Identification and validation of new therapeutic targets in pediatric leukemia through an aneuploidy-based synthetic lethality screen

An abnormal number of chromosomes, or aneuploidy, is the most common cytogenetic abnormality in cancer. Aneuploidy is observed in 70% of hematologic malignancies and 95% of solid tumors. The ability to target cells based on their chromosome content, consequently, presents a unique and unexploited opportunity in cancer therapeutics. The work we propose in this renewal grant will significantly advance our goal of identifying methods to selectively target and kill aneuploid cancer cells. Approximately 40,000 new cases of leukemia are diagnosed in children and adults each year in the United States. Despite significant improvements in therapy, leukemia causes more deaths than any other cancer among children and young adults under age 20. Trisomy 8 is the most common whole-chromosome cytogenetic abnormality in pediatric and adult AML and is seen in approximately 10-20% of all cases.  The role of the extra copy of chromosome 8 in leukemiogenesis, however, is a major and unresolved issue in the pathogenesis of AML.   In this proposal we will analyze data from a genome-wide screen where each human gene is depleted from acute myeloid leukemia cells to identify genes with trisomy 8-specific and AML-specific and lethality. A parallel screen will be performed in genetically identical cells that do or do not have extra copies of chromosome 8.  We anticipate that the genes indentified in this synthetic-lethality screen could serve as important therapeutic targets in pediatric leukemia and other tumors with extra copies of chromosome 8, such as Ewing's sarcoma.