Identification of genetic vulnerabilities in acute myeloid leukemia driven by the MLL-AF9 fusion gene

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The MLL-AF9 fusion gene, one of the most common genetic alterations in acute myeloid leukemia (AML), is difficult to target therapeutically. We have discovered a synthetic lethal interaction between MLL-AF9 and suppression of the cell cycle regulatory gene CDK6, suggesting that targeting of CDK6 may provide a substantive therapeutic window in MLL-AF9-positive AML and, possibly, leukemias associated with other MLL rearrangements. In the proposed project, we aim to perform an in-depth analysis of the relationship between MLL-AF9 and CDK6 to work towards the development of CDK6 as a genotype-selective therapeutic target. Specifically, we will (1) investigate the codependence between MLL-AF9 and CDK6 using additional human and murine experimental systems, with particular focus on experiments with primary hematopoietic cells; (2) characterize the functional consequences of CDK6 depletion in MLL-AF9-positive AML cells and explore the effects of pharmacologic CDK6 inhibition; and (3) investigate the mechanistic link between MLL-AF9 expression and CDK6 dependence. These studies may provide a new approach to treating MLL-rearranged leukemia.