THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA

AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. Using a bioinformatics approach and a whole-genome CRISPR screening approach, we identified regulators of selenium metabolism to be important for AML survival. Selenium is required for cells to synthesize selenocysteine, which is then used to produce selenoproteins. Since many selenoproteins are involved in redox regulation, we hypothesized that selenium metabolism is required for redox maintenance of AML. This hypothesis will be tested in the following three aims. In aim 1, we will use mouse models that we have generated that have mutations in the genes we identified in the CRISPR screen to examine the requirement of selenium metabolism in murine AML. In aim 2, we will use a mouse model that lacks the redox regulator, which we hypothesize to be downstream of the selenium metabolism pathway, to examine how this redox regulator promotes murine AML. In aim 3, we will study the mechanisms we discovered in human AML patient-derived xenograft models to examine the therapeutic potential of inhibiting selenium metabolism in AML. These genetic analyses with both murine and human AML models should bring novel insights into how AML regulates selenium metabolism and the therapeutic potential of targeting this mechanism.