MOLECULAR CORRELATES OF HOXB4 FUNCTION

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Hematopoeitic stem cells comprise a very small faction of bone marrow mononuclear cells, which retain the capacity for self-renewal as well as controlled differentiation into all of the cellular elements of the peripheral blood. The molecular signals that confer the stem cell phenotype and the mechanisms that control stem cell proliferation and differentiation are not completely understood. The homeobox gene HoxB4 is expressed in hematopoietic stem/progenitor cells but not in more differentiated cells. Studies by a number of different investigators have shown that enforced expression of HoxB4 in hematopoietic stem cells leads to enhancement of their ability to expand, both in vivo and in vitro, without inducing adverse events such as the development of leukemia. The overall research goal of this proposal is to investigate the molecular mechanisms of action of HoxB4 in stem cell expansion, using currently emerging tools for genomic scale analysis. These analyses will include a variety of technologies, including gene transfer followed by induced expression of the transferred gene(s), gene expression profiling using microarrays, chromatin immunoprecipitation followed by large scale screening to identify HoxB4 binding sites in genomic DNA, study of protein-protein interactions, functional studies of recombinant chimeric fusion proteins, inhibition of gene expression by RNAi and protein uptake experiments.