Molecular Mechanism of Leukemogenesis involving AML1-ETO

R01 CA104509-15 “Molecular Mechanism of Leukemogenesis involving AML1-ETO” PROJECT SUMMARY Cancer is the most devastating human disease in the world, affecting almost everyone directly or indirectly. Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematological cancer. One of the most common genetic abnormalities in AML is the t(8;21) chromosomal translocation, resulting in the fusion transcription factor AML1-ETO. Due to currently unclear reasons, t(8;21) AML patients are younger and respond to initial induction chemotherapy better than most other AML patients. However, only 50-60% of t(8;21) AML patients respond to initial chemotherapy and ~40% of initial responders relapse. Further treatment options after relapse are limited and prognosis is generally poor. Therefore, we still need to understand the unique molecular basis of t(8;21) AML to expand therapeutic options for treating and saving these patients. Our long-term goal is to identify critical molecular pathogenic events that promote development and maintenance of AML as potential therapeutic targets. The overall objectives of this competitive renewal application are to elucidate the critical chromatin remodeling events that promote t(8;21) AML and to characterize vulnerabilities of t(8;21) AML that will facilitate elimination of leukemia cells. Our central hypothesis is that molecular alterations directly caused by expression of AML1-ETO provide unique pathological conditions of t(8;21) AML, which can be targeted by novel therapies. To attain the overall objectives, the following two specific aims will be pursued: 1) Analyze the combinatory effect of t(8;21) and KIT mutations on leukemogenesis through integrative transcriptome and epigenome studies in mouse models and 2) Characterize glutathione and oxidative phosphorylation in sensitizing t(8;21) AML to cell death. Together, these proposed studies are based on our accumulated knowledge, our most recent findings, and the potential therapeutic impact of the work. Collectively, this proposal will address important unanswered questions in t(8;21) AML and provide valuable insights into the molecular pathology of human leukemia.