Knowledge of the mechanisms underlying the normal development of blood cells will lead to new understanding and treatments of various blood diseases, including leukemias. The long range goals are to further our understanding of the mechanisms involved in myelopoiesis and leukemia by understanding the transcription factors which regulate myeloid development from stem cells. The transcription factor CCAAT Enhancer Binding Protein alpha (C/EBP alpha) is required for differentiation of normal myeloid blasts and disrupted through multiple mechanisms in Acute Myeloid Leukemia (AML). Conditional knockout models demonstrate that loss of C/EBP alpha leads to increased self-renewal and repopulating ability of fetal liver hematopoietic stem cells (HSC), as well as a block in differentiation at a distinct stage of granulocytic differentiation. Over the next 5 years, we propose to extend the study of this critical transcription factor in hematopoietic stem cells. We therefore propose the following Specific Aims: (1) What is the role of C/EBP alpha with respect to numbers and function of adult HSC? (2) What is the role of cytokines on C/EBP family member expression and granulopoiesis? (3) How does C/EBPa regulate Bmi-1 and affect HSC function? These studies will lead to new insights into the role of this transcription factor in HSC and progenitor function, which is relevant to the understanding of normal hematopoietic differentiation and leukemogenesis.
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