Genetic modulators of erythro-megakaryocytic development

红巨核细胞发育的遗传调节剂

• 批准号: 8269868
• 负责人: STELLA T CHOU
• 金额: $ 13.39万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269868
• 关键词: Acute Megakaryocytic Leukemias; Animal Model; Attenuated; Blast Cell; Cells; Child; Childhood; Chromosomes, Human, Pair 21; Data; Development; Disease; Down Syndrome; Erythro; Erythroid; Fetal Liver; Flow Cytometry; Foundations; GATA1 gene; Gene Transfer; Genes; Genetic; Genetic Transcription; Hematopoiesis; Hematopoietic; Human; Immunodeficient Mouse; In Vitro; Malignant - descriptor; Malignant Neoplasms; Megakaryocytes; Mentors; Modeling; Mus; Mutation; Myelogenous; Normal tissue morphology; Oncogenes; Physicians; Population; Process; Proteins; Proto-Oncogenes; Research; Scientist; Small Interfering RNA; Somatic Mutation; Staging; Structure; Technology; Training; Transcription Process; Transcriptional Regulation; Transplantation; career; dosage; embryonic stem cell; experience; fetal; human GATA1 protein; in vivo; insight; leukemia; leukemogenesis; mutant; novel; overexpression; progenitor; programs; transcription factor

Somatic mutations in the gene encoding transcription factor GATA-1 are associated with acute megakaryoblastic leukemia (AMKL) in children with Down syndrome (DS, trisomy 21), although the mechanisms underlying this genetic interaction are unknown. In preliminary studies, I demonstrated that trisomy 21 itself increases the proliferative capacity of human erythroid and megakaryocyte progenitors. In parallel murine studies, I used genetically manipulated embryonic stem cells to show that loss of GATA-1 promotes the expansion of bipotential megakaryocyte-erythroid precursors (MEPs), a population that resembles AMKL blasts. Through genetic complementation of the mutant MEPs, I discovered that GATA-1 represses a program of myeloid differentiation, in part by inhibiting transcription of the proto- oncogene PU.1/Sfpi1. This effect is attenuated by AMKL-associated GATA1 mutations. Together, my findings generate two related hypotheses: First, GATA1 mutations and trisomy 21 produce distinct effects on hematopoiesis, which act together to promote leukemia. Second, GATA-1 promotes normal hematopoiesis by repressing PU.1/Sfpi1 transcription and this process may become dysregulated through genetic alterations associated with DS-AMKL. This application is to support a mentored research experience to elucidate how GATA-1 controls normal hematopoiesis and how dysregulated GATA-1 and DS synergize in leukemogenesis. I will extend my studies in DS fetal hematopoiesis to understand the mechanisms by which trisomy 21 expand erythroid and megakaryocytic progenitors (Aim 1). I will examine functional interactions between altered GATA-1 and trisomy 21 in human hematopoietic progenitors in vitro and in mice (Aim 2). Lastly, I will study the mechanisms by which wild type and AMKL-associated mutant forms of GATA-1 repress PU. 1/SfpH oncogene transcription (Aim 3). If successful, my research will provide insights into the transcriptional control of normal erythro- megakaryocytic development and how this process becomes disturbed in AMKL. The broader impact of this research is to better understand how a lineage-specific transcription factor functions in normal tissue development and cancer. Combined with my training and structured mentoring in this application, I believe that the proposed research will provide novel new insights into normal and malignant hematopoiesis and provide a strong foundation to establish my career as a pediatric physician-scientist.

编码转录因子 GATA-1 的基因的体细胞突变与急性 唐氏综合症（DS，21 三体）儿童的巨核细胞白血病 (AMKL)，尽管 这种遗传相互作用的机制尚不清楚。在初步研究中，我证明了 21 三体本身可增加人类红细胞和巨核细胞祖细胞的增殖能力。 在平行的小鼠研究中，我使用基因操纵的胚胎干细胞来证明， GATA-1促进双能巨核细胞-红系前体细胞（MEP）的扩张，这是一个群体 类似于 AMKL 爆炸。通过突变 MEP 的基因互补，我发现 GATA-1 抑制骨髓分化程序，部分是通过抑制原始细胞的转录来实现的。 癌基因 PU.1/Sfpi1。 AMKL 相关的 GATA1 突变会减弱这种效应。在一起，我的 研究结果产生了两个相关的假设：首先，GATA1 突变和 21 三体性产生不同的影响 造血作用，共同作用促进白血病。二、GATA-1促进正常 通过抑制 PU.1/Sfpi1 转录来促进造血，该过程可能会失调 通过与 DS-AMKL 相关的基因改变。此应用程序旨在支持指导研究 阐明 GATA-1 如何控制正常造血以及 GATA-1 和 DS 在白血病发生中发挥协同作用。我将扩展我对 DS 胎儿造血的研究，以了解 21 三体性扩增红系和巨核细胞祖细胞的机制（目标 1）。我会 检查人类造血中改变的 GATA-1 和 21 三体之间的功能相互作用 体外和小鼠体内的祖细胞（目标 2）。最后，我将研究野生型和 GATA-1 的 AMKL 相关突变形式抑制 PU。 1/SfpH 癌基因转录（目标 3）。如果 如果成功的话，我的研究将为正常红细胞的转录控制提供见解。 AMKL 中巨核细胞的发育以及这一过程如何受到干扰。更广泛的影响 这项研究是为了更好地了解谱系特异性转录因子如何在正常组织中发挥作用 发育和癌症。结合我在此应用程序中接受的培训和结构化指导，我 相信所提出的研究将为正常和恶性提供新颖的见解 造血并为我作为一名儿科医师科学家的职业生涯奠定了坚实的基础。