Transcription Factor GATA-1 in Erythro-Megakaryocytic Development and Leukemia

转录因子 GATA-1 在红巨核细胞发育和白血病中的作用

• 批准号: 7345627
• 负责人: Mitchell J Weiss
• 金额: $ 20.03万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345627
• 关键词: Acute; Acute Megakaryocytic Leukemias; Affect; Biological; Biological Assay; Biological Models; Blast Cell; Cells; Child; Chromosomes, Human, Pair 21; Commit; DNA; Development; Down Syndrome; Embryo; Embryo Loss; Erythro; Erythroid; Event; Exhibits; GATA1 gene; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic Programming; Genetic Transcription; Goals; Hematopoiesis; Hematopoietic; Histones; Human; Human Development; Individual; Induced Mutation; Kinetics; Laboratories; Lead; Link; Liquid substance; Malignant - descriptor; Mediating; Megakaryocyte Proliferation; Megakaryocytes; Methylcellulose; Modeling; Molecular; Mus; Mutation; Newborn Infant; Nuclear Protein; Nuclear Proteins; Numbers; Patients; Population; Production; Proteins; Regulation; Research Personnel; SCID Mice; Small Interfering RNA; Somatic Mutation; Staging; Stem cells; System; Tetracycline; Tetracyclines; Transplantation; Umbilical Cord Blood; chromatin immunoprecipitation; cofactor; embryonic stem cell; fetal; human GATA1 protein; human embryonic stem cell; improved; in vivo; leukemia; leukemogenesis; loss of function; man; mutant; progenitor; programs; promoter; research study; self-renewal; transcription factor; transient myeloproliferative disorder

DESCRIPTION (provided by applicant): Most leukemias are caused by somatic mutations that disrupt transcription factor function. One example is GATA-1, a nuclear protein required for erythroid and megakaryocytic maturation. Nearly all patients with Down's Syndrome-associated transient myeloproliferative disorder (TMD) or acute megakaryoblastic leukemia (AMKL) exhibit somatic GATA1 gene mutations that result in the exclusive production of an abnormal amino-truncated protein, termed GATA-1 short. We showed that in murine embryonic stem cells and embryos, loss of GATA-1 causes a previously unappreciated block at the bipotential megakaryocytic-erythroid progenitor (MEP) stage of hematopoiesis, where development also appears to be perturbed in AMKL. The leukemia-associated GATA-1 short protein fails to relieve this block and actually drives proliferation in a subset of arrested MEPs. Hence, we hypothesize that GATA-1 promotes normal MEP maturation and that derangements in this function contribute to Down's syndrome-associated TMD and AMKL. In particular, we believe that loss of specific GATA-1 functions activate an aberrant self-renewal program in MEPs, which contributes to development of the leukemic stem cell. Now, we will define the genetic program through which normal GATA-1 controls MEP development and investigate how this program becomes deranged by GATA-1 short in murine ES cells and in human fetal hematopoietic progenitors from both normal and trisomy 21 individuals.

描述（由申请人提供）：大多数白血病是由破坏转录因子功能的体细胞突变引起的。一个例子是加塔-1，一种红细胞和巨核细胞成熟所需的核蛋白。几乎所有患有唐氏综合征相关的暂时性骨髓增生性疾病（TMD）或急性巨核细胞白血病（AMKL）的患者都表现出体细胞GATA 1基因突变，其导致异常氨基截短蛋白（称为加塔-1短）的专门产生。我们发现，在小鼠胚胎干细胞和胚胎中，加塔-1的缺失导致造血的双能巨核细胞-红系祖细胞（MEP）阶段的先前未被认识到的阻滞，其中AMKL的发育似乎也受到干扰。白血病相关的加塔-1短蛋白不能缓解这种阻滞，实际上驱动了一部分被阻滞的MEP的增殖。因此，我们假设加塔-1促进正常的MEP成熟，并且该功能的紊乱有助于唐氏综合征相关的TMD和AMKL。特别是，我们认为特定加塔-1功能的丧失激活MEP中异常的自我更新程序，这有助于白血病干细胞的发展。现在，我们将定义正常加塔-1控制MEP发育的遗传程序，并研究该程序如何在小鼠ES细胞和正常和21三体个体的人胎儿造血祖细胞中被加塔-1短序列扰乱。