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.

转录因子GATA-1编码基因的体细胞突变与急性 唐氏综合征(DS，21三体)儿童的巨核细胞白血病(AMKL)，尽管 这种遗传相互作用背后的机制尚不清楚。在初步研究中，我证明了 21三体本身增加了人类红系和巨核系祖细胞的增殖能力。 在平行的小鼠研究中，我使用了基因操纵的胚胎干细胞来证明 GATA-1促进双潜能巨核细胞-红系前体细胞(MEPs)群体的扩张 这类似于AMKL爆炸。通过突变的MEP的遗传互补，我发现 GATA-1抑制髓系分化的程序，部分是通过抑制原-1的转录。 癌基因PU.1/Sfpi1。这种影响被AMKL相关的GATA1突变减弱。一起，我的 这些发现产生了两个相关的假设：第一，GATA1突变和21三体产生不同的影响 在造血方面，它们共同作用于促进白血病。第二，GATA-1促进正常 通过抑制PU.1/Sfpi1转录促进造血，这一过程可能会变得失调 通过与DS-AMKL相关的基因改变。此应用程序用于支持有指导的研究 阐明GATA-1如何控制正常造血以及GATA-1和GATA-1调控异常的经验 DS在白血病发生中具有协同作用。我将延长我在DS胎儿造血方面的研究，以了解 21三体扩大红系和巨核系祖细胞的机制(目标1)。这就做 检测GATA-1基因突变与21三体在人类造血系统中的功能相互作用 体外和小鼠体内的祖细胞(目标2)。最后，我将研究野生型和野生型 AMKL相关的GATA-1突变形式抑制PU。1/SfpH癌基因转录(目标3)。如果 如果成功，我的研究将为正常红细胞的转录控制提供洞察力。 巨核细胞发育以及这一过程如何在AMKL中被扰乱。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在正常组织中的功能 发展和癌症。结合我在此应用程序中的培训和结构化指导，我 相信这项拟议的研究将为正常和恶性提供新的见解 并为我成为一名儿科内科科学家奠定了坚实的基础。