Knowledge of the mechanisms underlying the normal development of blood cells is important in understanding and developing new treatments for various blood diseases, including leukemias. The long range goals of this project are to further our understanding of the mechanisms involved in leukemia by understanding the effect of various leukemia oncogenes on the transcription factors which regulate normal myeloid development from stem cells. Previous studies from our laboratory and others has led to the identification of the transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPa) and as being absolutely critical for differentiation of normal myeloid blasts, and identified abnormalities in C/EBPa as playing critical roles in a number of specific types of Acute Myeloid Leukemia (AML). Studies in the past grant period have demonstrated that AML oncogenes, including PML/RAR and activating mutations of FLT3 can affect the expression and function of C/EBPa, and that drugs that inhibit these oncogenes restore the function of this transcription factor. Over the next 5 years, we propose further our knowledge of how these oncogenes affect critical transcription factor function in cell differentiation in order to more effectively develop and utilize drug therapy aimed at these targets. These studies are highly interactive with other componentsof this program, in that we will continue our interactions with Project 1 in developing new drug compbinations targeting transcription factors, Project 2 to investigate the co-operation between leukemia oncogenes and loss of transcription factor function, as well as with Project 5 and Core B to confirm our hypotheses in cells derived from patients undergoing clinical trials. Finally, we will interact closely with the new Project 4 to investigate the effect of another important oncogene on transcription factor function. Therefore, we propose the following Specific Aims: (1) To investigate the effects of PML/RAR alpha on C/EBPa , and the response of C/EBP beta to all trans retinoic acid (ATRA);(2) To develop mouse models which combining loss of C/EBPa and tyrosine kinases in development of AML;and (3) To investigate the pathways between FLT3 activation, C/EBPa phosphorylation, and AML.
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