Zebrafish Chemical and Classical Genetics Approach to the Pathogenesis of T-ALL

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DESCRIPTION (provided by applicant): T cell acute lymphoblastic leukemia (T-ALL) is a cancer of T cell precursors that occurs in patients of all ages, and is especially common in older children and adolescents. Despite improvements in outcomes that have been achieved through the intensification of therapy, T-ALL remains fatal in 25% of children and 50-70% of adults. Although the molecular pathogenesis of T-ALL remains incompletely understood, aberrant activation of the MYC oncogene is a central abnormality in most cases of T-ALL, The central hypothesis of our work is that the most significant improvements in survival for these patients will come as a result of improvements in our understanding of the molecular mechanisms that mediate T-ALL leukemogenesis and MYC-induced oncogenesis. We have developed a conditional zebrafish model of MYC-induced T-ALL that closely resembles the most common subtype of human T-ALL. This zebrafish model now allows us to take full advantage of the strengths of the zebrafish system as a model of human disease through the performance of forward chemical genetic screens and conventional genetic analyses. The performance of forward chemical genetic rather than conventional mutagenesis screens will allow us to identify gene products that are targetable by small molecules, thus having obvious therapeutic implications in addition to elucidating the basic biologic processes involved. Thus, in an effort to reveal the mechanisms that mediate MYC-induced oncogenesis and T cell leukemogenesis, the specific aims of this proposal are: 1) To perform a forward chemical genetic screen in the zebrafish to identify targetable genes and pathways that are required for the survival of MYC-overexpressing thymocytes, but that are dispensable for the essential physiologic functions of MYC. 2) To establish the functional importance of genes involved in novel T-ALL genomic abnormalities as potential T-cell leukemia oncogenes and tumor suppressors using zebrafish genetic models of these lesions. The mentor and the group of advisors that Dr. Gutierrez has assembled to guide his career development represent some of the world's leading experts in cancer biology, zebrafish genetics, and chemical screens, and this environment will undoubtedly provide him with every opportunity to develop into a successful independent investigator.