Basic scientific research is rapidly merging with clinical research. We wish to increase our understanding of normal myelopoiesis at the molecular level, and correlate this with leukemogenesis. CCAAT/enhancer binding protein-alpha (C/EBPalpha) is essential for the development of neutrophils. Mice deficient for C/EBPalpha accumulate immature neutrophils in their peripheral blood, similar to the defect seen in human patients with Acute Myelogenous Leukemia (AML). Mice deficient for C/EBPalpha die soon after birth, before the onset of adult bone marrow hematopoiesis. We will attempt to generate an adult mouse model of AML by making chimeras using C/EBPalpha -/- embryonic stem cells. In addition, we have unpublished data showing that patients with AML have mutations in the C/EBPalpha gene. There are other mutations in C/EBPalpha that have been shown to affect the biochemical activity of C/EBPalpha. It is not obvious which biochemically defined protein domains are important for the in vivo function of a protein. Therefore, we will test all of these mutations to see if they have functional relevance regarding myelopoiesis using in vitro and in vivo assays. Our goal from these studies is to make a correlation between the structure of the C/EBPalpha protein and its function in myelopoiesis and leukemogenesis.
