Molecular Genetics of Blood Cell Development and Stem Cells
All blood cells arise from committed progenitors, which are descendants of pluripotent hematopoietic stem cells. The goal of our laboratory is to understand how commitment to specific blood lineages is programmed and how cell-specific patterns of gene expression are established. Since gene expression is controlled by nuclear regulatory factors (transcription factors), efforts have centered on identifying those crucial for the development of stem cells or individual lineages. Research encompasses conventional molecular biology and contemporary mouse genetics.Lineage specification and hematopoietic differentiationRed blood cells and megakaryocytes (which produce platelets) share a common precursor cell. We discovered a transcription factor, GATA1, that participates in the regulation of virtually all red cell (erythroid) and megakaryocyte-specific expressed genes. Expression of GATA1 in progenitors drives cells toward erythroid and megakaryocytic fates. Disruption of the Gata1 gene in mice leads to a failure of maturation of both lineages. In addition to controlling end-stage markers of these lineages, GATA1 influences proliferation and cell death decisions of precursor cells. Using this mouse model to dissect mechanisms of cell differentiation, we have sought to understand how GATA1 functions in transcription. This line of investigation led us to hypothesize and then discover a cofactor required for GATA1's function in these lineages. This novel cofactor, FOG (for friend of GATA1), is also essential for normal red blood cell and megakaryocyte development. Current research focuses on how FOG modulates the function of GATA1 and related factors during hematopoietic and nonhematopoietic cell development.Hematopoiesis-leukemia interfaceRemarkably, many genes essential for normal hematopoietic development are involved in chromosomal translocations in human leukemias. This finding reflects perturbation of normal homeostasis by expression of an altered protein or excessive production of an otherwise normal factor. We are studying several transcription factors (e.g., SCL/tal-1, TEL) affected by genetic events in leukemias. Our work is directed toward understanding the normal roles of these transcription factors in hematopoiesis and vascular development. In addition, efforts are ongoing to recreate in mice the common form of childhood leukemia, acute lymphoblastic leukemia, associated with fusion of the TEL and AML1 genes. This animal model will permit improved understanding of the pathogenesis of acute lymphoblastic leukemia and provide a system for testing new therapies.