GATA-2 MEDIATED REGULATION OF NORMAL AND LEUKEMIC STEM/PROGENITOR CELL FUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. GATA-2 is the second member of the zinc finger GATA family of transcription factors which influence cell fate in hematopoietic and other tissue systems. GATA-2 -/- are embryonic lethal at e10-11 with severe anemia; precludes analysis of adult hematopoietic compartment. GATA-2 +/- mice survive throughout adulthood and provide an amenable model to probe adult hematopoiesis. Indeed, Dr. Rodrigues will focus on "GATA-2 mediated regulation of normal and leukemic stem/progenitor cell function". Studying this transcription factor and determining its role has important repercussions not only for neoplasia, but for the transcriptional regulation of stem cells and tissue repair. The project uses the leukemic process as a model for transcriptional regulation of stem cells. Overall, the proposed hypothesis is that GATA-2 is a transcription factor that sustains myeloid leukemic stem cells. To address this hypothesis, the following specific aims will be addressed: 1) Knockdown GATA-2 in leukemic stem cell (LSC) compartment of mouse AML and evaluate how this impacts LSC function and leukemia progression in vivo. 2) Assess how reduction of GATA-2 impacts cellular LSC function in vitro e.g. cell cycle, apoptosis. 3) Evaluate how reduction of GATA-2 affects the LSC gene expression profile (GATA-2 LSC target genes) and, specifically, compare this to GATA-2 gene target program in normal HSCs/progenitors Ultimately, within the overall scope of studying transcriptional regulation of stem cell differentiation, the project will identify downstream mediators of GATA-2 that can be specifically targeted in LSCs/leukemia. The information gleaned from these studies may also afford insights into regulation of malignancy in other settings, including tissue injury and repair.