Leukemia

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John D. Crispino - One of the best experts on this subject based on the ideXlab platform.

  • gata1 mutations in down syndrome implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic Leukemia
    Pediatric Blood & Cancer, 2005
    Co-Authors: John D. Crispino
    Abstract:

    Although physicians have known for many decades that children with Down syndrome are predisposed to developing transient myeloproliferative disorder (TMD) and acute megakaryoblastic Leukemia (AMKL), many questions regarding these disorders remain unresolved. First, what is the relationship between TMD and AMKL? Second, what specific genetic alterations contribute to the leukemic process? Finally, what factors lead to the increased predisposition to these myeloid disorders? In this review I will summarize important new insights into the biology of TMD and AMKL gained from the recent discovery that GATA1, a gene that encodes an essential hematopoietic transcription factor, is mutated in the leukemic blasts from nearly all patients with these malignancies. In addition, I will discuss whether assaying for the presence of a GATA1 mutation can aid in the diagnosis of these and related megakaryoblastic Leukemias. Future research aimed at defining the activity of mutant GATA-1 protein and identifying interacting factors encoded by chromosome 21 will likely lead to an even greater understanding of this intriguing Leukemia.

  • gata1 mutations in down syndrome implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic Leukemia
    Pediatric Blood & Cancer, 2005
    Co-Authors: John D. Crispino
    Abstract:

    Although physicians have known for many decades that children with Down syndrome are predisposed to developing transient myeloproliferative disorder (TMD) and acute megakaryoblastic Leukemia (AMKL), many questions regarding these disorders remain unresolved. First, what is the relationship between TMD and AMKL? Second, what specific genetic alterations contribute to the leukemic process? Finally, what factors lead to the increased predisposition to these myeloid disorders? In this review I will summarize important new insights into the biology of TMD and AMKL gained from the recent discovery that GATA1, a gene that encodes an essential hematopoietic transcription factor, is mutated in the leukemic blasts from nearly all patients with these malignancies. In addition, I will discuss whether assaying for the presence of a GATA1 mutation can aid in the diagnosis of these and related megakaryoblastic Leukemias. Future research aimed at defining the activity of mutant GATA-1 protein and identifying interacting factors encoded by chromosome 21 will likely lead to an even greater understanding of this intriguing Leukemia. © 2004 Wiley-Liss, Inc.

  • mutations in gata1 in both transient myeloproliferative disorder and acute megakaryoblastic Leukemia of down syndrome
    Blood Cells Molecules and Diseases, 2003
    Co-Authors: Marianne Greene, Gina Mundschau, Michael A Mcdevitt, Joshua B Wechsler, Robert J. Arceci, Alan S Gamis, Sandeep Gurbuxani, Judith E. Karp, John D. Crispino
    Abstract:

    Abstract Mutations in transcription factors often contribute to human Leukemias by providing a block to normal differentiation. To determine whether mutations in the hematopoietic transcription factor GATA1 are associated with Leukemia, we assayed for alterations in the GATA1 gene in bone marrow samples from patients with various subtypes of acute Leukemia. Here we summarize our findings that GATA1 is mutated in the leukemic blasts of patients with Down syndrome acute megakaryoblastic Leukemia (DS-AMKL). We did not find mutations in GATA1 in leukemic cells of DS patients with other types of acute Leukemia, or in other patients with AMKL who did not have DS. Furthermore, we did not detect GATA1 mutations in DNAs from over 75 other patients with acute Leukemia or from 21 healthy individuals. Since the GATA1 mutations were restricted to DS-AMKL, we also investigated whether GATA1 was altered in the “preLeukemia” of DS, transient myeloproliferative disorder (TMD). TMD is a common myeloid disorder that affects 10% of DS newborns and evolves to AMKL in nearly 30% patients. We detected GATA1 mutations in TMD blasts from every infant examined. Together, these results demonstrate that GATA1 is likely to play a critical role in the etiology of TMD and DS-AMKL, and that mutagenesis of GATA1 represents a very early event in DS myeloid leukemogenesis. We hypothesize that disruption of normal GATA-1 function is an essential step in the initiation of megakaryoblastic Leukemia in DS.

Irving L. Weissman - One of the best experts on this subject based on the ideXlab platform.

  • increased expression of cd47 is a constant marker in mouse and human myeloid Leukemias
    Blood, 2005
    Co-Authors: David Traver, Catriona Jamieson, Sidd Jaiswal, Jason Gotlib, Mark P Chao, Irving L. Weissman
    Abstract:

    CD47, also known as integrin associated protein, is a ubiquitously expressed cell surface glycoprotein that interacts with a number of integrins, modulating leukocyte adhesion, migration, cell motility and platelet activation. CD47 is also the ligand for the macrophage inhibitory receptor signal regulatory protein α (SIRP α) and thus, impairs macrophage-mediated phagocytosis. Recent reports suggest that increased CD47 expression may play a role in the pathogenesis of lymphoproliferative disorders such as CLL (Mateo et al, Nat Med.1999; 5:1277) and multiple myeloma, and that a bivalent single-chain antibody fragment against human CD47 induces apoptosis of myeloma cells (Kikuchi et al, Leukemia Research2005; 29:445). However, little is known about the role of CD47 in the pathogenesis of myeloid Leukemias or the stage of hematopoiesis at which CD47 is expressed. In order to identify the stage of hematopoiesis at which alterations in CD47 arise and its role in the pathogenesis of myeloid Leukemias, we analyzed CD47 expression in hematopoietic stem cells (HSC), progenitors, and lineage-positive cells derived from three mouse transgenic models of myeloid Leukemia including: 1) mice homozygous for overexpression of human bcl-2 in the myeloid lineage (hMRP8 bcl-2 x bcl-2); 2) mice deficient in Fas together with myeloid targeted overexpression of bcl-2 (Faslpr/lpr hMRP8 bcl-2); and 3) mice with both human bcl-2 and BCR-ABL targeted to the myeloid lineage (hMRP8-BCR-ABLxhMRP8-bcl-2). Quantitative RT-PCR analysis demonstrated a 3.01+/− 1.54 fold increase in CD47 transcripts in leukemic compared with control (bcl2+) bone marrow (normalized to b-actin) while FACS analysis revealed approximately a 10-fold increase in CD47 protein expression, as measured by mean fluorescence intensity (MFI), in leukemic GMP compared with wild type GMP. Moreover, transplantation experiments revealed that all mice with both primary (n=14 mice) and secondary (n=19 mice) leukemic transplantation potential had an expansion of granulocyte-macrophage progenitors (GMP) with high level CD47 expression. Human CD47 expression analysis was performed via FACS on human normal, pre-leukemic myeloproliferative disorder (MPD) or AML HSC, progenitors, and lineage positive cells derived from marrow or peripheral blood. MPD samples (n=63) included polycythemia vera (PV; n=15), post-polycythemic myeloid metaplasia/myelofibrosis (PPMM/MF; n=5), essential thrombocythemia (ET; n=8), atypical chronic myelogenous Leukemia (aCML; n=2), CML (n=7), chronic eosinophilic Leukemia (CEL; n=1), chronic myelomonocytic Leukemia (CMML; n= 13) and acute myelogenous Leukemia (AML; n=12). As noted with the transgenic leukemic mouse models, progression of human myeloproliferative disorders to AML (n=12) was associated with an expansion of the GMP pool (70.6% +/− S.D. 2.15) compared with normal bone marrow (14.7% +/− S.D. 2.3). Furthermore, FACS analysis revealed that CD47 expression first increased 1.7 fold in AML compared with normal HSC and then increased to 2.2 fold greater than normal with commitment of AML progenitors to the myeloid lineage. CD47 was over-expressed by AML primitive progenitors and their progeny but not by the majority of MPD (MFI 2.3+/−S.D. 0.43) compared with normal bone marrow (MFI 1.9 +/−S.D. 0.07). Thus, increased CD47 expression may serve as a useful diagnostic marker for progression to AML and may represent a novel therapeutic target.

  • normal and leukemic hematopoiesis are Leukemias a stem cell disorder or a reacquisition of stem cell characteristics
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Emmanuelle Passegue, Catriona Jamieson, Laurie Ailles, Irving L. Weissman
    Abstract:

    Leukemia can be viewed as a newly formed, abnormal hematopoietic tissue initiated by a few leukemic stem cells (LSCs) that undergo an aberrant and poorly regulated process of organogenesis analogous to that of normal hematopoietic stem cells. A hallmark of all cancers is the capacity for unlimited self-renewal, which is also a defining characteristic of normal stem cells. Given this shared attribute, it has been proposed that Leukemias may be initiated by transforming events that take place in hematopoietic stem cells. Alternatively, Leukemias may also arise from more committed progenitors caused by mutations and/or selective expression of genes that enhance their otherwise limited self-renewal capabilities. Identifying the LSCs for each type of Leukemia is a current challenge and a critical step in understanding their respective biologies and may provide key insights into more effective treatments. Moreover, LSC identification and purification will provide a powerful diagnostic, prognostic, and therapeutic tool in the clinic.

  • bcl 2 cooperates with promyelocytic Leukemia retinoic acid receptor α chimeric protein pmlrarα to block neutrophil differentiation and initiate acute Leukemia
    Journal of Experimental Medicine, 2001
    Co-Authors: Scott C Kogan, Diane E. Brown, David B. Shultz, Bao-tran H. Truong, Marie-claude Guillemin, Eric Lagasse, Irving L. Weissman, Valerie Lallemandbreitenbach, Michael J. Bishop
    Abstract:

    The promyelocytic Leukemia retinoic acid receptor α (PMLRARα) chimeric protein is associated with acute promyelocytic Leukemia (APL). PMLRARα transgenic mice develop Leukemia only after several months, suggesting that PMLRARα does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRARα to initiate Leukemia. Evaluation of preleukemic animals showed that whereas PMLRARα alone modestly altered neutrophil maturation, the combination of PMLRARα and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARα and BCL-2 than in mice expressing PMLRARα alone, and all mice expressing both transgenes succumbed to Leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the Leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute Leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRARα to initiate APL.

  • BCL-2 cooperates with promyelocytic Leukemia retinoic acid receptor � (PMLRAR�) to block neutrophil differentiation and initiate acute Leukemia
    2001
    Co-Authors: C. Kogan, Diane E. Brown, David B. Shultz, Bao-tran H. Truong, Valerie Lallem, Marie-claude Guillemin, Eric Lagasse, Irving L. Weissman, Michael J. Bishop
    Abstract:

    The promyelocytic Leukemia retinoic acid receptor � (PMLRAR�) chimeric protein is associated with acute promyelocytic Leukemia (APL). PMLRAR � transgenic mice develop Leukemia only after several months, suggesting that PMLRAR � does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRAR � to initiate Leukemia. Evaluation of preleukemic animals showed that whereas PMLRAR � alone modestly altered neutrophil maturation, the combination of PMLRAR � and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRAR � and BCL-2 than in mice expressing PMLRAR � alone, and all mice expressing both transgenes succumbed to Leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the Leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute Leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRAR � to initiate APL. Key words: Leukemia • myeloid/Leukemia • promyelocytic • acute/leukopoiesis/PML protein/receptors • retinoic aci

Michael J. Bishop - One of the best experts on this subject based on the ideXlab platform.

  • bcl 2 cooperates with promyelocytic Leukemia retinoic acid receptor α chimeric protein pmlrarα to block neutrophil differentiation and initiate acute Leukemia
    Journal of Experimental Medicine, 2001
    Co-Authors: Scott C Kogan, Diane E. Brown, David B. Shultz, Bao-tran H. Truong, Marie-claude Guillemin, Eric Lagasse, Irving L. Weissman, Valerie Lallemandbreitenbach, Michael J. Bishop
    Abstract:

    The promyelocytic Leukemia retinoic acid receptor α (PMLRARα) chimeric protein is associated with acute promyelocytic Leukemia (APL). PMLRARα transgenic mice develop Leukemia only after several months, suggesting that PMLRARα does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRARα to initiate Leukemia. Evaluation of preleukemic animals showed that whereas PMLRARα alone modestly altered neutrophil maturation, the combination of PMLRARα and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARα and BCL-2 than in mice expressing PMLRARα alone, and all mice expressing both transgenes succumbed to Leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the Leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute Leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRARα to initiate APL.

  • BCL-2 cooperates with promyelocytic Leukemia retinoic acid receptor � (PMLRAR�) to block neutrophil differentiation and initiate acute Leukemia
    2001
    Co-Authors: C. Kogan, Diane E. Brown, David B. Shultz, Bao-tran H. Truong, Valerie Lallem, Marie-claude Guillemin, Eric Lagasse, Irving L. Weissman, Michael J. Bishop
    Abstract:

    The promyelocytic Leukemia retinoic acid receptor � (PMLRAR�) chimeric protein is associated with acute promyelocytic Leukemia (APL). PMLRAR � transgenic mice develop Leukemia only after several months, suggesting that PMLRAR � does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRAR � to initiate Leukemia. Evaluation of preleukemic animals showed that whereas PMLRAR � alone modestly altered neutrophil maturation, the combination of PMLRAR � and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRAR � and BCL-2 than in mice expressing PMLRAR � alone, and all mice expressing both transgenes succumbed to Leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the Leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute Leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRAR � to initiate APL. Key words: Leukemia • myeloid/Leukemia • promyelocytic • acute/leukopoiesis/PML protein/receptors • retinoic aci

Judith E. Karp - One of the best experts on this subject based on the ideXlab platform.

  • mutations in gata1 in both transient myeloproliferative disorder and acute megakaryoblastic Leukemia of down syndrome
    Blood Cells Molecules and Diseases, 2003
    Co-Authors: Marianne Greene, Gina Mundschau, Michael A Mcdevitt, Joshua B Wechsler, Robert J. Arceci, Alan S Gamis, Sandeep Gurbuxani, Judith E. Karp, John D. Crispino
    Abstract:

    Abstract Mutations in transcription factors often contribute to human Leukemias by providing a block to normal differentiation. To determine whether mutations in the hematopoietic transcription factor GATA1 are associated with Leukemia, we assayed for alterations in the GATA1 gene in bone marrow samples from patients with various subtypes of acute Leukemia. Here we summarize our findings that GATA1 is mutated in the leukemic blasts of patients with Down syndrome acute megakaryoblastic Leukemia (DS-AMKL). We did not find mutations in GATA1 in leukemic cells of DS patients with other types of acute Leukemia, or in other patients with AMKL who did not have DS. Furthermore, we did not detect GATA1 mutations in DNAs from over 75 other patients with acute Leukemia or from 21 healthy individuals. Since the GATA1 mutations were restricted to DS-AMKL, we also investigated whether GATA1 was altered in the “preLeukemia” of DS, transient myeloproliferative disorder (TMD). TMD is a common myeloid disorder that affects 10% of DS newborns and evolves to AMKL in nearly 30% patients. We detected GATA1 mutations in TMD blasts from every infant examined. Together, these results demonstrate that GATA1 is likely to play a critical role in the etiology of TMD and DS-AMKL, and that mutagenesis of GATA1 represents a very early event in DS myeloid leukemogenesis. We hypothesize that disruption of normal GATA-1 function is an essential step in the initiation of megakaryoblastic Leukemia in DS.

  • timed sequential therapy of acute Leukemia with flavopiridol in vitro model for a phase i clinical trial
    Clinical Cancer Research, 2003
    Co-Authors: Judith E. Karp, Jacqueline Greer, Douglas D Ross, Takeo Nakanishi, Weidong Yang, Michael L Tidwell, Yuetong Wei, Dean L Mann, John J Wright
    Abstract:

    Purpose: The survival of adults with acute Leukemias remains unsatisfactory and requires new treatment approaches. Flavopiridol modulates cell cycle progression, inhibits transcription, and induces apoptosis. We designed an in vitro model of timed sequential therapy for acute Leukemia to determine whether flavopiridol can: ( a ) trigger apoptosis in fresh acute Leukemia; and ( b ) recruit surviving leukemic cells to a proliferative state, thereby priming such cells for the S-phase-related cytotoxicity of 1-β-d-arabinofuranosylcytosine (ara-C). Experimental Design: Bone marrow cells from 20 adults with relapsed and refractory acute Leukemias were enriched for blasts by Ficoll Hypaque sedimentation. Blasts were cultured on day 0 in flavopiridol 250 nm for 24 h, removed from flavopiridol for 24 h, and then cultured in ara-C 1 μm for an additional 72 h (F 250 A 1 ). Apoptosis and cell cycle phase distribution were estimated from cells stained with propidium iodide. Cell survival was determined after the 72 h ara-C exposure by double cytofluorescence assay with fluorescein diacetate and propidium iodide. Results: Flavopiridol induced a 4.3-fold increase in apoptosis in human Leukemia samples within the first 24 h of culture. Subsequent removal of flavopiridol led to a 1.7-fold increase in the proportion of cells in S phase by day 2. Mean survival in F 250 A 1 cultures after 72 h exposure to ara-C was 35.6% compared with flavopiridol alone (F 250 A 0 , 56.1%; P = 0.0003) and ara-C alone (F 0 A 1 , 65.2%; P Conclusions: Flavopiridol induces apoptosis in marrow blasts from patients with refractory acute Leukemias. Furthermore, flavopiridol pretreatment increases the proapoptotic and cytotoxic effects of ara-C. The advantage of sequential FP 250 A 1 over either agent alone is seen for both acute myelogenous Leukemia and acute lymphoblastic Leukemia. These findings support a clinical trial of timed sequential therapy where flavopiridol is given for cytoreduction and subsequent priming of remaining leukemic cells for enhanced cycle-dependent drug cytotoxicity.

U Testa - One of the best experts on this subject based on the ideXlab platform.

  • MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid Leukemias
    Blood Cancer Journal, 2011
    Co-Authors: I Spinello, M T Quaranta, R Riccioni, V Riti, L Pasquini, A Boe, E Pelosi, A Vitale, R Foà, U Testa
    Abstract:

    CXCR4 is a negative prognostic marker in acute myeloid Leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in Leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-Leukemia drugs, for development of new therapeutic strategies.

  • MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid Leukemias
    'Springer Science and Business Media LLC', 2011
    Co-Authors: I Spinello, R Riccioni, V Riti, L Pasquini, A Boe, E Pelosi, A Vitale, T. M. Quaranta, Foa Roberto, U Testa
    Abstract:

    CXCR4 is a negative prognostic marker in acute myeloid Leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in Leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-Leukemia drugs, for development of new therapeutic strategies. Blood Cancer Journal (2011) 1, e26; doi: 10.1038/bcj.2011.24; published online 24 June 201