Hematopoietic pluripotent or long-term reconstituting stem/progenitor cells represent a very small fraction of cells in the bone marrow which have the capacity for both self-renewal and differentiation along multiple pathways ultimately giving rise to all of the cellular elements of peripheral blood. Much remains to be understood about these cells and the patterns of gene expression that characterize them. In preliminary experiments, we have isolated a number of gene products (mRNAs/cDNAs) that are preferentially expressed in highly purified/enriched preparations of murine hematopoietic stem cells. One of these cDNAs derives from a homeobox gene that has been previously shown to have a tissue-restricted pattern of expression during murine development and mutations of which have been shown to be associated with (and are presumably responsible for) developmental disorders in humans. We now propose to directly study the function of this homeobox gene in the regulation of hematopoiesis by carrying out a number of studies in the laboratories of INSERM Unit 362 (W. Vainchenker, Director) at the Institut Gustave Roussy in Villejuif, France, where a number of different functional assays of hematopoietic stem cell proliferation and differentiation are available, as well as retroviral-based gene transfer techniques for transduction of hematopoietic stem/progenitor cells. The proposed research should provide a synergistic interaction between the laboratories of the applicant and the host institution, resulting in long-term collaborations and research productivity.
