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. Studies funded during the first cycle of this grant led to the identification of the transcription factor CCAAT Enhancer Binding Protein a (C/EBPa) as being absolutely critical for differentiation of normal myeloid blasts, and identified abnormalities in C/EBPa DNA binding as playing a critical role in Acute Myeloid Leukemia (AML), as noted in the Progress Report. Over the next 5 years, we propose to extend the study of this critical transcription factor in cell differentiation. We therefore propose the following Specific Aims: (1) The normal C/EBPa gene can encode both a 42 kDa and 30 kDa form of the protein, and recently it has demonstrated that mutations in the C/EBPa gene which lead to a relative increase in the 30 kDa form lead to loss of C/EBPa DNA binding activity. Therefore, it is important to study why the 30 kDa form binds poorly and inhibits the 42 kDa form. These experiments will include studies of the DNA binding properties of the different isoforms of C/EBPa. Investigating the mechanism by which the 30 kDa form fails to bind DNA efficiently, and how the 30 kDa form inhibits DNA binding activity of the 42 kDa form. (2) We have developed C/EBPa knockout cell lines and ES cells. The ability to perform structure-function analysis of the C/EBPa protein using these reagents will provide important insights into not only the role of C/EBPa, but also the proteins which interact with its various domains, on myelopoiesis. Therefore, we will perform a functional analysis of C/EBPa protein using rescue assays of C/EBPa knockout cells, testing the ability of wild-type and C/EBPa mutants to restore myeloid differentiation of C/EBPa -/cell lines and in vivo, as well as the role of specific interactions of C/EBPa and other proteins in myeloid development. (3) All of our previous studies in C/EBPa knockout mice have been limited to embryonic or newborn animals due to newborn lethality from hypoglycemia. We have developed conditional C/EBPa knockout mice which will allow us to investigate the role of C/EBPa in development of adult hematopoiesis.
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