ chain on Pax5-transduced CD19+ cells suggests that the Pax5 transgene may not interfere with their differentiation. This report is the first to describe the effects of forced Pax5 expression in human hematopoietic progenitors. PMID:18415655

  9. Impact of hematopoietic chimerism at day +14 on engraftment after unrelated donor umbilical cord blood transplantation for hematologic malignancies

    PubMed Central

    Moscardó, Federico; Sanz, Jaime; Senent, Leonor; Cantero, Susana; de la Rubia, Javier; Montesinos, Pau; Planelles, Dolores; Lorenzo, Ignacio; Cervera, Jose; Palau, Javier; Sanz, Miguel A.; Sanz, Guillermo F.

    2009-01-01

    Background Cord blood transplant is a feasible treatment alternative for adult patients with hematologic malignancies lacking a suitable HLA-matched donor. However, the kinetics of myeloid recovery is slow, and primary graft failure cannot be detected easily early after transplantation. We investigated the impact of hematopoietic chimerism status from unselected marrow cells 14 days after transplantation on predicting engraftment after a cord blood transplant. Design and Methods Seventy-one adult patients with hematologic malignancies undergoing single-unit unrelated donor cord blood transplantation after a myeloablative conditioning regimen were included in the study. All patients received conditioning regimens based on busulfan, thiotepa and antithymocyte globulin. Chimerism status was assessed analyzing short tandem repeat polymorphisms. Results The cumulative incidence of myeloid engraftment at 1 month was significantly lower in patients with mixed chimerism than in those with complete donor chimerism (55% vs. 94%; p<0.0001). For patients achieving myeloid recovery, the median time of engraftment was 16 days when donor chimerism at day + 14 was higher than 90%, compared with 24 days when donor chimerism was below this level (p<0.001). A donor chimerism level of 65% was found to be the best cut-off point for predicting primary graft failure, with a sensitivity of 97% and a specificity of 80%. The incidence of primary graft failure was 67% for patients with less than 65% donor chimerism at day +14 as compared to only 2% for those with more than 65% donor chimerism (p<0.001). Patients with mixed chimerism also had a lower cumulative incidence of platelet engraftment than those with complete chimerism (62% vs. 89%; p=0.01). Conclusions Donor-recipient chimerism status at day +14 predicts engraftment after a single-unit cord blood transplant in adults. PMID:19483157

  10. Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia.

    PubMed

    Mulero-Navarro, Sonia; Sevilla, Ana; Roman, Angel C; Lee, Dung-Fang; D'Souza, Sunita L; Pardo, Sherly; Riess, Ilan; Su, Jie; Cohen, Ninette; Schaniel, Christoph; Rodriguez, Nelson A; Baccarini, Alessia; Brown, Brian D; Cavé, Hélène; Caye, Aurélie; Strullu, Marion; Yalcin, Safak; Park, Christopher Y; Dhandapany, Perundurai S; Yongchao, Ge; Edelmann, Lisa; Bahieg, Sawsan; Raynal, Patrick; Flex, Elisabetta; Tartaglia, Marco; Moore, Kateri A; Lemischka, Ihor R; Gelb, Bruce D

    2015-10-20

    Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML). Germline PTPN11 defects cause Noonan syndrome (NS), and specific inherited mutations cause NS/JMML. Here, we report that hematopoietic cells differentiated from human induced pluripotent stem cells (hiPSCs) harboring NS/JMML-causing PTPN11 mutations recapitulated JMML features. hiPSC-derived NS/JMML myeloid cells exhibited increased signaling through STAT5 and upregulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were upregulated in 11/19 JMML bone marrow mononuclear cells harboring PTPN11 mutations, but not those without PTPN11 defects. Reducing miR-223's function in NS/JMML hiPSCs normalized myelogenesis. MicroRNA target gene expression levels were reduced in hiPSC-derived myeloid cells as well as in JMML cells with PTPN11 mutations. Thus, studying an inherited human cancer syndrome with hiPSCs illuminated early oncogenesis prior to the accumulation of secondary genomic alterations, enabling us to discover microRNA dysregulation, establishing a genotype-phenotype association for JMML and providing therapeutic targets. PMID:26456833

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

    ClinicalTrials.gov

    2015-03-02

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

  12. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment

    PubMed Central

    Grafone, Tiziana; Palmisano, Michela; Nicci, Chiara; Storti, Sergio

    2012-01-01

    Hematopoiesis, the process by which the hematopoietic stem cells and progenitors differentiate into blood cells of various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Despite the many controls that regulate hematopoiesis, mutations in the regulatory genes capable of promoting leukemogenesis may occur. The FLT3 gene encodes a tyrosine kinase receptor that plays a key role in controlling survival, proliferation and differentiation of hematopoietic cells. Mutations in this gene are critical in causing a deregulation of the delicate balance between cell proliferation and differentiation. In this review, we provide an update on the structure, synthesis and activation of the FLT3 receptor and the subsequent activation of multiple downstream signaling pathways. We also review activating FLT3 mutations that are frequently identified in acute myeloid leukemia, cause activation of more complex downstream signaling pathways and promote leukemogenesis. Finally, FLT3 has emerged as an important target for molecular therapy. We, therefore, report on some recent therapies directed against it. PMID:25992210

  13. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia

    PubMed Central

    Shi, Junwei; Wang, Eric; Zuber, Johannes; Rappaport, Amy; Taylor, Meredith; Johns, Christopher

    2014-01-01

    The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein MLL can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that is known to require additional epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb Repressive Complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12, or Ezh1/Ezh2 led to proliferation-arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly due to its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer. PMID:22469984

  14. Clonal contributions of small numbers of retrovirally marked hematopoietic stem cells engrafted in unirradiated neonatal W/Wv mice.

    PubMed

    Capel, B; Hawley, R; Covarrubias, L; Hawley, T; Mintz, B

    1989-06-01

    Mice were repopulated with small numbers of retrovirally marked hematopoietic cells operationally definable as totipotent hematopoietic stem cells, without engraftment of cells at later stages of hematopoiesis, in order to facilitate analysis of stem cell clonal histories. This result depended upon the use of unirradiated W/Wv newborn recipients. Before transplantation, viral integration markers were introduced during cocultivation of fetal liver or bone marrow cells with helper cell lines exporting defective recombinant murine retroviruses of the HHAM series. Omission of selection in culture [although the vector contained the bacterial neomycin-resistance (neo) gene] also limited the proportion of stem cells that were virally labeled. Under these conditions, engraftment was restricted to a small population of marked and unmarked normal donor stem cells, due to their competitive advantage over the corresponding defective cells of the mutant hosts. A relatively simple and coherent pattern emerged, of one or a few virally marked clones, in contrast to previous studies. In order to establish the totipotent hematopoietic stem cell identity of the engrafted cells, tissues were sampled for viral and inbred-strain markers for periods close to one year after transplantation. The virally labeled clones were characterized as stem cell clones by their extensive self-renewal and by formation of the wide range of myeloid and lymphoid lineages tested. Results clearly documented concurrent contributions of cohorts of stem cells to hematopoiesis. A given stem cell can increase or decrease its proliferative activity, become completely inactive or lost, or become active after a long latent period. The contribution of a single clone present in a particular lineage was usually between 5% and 20%. PMID:2567516

  15. Tightly regulated 'all-in-one' lentiviral vectors for protection of human hematopoietic cells from anticancer chemotherapy.

    PubMed

    Lachmann, N; Brennig, S; Hillje, R; Schermeier, H; Phaltane, R; Dahlmann, J; Gruh, I; Heinz, N; Schiedlmeier, B; Baum, C; Moritz, T

    2015-11-01

    Successful application of gene therapy strategies may require stringently regulated transgene expression. Along this line, we describe a doxycycline (Dox)-inducible 'all-in-one' lentiviral vector design using the pTET-T11 (TII) minimal-promoter and a reverse transactivator protein (rtTA2S-M2) driven by the phosphoglycerate kinase promoter allowing for tight regulation of transgene expression (Lv.TII vectors). Vector design was evaluated in human hematopoietic cells in the context of cytidine deaminase (hCDD)-based myeloprotective gene therapy. Upon Dox administration, a rapid (16-24 h) and dose-dependent (>0.04 μg ml(-1) Dox) onset of transgene expression was detected in Lv.TII.CDD gene-modified K562 cells as well as in primary human CD34(+) hematopoietic cells. Importantly, in both cell models low background transgene expression was observed in the absence of Dox. Functionality of Dox-inducible hCDD expression was demonstrated by >10-fold increase in cytosine arabinoside (1-β-d-arabinofuranosylcytosine, Ara-C) resistance of Lv.TII.CDD-transduced K562 cells. In addition, Lv.TII.CDD-transduced CD34(+)-derived myeloid cells were protected from up to 300 nm Ara-C (control affected from 50 nm onwards). These data clearly demonstrate the suitability of our self-inactivating lentiviral vector to induce robust, tightly regulated transgene expression in human hematopoietic cells with minimal background activity and highlight the potential of our construct in myeloprotective gene therapy strategies.

  16. Generation of Nonlinear Vortex Precursors.

    PubMed

    Chen, Yue-Yue; Feng, Xun-Li; Liu, Chengpu

    2016-07-01

    We numerically study the propagation of a few-cycle pulse carrying orbital angular momentum (OAM) through a dense atomic system. Nonlinear precursors consisting of high-order vortex harmonics are generated in the transmitted field due to carrier effects associated with ultrafast Bloch oscillation. The nonlinear precursors survive to propagation effects and are well separated with the main pulse, which provides a straightforward way to measure precursors. By virtue of carrying high-order OAM, the obtained vortex precursors as information carriers have potential applications in optical information and communication fields where controllable loss, large information-carrying capacity, and high speed communication are required.

  17. Generation of Nonlinear Vortex Precursors.

    PubMed

    Chen, Yue-Yue; Feng, Xun-Li; Liu, Chengpu

    2016-07-01

    We numerically study the propagation of a few-cycle pulse carrying orbital angular momentum (OAM) through a dense atomic system. Nonlinear precursors consisting of high-order vortex harmonics are generated in the transmitted field due to carrier effects associated with ultrafast Bloch oscillation. The nonlinear precursors survive to propagation effects and are well separated with the main pulse, which provides a straightforward way to measure precursors. By virtue of carrying high-order OAM, the obtained vortex precursors as information carriers have potential applications in optical information and communication fields where controllable loss, large information-carrying capacity, and high speed communication are required. PMID:27447507

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

    PubMed

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

    2010-03-01

    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.

  19. Distal regulation of c-myb expression during IL-6-induced differentiation in murine myeloid progenitor M1 cells

    PubMed Central

    Zhang, Junfang; Han, Bingshe; Li, Xiaoxia; Bies, Juraj; Jiang, Penglei; Koller, Richard P; Wolff, Linda

    2016-01-01

    The c-Myb transcription factor is a major regulator that controls differentiation and proliferation of hematopoietic progenitor cells, which is frequently deregulated in hematological diseases, such as lymphoma and leukemia. Understanding of the mechanisms regulating the transcription of c-myb gene is challenging as it lacks a typical promoter and multiple factors are involved. Our previous studies identified some distal regulatory elements in the upstream regions of c-myb gene in murine myeloid progenitor M1 cells, but the detailed mechanisms still remain unclear. In the present study, we found that a cell differentiation-related DNase1 hypersensitive site is located at a −28k region upstream of c-myb gene and that transcription factors Hoxa9, Meis1 and PU.1 bind to the −28k region. Circular chromosome conformation capture (4C) assay confirmed the interaction between the −28k region and the c-myb promoter, which is supported by the enrichment of CTCF and Cohesin. Our analysis also points to a critical role for Hoxa9 and PU.1 in distal regulation of c-myb expression in murine myeloid cells and cell differentiation. Overexpression of Hoxa9 disrupted the IL-6-induced differentiation of M1 cells and upregulated c-myb expression through binding of the −28k region. Taken together, our results provide an evidence for critical role of the −28k region in distal regulatory mechanism for c-myb gene expression during differentiation of myeloid progenitor M1 cells. PMID:27607579

  20. Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia.

    PubMed

    Mehrotra, B; George, T I; Kavanau, K; Avet-Loiseau, H; Moore, D; Willman, C L; Slovak, M L; Atwater, S; Head, D R; Pallavicini, M G

    1995-08-01

    Leukemia may be viewed as a clonal expansion of blast cells; however, the role of primitive cells and/or stem cells in disease etiology and progression is unclear. We investigated stem cell involvement in leukemia using fluorescence in situ hybridization (FISH), immunofluorescence labeling of hematopoietic subpopulations, and flow cytometric analysis/sorting to discriminate and quantify cytogenetically aberrant stem cells in 12 acute myeloid leukemia (AML) and three myelodysplastic (MDS) specimens. Flow cytometric analysis and sorting were used to discriminate and collect a primitive subpopulation enriched in stem cells expressing CD34+ and lacking CD33 and CD38 (CD34+lin-). A subpopulation containing progenitors and differentiating myeloid cells expressed CD34, CD33, and CD38 (CD34+lin+). Nine specimens contained less than 10% CD34+ cells and, thus, were considered to be CD34- leukemias. Mature lymphoid, myeloid, and erythroid subpopulations were sorted on the basis of antigen-linked immunofluorescence. Cytogenetically aberrant cells in sorted subpopulations were identified using FISH with enumerator probes selected on the basis of diagnosis karyotype. Cytogenetically aberrant CD34+lin- cells were present at frequencies between 9% and 99% in all specimens. CD34+lin- cytogenetically aberrant cells comprised between 0.05% and 11.9% of the marrow/blood specimens. Cytogenetically aberrant CD34+lin+ cells constituted 0.01% tp 56% of the marrow/blood population. These data demonstrate that aberrant cells are present in primitive CD34+ stem cell compartments, even in CD34- leukemias. Stem cell involvement was confirmed further by sorting lymphoid and erythroid subpopulations from eight specimens in which the predominant leukemic population lacked lymphoid/erythroid differentiation markers. In these specimens, as well as in multiple lineages, suggests involvement of a cell(s) with multilineage capabilities. The ability of aberrant CD34+lin- stem cells to contribute to

  1. A rare cause of mechanical obstruction: Intestinal myeloid sarcoma

    PubMed Central

    Yoldaş, Tayfun; Erol, Varlık; Demir, Batuhan; Hoşcoşkun, Cüneyt

    2014-01-01

    Myeloid sarcoma is a rare aggressive tumour that originates from immature extramedullary myeloid cells. It can be seen as a relapse in patients with acute myeloid leukaemia. Sometimes it can be seen in the form of a solid tumour without any evidence of leukaemia. A case of a 44-year-old male patient who was admitted with symptoms and signs of mechanical intestinal bowel obstruction was operated on. The operation findings showed small bowel obstruction due to a mass. The mass was then resected with end-to-end intestinal anastomosis. The resected mass pathology results were consistent with myeloid sarcoma. The post-operative period was uneventful and adjuvant therapy was applied. In this case report we aimed to evaluate the clinical signs and treatment modalities of small intestinal myeloid sarcoma. PMID:25931908

  2. Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia.

    PubMed

    Lee-Sherick, A B; Eisenman, K M; Sather, S; McGranahan, A; Armistead, P M; McGary, C S; Hunsucker, S A; Schlegel, J; Martinson, H; Cannon, C; Keating, A K; Earp, H S; Liang, X; DeRyckere, D; Graham, D K

    2013-11-14

    Acute myeloid leukemia (AML) continues to be extremely difficult to treat successfully, and the unacceptably low overall survival rates mandate that we assess new potential therapies to ameliorate poor clinical response to conventional therapy. Abnormal tyrosine kinase activation in AML has been associated with poor prognosis and provides strategic targets for novel therapy development. We found that Mer receptor tyrosine kinase was over-expressed in a majority of pediatric (29/36, 80%) and adult (10/10, 100%) primary AML patient blasts at the time of diagnosis, and 100% of patient samples at the time of relapse. Mer was also found to be expressed in 12 of 14 AML cell lines (86%). In contrast, normal bone marrow myeloid precursors expressed little to no Mer. Following AML cell line stimulation with Gas6, a Mer ligand, we observed activation of prosurvival and proliferative signaling pathways, including phosphorylation of ERK1/2, p38, MSK1, CREB, ATF1, AKT and STAT6. To assess the phenotypic role of Mer in AML, two independent short-hairpin RNA (shRNA) constructs were used to decrease Mer expression in the AML cell lines Nomo-1 and Kasumi-1. Reduction of Mer protein levels significantly increased rates of myeloblast apoptosis two to threefold in response to serum starvation. Furthermore, myeloblasts with knocked-down Mer demonstrated decreased colony formation by 67-87%, relative to control cell lines (P<0.01). NOD-SCID-gamma mice transplanted with Nomo-1 myeloblasts with reduced levels of Mer had a significant prolongation in survival compared with mice transplanted with the parental or control cell lines (median survival 17 days in parental and control cell lines, versus 32-36 days in Mer knockdown cell lines, P<0.0001). These data suggest a role for Mer in acute myeloid leukemogenesis and indicate that targeted inhibition of Mer may be an effective therapeutic strategy in pediatric and adult AML. PMID:23474756

  3. Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia

    PubMed Central

    Lee-Sherick, A B; Eisenman, K M; Sather, S; McGranahan, A; Armistead, P M; McGary, C S; Hunsucker, S A; Schlegel, J; Martinson, H; Cannon, C; Keating, A K; Earp, H S; Liang, X; DeRyckere, D; Graham, D K

    2013-01-01

    Acute myeloid leukemia (AML) continues to be extremely difficult to treat successfully, and the unacceptably low overall survival rates mandate that we assess new potential therapies to ameliorate poor clinical response to conventional therapy. Abnormal tyrosine kinase activation in AML has been associated with poor prognosis and provides strategic targets for novel therapy development. We found that Mer receptor tyrosine kinase was over-expressed in a majority of pediatric (29/36, 80%) and adult (10/10, 100%) primary AML patient blasts at the time of diagnosis, and 100% of patient samples at the time of relapse. Mer was also found to be expressed in 12 of 14 AML cell lines (86%). In contrast, normal bone marrow myeloid precursors expressed little to no Mer. Following AML cell line stimulation with Gas6, a Mer ligand, we observed activation of prosurvival and proliferative signaling pathways, including phosphorylation of ERK1/2, p38, MSK1, CREB, ATF1, AKT and STAT6. To assess the phenotypic role of Mer in AML, two independent short-hairpin RNA (shRNA) constructs were used to decrease Mer expression in the AML cell lines Nomo-1 and Kasumi-1. Reduction of Mer protein levels significantly increased rates of myeloblast apoptosis two to threefold in response to serum starvation. Furthermore, myeloblasts with knocked-down Mer demonstrated decreased colony formation by 67–87%, relative to control cell lines (P<0.01). NOD-SCID-gamma mice transplanted with Nomo-1 myeloblasts with reduced levels of Mer had a significant prolongation in survival compared with mice transplanted with the parental or control cell lines (median survival 17 days in parental and control cell lines, versus 32–36 days in Mer knockdown cell lines, P<0.0001). These data suggest a role for Mer in acute myeloid leukemogenesis and indicate that targeted inhibition of Mer may be an effective therapeutic strategy in pediatric and adult AML. PMID:23474756

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

    ClinicalTrials.gov

    2014-04-03

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic Syndrome With Isolated Del(5q); Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  5. Myeloid Cells' Evasion of Melanoma Immunity

    PubMed Central

    Wang, Jun; Chen, Lieping

    2015-01-01

    An immune-suppressive role of myeloid-derived suppressor cells (MDSCs) in melanoma has long been speculated, whereas molecular mechanisms underlying this role are not well understood. Here, Chung and colleagues show that dendritic cell-associated, heparan sulfate proteoglycans-dependent integrin ligand (DC-HIL), a cell surface immune-modulatory molecule, is highly expressed on tumor-associated MDSCs. Genetic ablation or antibody blockade of DC-HIL delays the growth of transplantable B16 melanoma in syngeneic mice, which is accompanied by enhanced antitumor T-cell activities. These findings support a role for DC-HIL in immune evasion within the melanoma microenvironment. PMID:25318429

  6. Redefining Myeloid Cell Subsets in Murine Spleen

    PubMed Central

    Hey, Ying-Ying; Tan, Jonathan K. H.; O’Neill, Helen C.

    2016-01-01

    Spleen is known to contain multiple dendritic and myeloid cell subsets, distinguishable on the basis of phenotype, function and anatomical location. As a result of recent intensive flow cytometric analyses, splenic dendritic cell (DC) subsets are now better characterized than other myeloid subsets. In order to identify and fully characterize a novel splenic subset termed “L-DC” in relation to other myeloid cells, it was necessary to investigate myeloid subsets in more detail. In terms of cell surface phenotype, L-DC were initially characterized as a CD11bhiCD11cloMHCII−Ly6C−Ly6G− subset in murine spleen. Their expression of CD43, lack of MHCII, and a low level of CD11c was shown to best differentiate L-DC by phenotype from conventional DC subsets. A complete analysis of all subsets in spleen led to the classification of CD11bhiCD11cloMHCII−Ly6CloLy6G− cells as monocytes expressing CX3CR1, CD43 and CD115. Siglec-F expression was used to identify a specific eosinophil population, distinguishable from both Ly6Clo and Ly6Chi monocytes, and other DC