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  1. Article ; Online: Liver kinase B1 (LKB1) in murine erythroid progenitors modulates erythropoietin setpoint in association with maturation control.

    White, Zollie / Elagib, Kamaleldin E / Gru, Alejandro A / Goldfarb, Adam N

    Blood cells, molecules & diseases

    2022  Volume 97, Page(s) 102688

    Abstract: Erythropoiesis is a tightly regulated process. It is stimulated by decreased oxygen in circulation, which leads to the secretion of the hormone erythropoietin (Epo) by the kidneys. An additional layer of control involves the coordinated sensing and use ... ...

    Abstract Erythropoiesis is a tightly regulated process. It is stimulated by decreased oxygen in circulation, which leads to the secretion of the hormone erythropoietin (Epo) by the kidneys. An additional layer of control involves the coordinated sensing and use of nutrients. Much cellular machinery contributes to sensing and responding to nutrient status in cells, and one key participant is the kinase LKB1. The current study examines the role of LKB1 in erythropoiesis using a murine in vivo and ex vivo conditional knockout system. In vivo analysis showed erythroid loss of LKB1 to be associated with a robust increase in serum Epo and mild reticulocytosis. Despite these abnormalities, no evidence of anemia or hemolysis was found. Further characterization using an ex vivo progenitor culture assay demonstrated accelerated erythroid maturation in the LKB1-deficient cells. Based on pharmacologic evidence, this phenotype appeared to result from impaired AMP-activated protein kinase (AMPK) signaling downstream of LKB1. These findings reveal a role for LKB1 in fine-tuning Epo-driven erythropoiesis in association with maturational control.
    MeSH term(s) AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Animals ; Erythroid Precursor Cells/metabolism ; Erythropoiesis/genetics ; Erythropoiesis/physiology ; Erythropoietin/genetics ; Erythropoietin/metabolism ; Humans ; Liver/metabolism ; Mice ; Receptors, Erythropoietin/genetics ; Receptors, Erythropoietin/metabolism
    Chemical Substances Receptors, Erythropoietin ; Erythropoietin (11096-26-7) ; Stk11 protein, mouse (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
    Language English
    Publishing date 2022-06-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1237083-6
    ISSN 1096-0961 ; 1079-9796
    ISSN (online) 1096-0961
    ISSN 1079-9796
    DOI 10.1016/j.bcmd.2022.102688
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Megakaryocyte ontogeny: Clinical and molecular significance.

    Elagib, Kamaleldin E / Brock, Ashton T / Goldfarb, Adam N

    Experimental hematology

    2018  Volume 61, Page(s) 1–9

    Abstract: Fetal megakaryocytes (Mks) differ from adult Mks in key parameters that affect their capacity for platelet production. However, despite being smaller, more proliferative, and less polyploid, fetal Mks generally mature in the same manner as adult Mks. The ...

    Abstract Fetal megakaryocytes (Mks) differ from adult Mks in key parameters that affect their capacity for platelet production. However, despite being smaller, more proliferative, and less polyploid, fetal Mks generally mature in the same manner as adult Mks. The phenotypic features unique to fetal Mks predispose patients to several disease conditions, including infantile thrombocytopenia, infantile megakaryoblastic leukemias, and poor platelet recovery after umbilical cord blood stem cell transplantations. Ontogenic Mk differences also affect new strategies being developed to address global shortages of platelet transfusion units. These donor-independent, ex vivo production platforms are hampered by the limited proliferative capacity of adult-type Mks and the inferior platelet production by fetal-type Mks. Understanding the molecular programs that distinguish fetal versus adult megakaryopoiesis will help in improving approaches to these clinical problems. This review summarizes the phenotypic differences between fetal and adult Mks, the disease states associated with fetal megakaryopoiesis, and recent advances in the understanding of mechanisms that determine ontogenic Mk transitions.
    MeSH term(s) Fetal Blood/cytology ; Humans ; Megakaryocytes/cytology ; Megakaryocytes/pathology ; Models, Biological ; Morphogenesis/physiology ; Phenotype ; Thrombocytopenia/pathology
    Language English
    Publishing date 2018-03-02
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 185107-x
    ISSN 1873-2399 ; 0531-5573 ; 0301-472X
    ISSN (online) 1873-2399
    ISSN 0531-5573 ; 0301-472X
    DOI 10.1016/j.exphem.2018.02.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Megakaryocytic irreversible P-TEFb activation.

    Elagib, Kamaleldin E / Goldfarb, Adam N

    Cell cycle (Georgetown, Tex.)

    2014  Volume 13, Issue 12, Page(s) 1827–1828

    MeSH term(s) Animals ; Calpain/physiology ; Cell Transformation, Neoplastic/pathology ; GATA1 Transcription Factor/genetics ; Humans ; Leukemia/pathology ; Megakaryocytes/pathology ; Mutation/genetics ; Positive Transcriptional Elongation Factor B/metabolism ; Ribonucleoproteins, Small Nuclear/metabolism
    Chemical Substances GATA1 Transcription Factor ; Ribonucleoproteins, Small Nuclear ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; Calpain (EC 3.4.22.-)
    Language English
    Publishing date 2014-05-27
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.29324
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  4. Article ; Online: Cyclic AMP signaling inhibits megakaryocytic differentiation by targeting transcription factor 3 (E2A) cyclin-dependent kinase inhibitor 1A (CDKN1A) transcriptional axis.

    Rubinstein, Jeremy D / Elagib, Kamaleldin E / Goldfarb, Adam N

    The Journal of biological chemistry

    2012  Volume 287, Issue 23, Page(s) 19207–19215

    Abstract: Signaling via the intracellular second messenger cyclic AMP (cAMP) has long been implicated in the repression of megakaryocytic differentiation. However, the mechanisms by which cAMP signaling impairs megakaryopoiesis have never been elucidated. In a ... ...

    Abstract Signaling via the intracellular second messenger cyclic AMP (cAMP) has long been implicated in the repression of megakaryocytic differentiation. However, the mechanisms by which cAMP signaling impairs megakaryopoiesis have never been elucidated. In a human CD34(+) cell culture model, we show that the adenylyl cyclase agonist forskolin inhibits megakaryocytic differentiation in a protein kinase A-dependent manner. Using this system to screen for downstream effectors, we identified the transcription factor E2A as a key target in a novel repressive signaling pathway. Specifically, forskolin acting through protein kinase A-induced E2A down-regulation and enforced expression of E2A overrode the inhibitory effects of forskolin on megakaryopoiesis. The dependence of megakaryopoiesis on critical thresholds of E2A expression was confirmed in vivo in haploinsufficient mice and ex vivo using shRNA knockdown in human progenitors. Using a variety of approaches, we further identified p21 (encoded by CDKN1A) as a functionally important megakaryopoietic regulator residing downstream of E2A. These results thus implicate the E2A-CDKN1A transcriptional axis in the control of megakaryopoiesis and reveal the lineage-selective inhibition of this axis as a likely mechanistic basis for the inhibitory effects of cAMP signaling.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Differentiation/physiology ; Cyclic AMP/genetics ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; HEK293 Cells ; Humans ; Megakaryocytes/cytology ; Megakaryocytes/metabolism ; Mice ; Mice, Mutant Strains ; Second Messenger Systems/physiology ; Thrombopoiesis/physiology ; Transcription, Genetic/physiology
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; CDKN1A protein, human ; Cdkn1a protein, mouse ; Cyclin-Dependent Kinase Inhibitor p21 ; TCF3 protein, human ; Tcf3 protein, mouse ; Cyclic AMP (E0399OZS9N) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
    Language English
    Publishing date 2012-04-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M112.366476
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  5. Article: Regulation of RUNX1 transcriptional function by GATA-1.

    Elagib, Kamaleldin E / Goldfarb, Adam N

    Critical reviews in eukaryotic gene expression

    2007  Volume 17, Issue 4, Page(s) 271–280

    Abstract: Runt-related transcription factor 1 (RUNX1) and GATA-1 are both transcription factors known to play essential roles in hematopoiesis. Genetic alterations of each are associated with abnormal platelet development, as well as predisposition to leukemia. In ...

    Abstract Runt-related transcription factor 1 (RUNX1) and GATA-1 are both transcription factors known to play essential roles in hematopoiesis. Genetic alterations of each are associated with abnormal platelet development, as well as predisposition to leukemia. In addition, in vitro and animal studies indicate that both factors are involved in megakaryopoiesis. We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. Moreover, transcriptional cooperation of RUNX1 with GATA-1 is conserved back to Drosophila in which RUNX1 and GATA-1 homologs cooperate in crystal cell development. In this article, we will review the molecular and functional significance of the transcriptional cross talk between RUNX1 and GATA-1. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation.
    MeSH term(s) Animals ; Core Binding Factor Alpha 2 Subunit/genetics ; GATA1 Transcription Factor/genetics ; GATA1 Transcription Factor/physiology ; Gene Expression Regulation/physiology ; Humans ; Megakaryocytes/cytology ; Mice ; Mutation ; Phosphorylation ; Transcription, Genetic/physiology
    Chemical Substances Core Binding Factor Alpha 2 Subunit ; GATA1 Transcription Factor ; Gata1 protein, mouse ; Runx1 protein, mouse
    Language English
    Publishing date 2007-08-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1071345-1
    ISSN 1045-4403
    ISSN 1045-4403
    DOI 10.1615/critreveukargeneexpr.v17.i4.20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Oncogenic pathways of AML1-ETO in acute myeloid leukemia: multifaceted manipulation of marrow maturation.

    Elagib, Kamaleldin E / Goldfarb, Adam N

    Cancer letters

    2007  Volume 251, Issue 2, Page(s) 179–186

    Abstract: The leukemic fusion protein AML1-ETO occurs frequently in human acute myeloid leukemia (AML) and has received much attention over the past decade. An initial model for its pathogenetic effects emphasized the conversion of a hematopoietic transcriptional ... ...

    Abstract The leukemic fusion protein AML1-ETO occurs frequently in human acute myeloid leukemia (AML) and has received much attention over the past decade. An initial model for its pathogenetic effects emphasized the conversion of a hematopoietic transcriptional activator, RUNX1 (or AML1), into a leukemogenic repressor which blocked myeloid differentiation at the level of target gene regulation. This view has been absorbed into a larger picture of AML1-ETO pathogenesis, encompassing dysregulation of hematopoietic stem cell homeostasis at several mechanistic levels. Recent reports have highlighted a multifaceted capacity of AML1-ETO directly to inhibit key hematopoietic transcription factors that function as tumor suppressors at several nodal points during hematopoietic differentiation. A new model is presented in which AML1-ETO coordinates expansion of the stem cell compartment with diminished lineage commitment and with genome instability.
    MeSH term(s) Acute Disease ; Animals ; Bone Marrow/physiology ; Cell Differentiation ; Core Binding Factor Alpha 2 Subunit/metabolism ; Hematopoiesis ; Hematopoietic Stem Cells/physiology ; Humans ; Leukemia, Myeloid/metabolism ; Models, Biological ; Mutation ; Oncogene Proteins, Fusion/metabolism ; RUNX1 Translocation Partner 1 Protein ; Tumor Suppressor Proteins/drug effects
    Chemical Substances AML1-ETO fusion protein, human ; Core Binding Factor Alpha 2 Subunit ; Oncogene Proteins, Fusion ; RUNX1 Translocation Partner 1 Protein ; Tumor Suppressor Proteins
    Language English
    Publishing date 2007-06-28
    Publishing country Ireland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2006.10.010
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  7. Article ; Online: Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia.

    Goldfarb, Adam N / Freeman, Katie C / Sahu, Ranjit K / Elagib, Kamaleldin E / Holy, Maja / Arneja, Abhinav / Polanowska-Grabowska, Renata / Gru, Alejandro A / White, Zollie / Khalil, Shadi / Kerins, Michael J / Ooi, Aikseng / Leitinger, Norbert / Luckey, Chance John / Delehanty, Lorrie L

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1645

    Abstract: Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton ... ...

    Abstract Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton and associated Golgi disruption. Isocitrate supplementation, known to abrogate the erythroid iron restriction response, induces reassembly of microtubules and Golgi in iron deprived progenitors. Ferritin, based on proteomic profiles, regulation by iron and isocitrate, and putative interaction with microtubules, is assessed as a candidate mediator. Knockdown of ferritin heavy chain (FTH1) in iron replete progenitors induces microtubule collapse and erythropoietic blockade; conversely, enforced ferritin expression rescues erythroid differentiation under conditions of iron restriction. Fumarate, a known ferritin inducer, synergizes with isocitrate in reversing molecular and cellular defects of iron restriction and in oral remediation of murine anemia. These findings identify a cytoskeletal component of erythroid iron restriction and demonstrate potential for its therapeutic targeting in ACDI.
    MeSH term(s) Anemia/metabolism ; Anemia/therapy ; Animals ; Cell Proliferation ; Cytoskeleton/metabolism ; Disease Models, Animal ; Erythroid Cells/metabolism ; Erythropoiesis/physiology ; Female ; Ferritins/metabolism ; Iron/metabolism ; Isocitrates ; Male ; Mice ; Mice, Inbred C57BL ; Microtubules/metabolism ; Oxidoreductases/metabolism ; Proteomics
    Chemical Substances Isocitrates ; Ferritins (9007-73-2) ; isocitric acid (9RW6G5D4MQ) ; Iron (E1UOL152H7) ; Fth1 protein, mouse (EC 1.-) ; Oxidoreductases (EC 1.-)
    Language English
    Publishing date 2021-03-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-21938-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes.

    Elagib, Kamaleldin E / Brock, Ashton / Clementelli, Cara M / Mosoyan, Goar / Delehanty, Lorrie L / Sahu, Ranjit K / Pacheco-Benichou, Alexandra / Fruit, Corinne / Besson, Thierry / Morris, Stephan W / Eto, Koji / Jobaliya, Chintan / French, Deborah L / Gadue, Paul / Singh, Sandeep / Shi, Xinrui / Qin, Fujun / Cornelison, Robert / Li, Hui /
    Iancu-Rubin, Camelia / Goldfarb, Adam N

    The Journal of clinical investigation

    2022  Volume 132, Issue 19

    Abstract: Infantile (fetal and neonatal) megakaryocytes (Mks) have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in ...

    Abstract Infantile (fetal and neonatal) megakaryocytes (Mks) have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived Mks. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with the potential to affect MKL1 function and found that DYRK1A inhibition dramatically enhanced Mk morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal Mks. Mks derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss-of-function studies confirmed MKL1 involvement in this morphogenetic pathway. Expression of Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile Mks.
    MeSH term(s) Actins/metabolism ; Blood Platelets/metabolism ; Humans ; Infant, Newborn ; Megakaryocytes/metabolism ; Phenotype ; Protein Serine-Threonine Kinases ; Protein-Tyrosine Kinases ; Thrombocytopenia/genetics ; Thrombopoiesis/genetics ; Dyrk Kinases
    Chemical Substances Actins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2022-10-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI154839
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  9. Article: AML-1-ETO-Mediated erythroid inhibition: new paradigms for differentiation blockade by a leukemic fusion protein.

    Choi, Youngjin / Elagib, Kamaleldin E / Goldfarb, Adam N

    Critical reviews in eukaryotic gene expression

    2005  Volume 15, Issue 3, Page(s) 207–216

    Abstract: The chromosomal translocation t(8;21), generating the AML1-ETO fusion protein, is frequently associated with French-American-British (FAB) type M2 acute myeloid leukemia (AML). t(8;21) fuses the runt domain from the hematopoietic transcription factor ... ...

    Abstract The chromosomal translocation t(8;21), generating the AML1-ETO fusion protein, is frequently associated with French-American-British (FAB) type M2 acute myeloid leukemia (AML). t(8;21) fuses the runt domain from the hematopoietic transcription factor RUNX1 with almost the entire transcriptional repressor ETO. AML1-ETO inhibits normal definitive hematopoiesis and blocks erythroid differentiation. Several mechanistic models for the role of AML1-ETO in leukemia development have emerged over the last decade. Most of these models have emphasized the capacity of the fusion protein to redirect repressive cofactors, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), to RUNX target genes, thereby reversing the hematopoietic transcriptional program activated by wild-type RUNX1a phenomenon referred to collectively in this review as the "classical" corepressor model. Because erythropoiesis occurs in a RUNX-independent manner, this dominant-negative "classical" model cannot explain the prominent repression of red-cell development by AML1-ETO. This review will consider the clinical and mechanistic significance of erythroid inhibition by AML1-ETO. Additional models to account for this mysterious oncogenic function are proposed.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Animals ; Cell Differentiation/genetics ; Cells, Cultured ; Chromosomes, Human, Pair 21 ; Chromosomes, Human, Pair 8 ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor Alpha 2 Subunit/physiology ; Erythroid Cells/cytology ; Erythropoiesis/genetics ; GATA1 Transcription Factor/physiology ; Histone Deacetylases/genetics ; Humans ; Leukemia, Myeloid, Acute/diagnosis ; Leukemia, Myeloid, Acute/genetics ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/physiology ; RUNX1 Translocation Partner 1 Protein ; Signal Transduction/genetics ; Translocation, Genetic
    Chemical Substances AML1-ETO fusion protein, human ; Adaptor Proteins, Signal Transducing ; Core Binding Factor Alpha 2 Subunit ; GATA1 Transcription Factor ; GATA1 protein, human ; Oncogene Proteins, Fusion ; RUNX1 Translocation Partner 1 Protein ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2005-12-31
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1071345-1
    ISSN 1045-4403
    ISSN 1045-4403
    DOI 10.1615/critreveukargeneexpr.v15.i3.30
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1.

    Choi, Youngjin / Elagib, Kamaleldin E / Delehanty, Lorrie L / Goldfarb, Adam N

    Cancer research

    2006  Volume 66, Issue 6, Page(s) 2990–2996

    Abstract: Human acute myeloid leukemias with the t(8;21) translocation express the AML1-ETO fusion protein in the hematopoietic stem cell compartment and show impairment in erythroid differentiation. This clinical finding is reproduced in multiple murine and cell ... ...

    Abstract Human acute myeloid leukemias with the t(8;21) translocation express the AML1-ETO fusion protein in the hematopoietic stem cell compartment and show impairment in erythroid differentiation. This clinical finding is reproduced in multiple murine and cell culture model systems in which AML1-ETO specifically interferes with erythroid maturation. Using purified normal human early hematopoietic progenitor cells, we find that AML1-ETO impedes the earliest discernable steps of erythroid lineage commitment. Correspondingly, GATA-1, a central transcriptional regulator of erythroid differentiation, undergoes repression by AML1-ETO in a nonconventional histone deacetylase-independent manner. In particular, GATA-1 acetylation by its transcriptional coactivator, p300/CBP, a critical regulatory step in programming erythroid development, is efficiently blocked by AML1-ETO. Fusion of a heterologous E1A coactivator recruitment module to GATA-1 overrides the inhibitory effects of AML1-ETO on GATA-1 acetylation and transactivation. Furthermore, the E1A-GATA-1 fusion, but not wild-type GATA-1, rescues erythroid lineage commitment in primary human progenitors expressing AML1-ETO. These results ascribe a novel repressive mechanism to AML1-ETO, blockade of GATA-1 acetylation, which correlates with its inhibitory effects on primary erythroid lineage commitment.
    MeSH term(s) Acetylation ; Antigens, CD34/biosynthesis ; Antigens, CD34/immunology ; CD36 Antigens/biosynthesis ; CD36 Antigens/immunology ; Cell Differentiation/physiology ; Cell Line ; Cell Lineage ; Core Binding Factor Alpha 2 Subunit/biosynthesis ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor Alpha 2 Subunit/physiology ; Erythroid Precursor Cells/cytology ; Erythroid Precursor Cells/immunology ; Erythroid Precursor Cells/metabolism ; Erythroid Precursor Cells/physiology ; GATA1 Transcription Factor/metabolism ; Humans ; K562 Cells ; Oncogene Proteins, Fusion/biosynthesis ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/physiology ; RUNX1 Translocation Partner 1 Protein ; Transcriptional Activation ; Transfection ; Zinc Fingers/physiology ; p300-CBP Transcription Factors/metabolism
    Chemical Substances AML1-ETO fusion protein, human ; Antigens, CD34 ; CD36 Antigens ; Core Binding Factor Alpha 2 Subunit ; GATA1 Transcription Factor ; GATA1 protein, human ; Oncogene Proteins, Fusion ; RUNX1 Translocation Partner 1 Protein ; p300-CBP Transcription Factors (EC 2.3.1.48)
    Language English
    Publishing date 2006-03-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-05-2944
    Database MEDical Literature Analysis and Retrieval System OnLINE

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