This research proposal, prepared by Dr. Seongseok Yun, describes a five-year training program for the development of an academic career in cancer research. Dr. Yun has several years of experience in molecular pharmacology and cancer biology specifically focusing on hematologic neoplasms. Dr. Yun has recently begun to study the role of TFEB in acute myeloid leukemia (AML) development and maintenance in Dr. Cleveland?s laboratory. Dr. Yun identified that MYC represses TFEB and TFEB expression promotes myeloid differentiation and cell death. Dr. Yun now proposes a detailed molecular and cell biological characterization of TFEB in MYC- driven AML. MYC oncoprotein is a transcriptional factor that coordinates the expression of genes involve in glycolysis, glutaminolysis, and nutrient transport, thus promoting a shift to aerobic glycolysis. Although preclinical studies have shown that MYC overexpression is sufficient to induce AML in mice, how MYC drives AML is not resolved. Based upon preliminary observations that TFEB expression induces myeloid differentiation and cell death, Dr. Yun proposes to characterize tumor suppressive role of TFEB in MYC-driven AML in vivo and in vitro. To this end, Dr. Yun will utilize novel tools to study the effect of TFEB on AML suppression in Rosa26-LSL-MYC mouse transplant model. Dr. Yun will assess whether MYC functions as a direct TFEB transcriptional repressor and examine if TFEB expression impairs development and maintenance of MYC-driven AML in vivo. Also, he will characterize the mechanisms of TFEB tumor suppression, specifically focusing on it roles in the epigenetic modulation. These analyses will shed light on the tumor suppressive function of TFEB in AML and provide novel therapeutic approaches. Dr. Yun is committed to a career in biomedical research and has outlined a comprehensive Career Development program to achieve his goal of independence. Dr. Cleveland?s laboratory will provide Dr. Yun with the opportunity to gain additional expertise to become a well-rounded physician scientist. Dr. Yun will benefit from Moffitt and USF?s stimulating environment that is created by close interactions with outstanding faculty and by multiple core facilities that provide excellent research support. This program includes lectures and seminar series, scientific conferences, and educational workshops and courses at Moffitt and USF. In addition, the guidance and advice from Dr. Yun?s advisory committee and his collaborators - leaders in the field of hematological malignancies who have proven track record of supporting the transition of their trainees to independence ? will greatly facilitate his transition to an independent investigator position.
Despite recent advances in our understanding of the underlying genetic abnormalities in acute myeloid leukemia (AML) and the development of targeted therapies, AML remains a fatal hematologic malignancy due to the emergence of drug resistance and clonal expansion of residual leukemic clones. Thus, there is an urgent need to devise novel treatment strategies that target the molecular and genetic aberrations driving leukemic clonal expansion and resistance. This K08 research program focuses on defining the role of the autophagy regulator TFEB as a tumor suppressor that disables AML by inducing terminal myeloid differentiation, and validating the TFEB-autophagy pathway as a therapeutic strategy that will overcome drug resistance in AML.