Transcription Factor GATA-1 in Erythro-Megakaryocytic De

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DESCRIPTION (provided by applicant): Most leukemias are caused by somatic mutations that disrupt transcription factor function. One example is GATA-1, a nuclear protein required for erythroid and megakaryocytic maturation. Nearly all patients with Down's Syndrome-associated transient myeloproliferative disorder (TMD) or acute megakaryoblastic leukemia (AMKL) exhibit somatic GATA1 gene mutations that result in the exclusive production of an abnormal amino-truncated protein, termed GATA-1 short. We showed that in murine embryonic stem cells and embryos, loss of GATA-1 causes a previously unappreciated block at the bipotential megakaryocytic-erythroid progenitor (MEP) stage of hematopoiesis, where development also appears to be perturbed in AMKL. The leukemia-associated GATA-1 short protein fails to relieve this block and actually drives proliferation in a subset of arrested MEPs. Hence, we hypothesize that GATA-1 promotes normal MEP maturation and that derangements in this function contribute to Down's syndrome-associated TMD and AMKL. In particular, we believe that loss of specific GATA-1 functions activate an aberrant self-renewal program in MEPs, which contributes to development of the leukemic stem cell. Now, we will define the genetic program through which normal GATA-1 controls MEP development and investigate how this program becomes deranged by GATA-1 short in murine ES cells and in human fetal hematopoietic progenitors from both normal and trisomy 21 individuals.