MYELOID TRANSCRIPTION FACTORS AND LEUKEMIA

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Abstract

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 In addition, we have unpublished data showing that patients with AML have mutations in the C/EBPalpha gene.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.