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中的体细胞突变与急性有关 唐氏综合症儿童（DS，三体术21）中的巨核细胞白血病（AMKL），尽管 这种遗传相互作用的基础机制尚不清楚。在初步研究中，我证明了 三体术本身增加了人类红细胞和巨核细胞祖细胞的增殖能力。 在平行的鼠研究中，我使用遗传操纵的胚胎干细胞表明了 GATA-1促进了双能巨核细胞 - 雌雄病前体（MEP）的扩展，人口 这类似于AMKL爆炸。通过突变体MEP的遗传互补，我发现 GATA-1抑制髓样分化的程序，部分原因是抑制原始的转录 癌基因PU.1/SFPI1。这种效果通过AMKL相关的GATA1突变减弱。在一起，我的 发现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 关于造血作用，共同促进白血病。其次，GATA-1促进正常 通过抑制PU.1/sfpi1转录，造血作用可能会变得失调 通过与DS-AMKL相关的遗传改变。该应用是为了支持一项指导的研究 阐明GATA-1如何控制正常造血的经验以及如何失调的GATA-1和 DS在白血病中协同作用。我将扩展我在DS胎儿造血的研究，以了解 三体21扩展红细胞和巨核细胞祖细胞的机制（AIM 1）。我会 检查人类造血的改变的GATA-1和三体性21的功能相互作用 体外和小鼠的祖细胞（AIM 2）。最后，我将研究野生类型和野生类型的机制 GATA-1抑制PU的AMKL相关突变形式。 1/SFPH癌基因转录（AIM 3）。如果 成功的是，我的研究将提供有关正常红细胞的转录控制的见解 巨核细胞的发展以及该过程如何在AMKL中受到干扰。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起作用 发展与癌症。结合我的培训和结构化指导，我 相信拟议的研究将为正常和恶性提供新的新见解 造血，并为建立我作为儿科医师科学家的职业提供了坚实的基础。