TRANSCRIPTION FACTORS/ GENETIC SEQUENCES REQUIRED FOR CD34 IN EARLY HEMATOPOIESIS

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The long-term goal of my research program is to define the molecular mechanisms that regulate nearly hematopoiesis. To do this I am using the murine CD34 gene as a model system. CD34 is the best characterized antigen that can be used to isolate hematopoietic reconstituting cells for human stem cell transplantation. It's expression is coordinately regulated with lineage commitment in hematopoietic differentiation such that CD34 is expressed on hematopoietic stem and progenitor cells, and as maturation progresses, expression decreases and all mature blood cells are CD34 negative. Forced over-expression of CD34 inhibits terminal differentiation suggesting that CD34 down-regulation is required for the differentiation process. In work to date, I have identified critical regions of the CD34 gene that enhance expression from the CD34 promoter in a tissue-specific manner. The aims presented in this proposal approach the study of early hematopoietic differentiation from several directions-1.) The isolation and identification of a potentially novel stem cell-specific transcription factor, 2.) The establishment of a family of genes that share the stage specific expression pattern of CD34, and therefore may be coordinately regulated, 3.) The isolation and identification of the DNA sequences required for position-independent, copy-number dependent, ell typed specific expression of CD34 in vivo, and 4.) Identification of these genes that are required for myeloid differentiation, but are inhibited when CD34 down-regulation is prevented. Each of this goals contributes to a better understanding of how hematopoietic stem cells are regulated. This increased understanding of how a stem cell "knows" to remain a stem cell, or to divide and differentiate into any of the mature cells in the peripheral blood has direct implications for the pathogenesis of leukemia and other hematopoietic disorders such as myelodysplasia and aplastic anemia.