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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CAMP (01))
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Mufson, R Allan
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University of Virginia
Schools of Medicine
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Elagib, Kamaleldin E; Rubinstein, Jeremy D; Delehanty, Lorrie L et al. (2013) Calpain 2 activation of P-TEFb drives megakaryocyte morphogenesis and is disrupted by leukemogenic GATA1 mutation. Dev Cell 27:607-20
Goldfarb, Adam N (2009) Megakaryocytic programming by a transcriptional regulatory loop: A circle connecting RUNX1, GATA-1, and P-TEFb. J Cell Biochem 107:377-82
Elagib, Kamaleldin E; Goldfarb, Adam N (2007) Oncogenic pathways of AML1-ETO in acute myeloid leukemia: multifaceted manipulation of marrow maturation. Cancer Lett 251:179-86
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Choi, Youngjin; Elagib, Kamaleldin E; Delehanty, Lorrie L et al. (2006) Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1. Cancer Res 66:2990-6
Elagib, Kamaleldin E; Xiao, Mang; Hussaini, Isa M et al. (2004) Jun blockade of erythropoiesis: role for repression of GATA-1 by HERP2. Mol Cell Biol 24:7779-94