Project 2: Defining and exploiting genetic dependencies in complex karyotype AML

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ABSTRACT Complex karyotype acute myeloid leukemia (CK AML) is defined by the presence of 3 or more detectable cytogenetic abnormalities and has one of the least favorable prognoses of any leukemia genotype. Genomic characterization indicates that this disease lacks conventional druggable oncoproteins, but instead is characterized by a set of recurrent segmental deletions and mutations in the TP53 tumor suppressor gene, the latter of which are absent from normal karyotype AML and confer resistance to standard chemotherapies. To better characterize the pathogenesis of CK AML and to develop new strategies to treat this disease, we will exhaustively analyze the genomes of a large cohort of CK AML samples using a new low-cost, high-resolution platform optimized in our group called “digital karyotyping”. These molecular features will be correlated with patient outcomes data, and used to generate murine and human models that accurately recapitulate CK AML- specific features. We will use these models to test a new therapeutic strategy for countering the pro-tumorigenic effects of p53 loss. This concept builds on preliminary data showing that p53 loss can perturb cellular metabolism in a manner that alters gene expression and drives aberrant self-renewal, and that reversing these effects with small molecule inhibitors can drive differentiation of p53-deficient AML. Specifically, we have found that p53 mutations reduce levels of the metabolite aKG, producing similar effects of oncogenic IDH1/2 mutant proteins that have proven to be drug targets in other sub-types of AML. In models studied to date, the tumor suppressive effects of p53 are recapitulated by inhibiting the TCA enzyme 2-oxoglutarate dehydrogenase (OGDH) and, as such, we consider OGDH a prime candidate for validation and development in CK AML. Successful completion of the proposed research will produce a detailed understanding of the genetic changes that accompany CK AML and allow for more faithful modeling of human disease. In addition, we hypothesize that oxoglutarate dehydrogenase (OGDH) a promising therapeutic target for the treatment of CK AML. Validating our novel drug target will pave the way for clinical trials in this indication. Given the paucity of effective therapeutic options for patients with CK AML, the proposed studies address an urgent, unmet clinical need.