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.
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