Knowledge of the mechanisms underlying the normal development of blood cells is important inunderstanding and developing new treatments for various blood diseases, including leukemias. The longrange goals of this project are to further our understanding of the mechanisms involved in leukemia byunderstanding the effect of various leukemia oncogenes on the transcription factors which regulate normalmyeloid development from stem cells. Previous studies from our laboratory and others has led to theidentification of the transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPa) and as beingabsolutely critical for differentiation of normal myeloid blasts, and identified abnormalities in C/EBPa asplaying critical roles in a number of specific types of Acute Myeloid Leukemia (AML). Studies in the pastgrant period have demonstrated that AML oncogenes, including PML/RAR and activating mutations of FLT3can affect the expression and function of C/EBPa, and that drugs that inhibit these oncogenes restore thefunction of this transcription factor. Over the next 5 years, we propose further our knowledge of how theseoncogenes affect critical transcription factor function in cell differentiation in order to more effectively developand utilize drug therapy aimed at these targets. These studies are highly interactive with other componentsofthis program, in that we will continue our interactions with Project 1 in developing new drug compbinationstargeting transcription factors, Project 2 to investigate the co-operation between leukemia oncogenes andloss of transcription factor function, as well as with Project 5 and Core B to confirm our hypotheses in cellsderived from patients undergoing clinical trials. Finally, we will interact closely with the new Project 4 toinvestigate the effect of another important oncogene on transcription factor function. Therefore, we proposethe following Specific Aims: (1) To investigate the effects of PML/RAR alpha on C/EBPa , and the responseof C/EBP beta to all trans retinoic acid (ATRA); (2) To develop mouse models which combining loss ofC/EBPa and tyrosine kinases in development of AML; and (3) To investigate the pathways between FLT3activation, C/EBPa phosphorylation, and AML.
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