Proliferating bone marrow precursors (""""""""stem cells"""""""") differentiate to produce mature hematopoietic cells. The molecular controls governing commitment to and differentiation of the myeloid (granulocyte/monocyte) lineage, the lineage in which a block in differentiation results in over 90% of acute leukemias in adults, have not been fully elucidated. One hypothesis is that the expression of lineage specific transcription factors play a major role in commitment and differentiation. The overall goal of this continuation proposal is to continue to study how factors such as PU.1 regulate the expression of the gene encoding CD11b (Mac-1 alpha), a cell surface adhesion protein which is specifically expressed in myeloid cells and strongly up-regulated during the course of human myeloid differentiation as a model to understand (1) commitment of normal hematopoietic precursors to the myeloid lineage; and (2) the process of normal myeloid maturation from myeloid blasts to mature myeloid cells, a process which is blocked in acute myelogenous leukemia (AML). Therefore, in order to further characterize the molecular mechanisms of the regulation and expression of the CD11b gene in myeloid cells, and the role of the PU.1 transcription factor in myeloid commitment and differentiation, we propose the following specific aims: (1) To determine if the PU.1 and Sp1 transcription factors function as important determinants of the myeloid specific expression of the CD11b promoter in ES cells and transgenic mice; (2) To determine the expression pattern of the PU.1 protein during myeloid commitment, and the molecular controls of the regulation of PU.1 expression; and (3) T determine the importance of the PU.1 factor in vivo for CD11b expression, myeloid lineage commitment, and differentiation.
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