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Involvement of RUNX1 in Megakaryocytic Differentiation

RUNX1 参与巨核细胞分化

基本信息

批准号：
7234821
负责人：
Adam N. Goldfarb
金额：
$ 25.2万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-23 至 2008-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Understanding the transcriptional regulation of megakaryocytic lineage commitment will provide guidance in designing treatments for many bone marrow disorders associated with thrombocytopenia. We have identified the myeloid transcription factor RUNX1 as a protein upregulated early in megakaryocytic differentiation and downregulated early in erythroid differentiation. This expression pattern is unique in that virtually all other megakaryocytic transcription factors, such as GATA-1, FOG-1, NF-E2, and SCL/tal, display shared expression in both megakaryocytic and erythroid lineages. The restricted coexpression of RUNX1 and GATA-1 in megakaryocytes led us to discover that these factors strongly cooperate in the activation of a megakaryocytic promoter. This cooperation depends on RUNX1 binding sites present in the promoter and on the RUNX1 cofactor CBFbeta. Co-immunoprecipitation assays demonstrate physical association of RUNX1/CBFbeta with GATA. This novel functional and physical association correlates with the recent clinical implications of both the GATA-1 and RUNX1 genes in hereditary syndromes with thrombocytopenia. A dominant-negative variant of RUNX1 consists of a fusion with the ETO transcriptional repressor that results from the t(8;21) chromosomal abnormality frequently found in acute myeloid leukemia. We have found that the RUNX1-ETO oncoprotein, in contrast to wild type RUNX1, potently inhibits GATA-1 activation of a megakaryocytic promoter. In addition, RUNX1-ETO demonstrates physical interaction with GATA-1. Thus, one of the oncogenic effects of RUNX1-ETO may consist of blocking GATA driven hematopoietic differentiation. The major aims of this project are: 1) Delineation of the developmental consequences and molecular mechanisms of RUNX1 synergy with GATA-1 in megakaryopoiesis; 2) Determination of the developmental consequences and molecular mechanisms of RUNX1-ETO inhibition of GATA factors.

描述（由申请人提供）：了解巨核细胞谱系定型的转录调控将为许多血小板减少相关骨髓疾病的治疗设计提供指导。我们已经确定了髓系转录因子RUNX 1作为一种蛋白质在巨核细胞分化早期上调和在红系分化早期下调。这种表达模式是独特的，因为几乎所有其他巨核细胞转录因子，如加塔-1、FOG-1、NF-E2和SCL/tal，在巨核细胞和红细胞谱系中显示共有表达。 RUNX 1和加塔-1在巨核细胞中的限制性共表达使我们发现这些因子在巨核细胞启动子的激活中强烈合作。这种合作依赖于启动子中存在的RUNX 1结合位点和RUNX 1辅因子CBFbeta。免疫共沉淀试验证明RUNX 1/CBF β与加塔的物理结合。这种新的功能和物理关联与加塔-1和RUNX 1基因在遗传性血小板减少综合征中的最新临床意义相关。 RUNX 1的显性阴性变异体由与ETO转录抑制因子的融合组成，ETO转录抑制因子由急性髓性白血病中常见的t（8;21）染色体异常引起。我们已经发现，与野生型RUNX 1相反，RUNX 1-ETO癌蛋白有效地抑制巨核细胞启动子的加塔-1激活。此外，RUNX 1-ETO证明了与加塔-1的物理相互作用。因此，RUNX 1-ETO的致癌作用之一可能包括阻断加塔驱动的造血分化。本项目的主要目的是：1）描述RUNX 1与加塔-1协同作用在巨核细胞生成中的发育后果和分子机制; 2）确定RUNX 1-ETO抑制加塔因子的发育后果和分子机制。