Knowledge of the mechanisms underlying the normal development of blood cells will lead to new understanding of the pathogenesis of acute leukemias. The long range goals are to further our understanding of the mechanisms involved in leukemia, to develop new prognostic classifications based on molecular mechanisms, and then to experimentally validate these target genes and pathways in order to eventually develop more specific, less toxic therapies for leukemia and other cancers. The transcription factor C/EBP alpha is absolutely critical for differentiation of normal myeloid blasts, and disrupted (mutations or decreased expression) in specific subtypes of AML. Recent studies have demonstrated distinct gene expression clusters in patients with mutations in C/EBP alpha, as well as new target genes. Over the next 5 years, we propose to establish that these clusters can be utilized for new prognostic strategies, as well as to understand more about the mechanism of how mutations of C/EBP alpha lead to a block in differentiation in order to develop strategies for specific treatments based on knowledge of the molecular mechanisms. We therefore propose the following Specific Aims: (1) To characterize human AML clusters whose gene expression pattern is characteristic of C/EBP alpha mutations (""""""""C/EBP alpha clusters""""""""); (2) To study the mechanisms by which C/EBP alpha mutant proteins fail to induce granulocytic differentiation; and (3) To test the function of C/EBP alpha mutant protein in vivo. These studies will lead to novel prognostic tools, as well as the identification of novel target pathways for therapeutic intervention in the future. Relevance of this research to public health:
The aim of this research is to better understand the genes involved in the development of acute myeloid leukemia (AML) in order to develop better diagnostic and prognostic tools as well as new therapies. In this proposal, we will characterize a specific type of AML, one that is characterized by abnormalities in a gene called C/EBP alpha, which in non-leukemic cells directs the differentiation process. We will develop diagnostic tools to identify these patients, as well as study the mechanisms of how the failure of the abnormal C/EBP alpha gene product to direct differentiation leads to the development of leukemia. ? ? ? ?
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