Targeting polyamine metabolism and eIF5A hypusination in pediatric acute myeloid leukemia

Abstract Pediatric acute myeloid leukemia (AML) is a devasting disease with 5-year survival outcomes of approximately 60%. Therefore, there is an urgent need to develop novel therapies for pediatric AML patients. Numerous studies have demonstrated that cellular metabolism is a key vulnerability in adult AML; however, metabolism in pediatric AML is less robustly characterized, limiting the development of metabolism targeting therapies for pediatric patients. We have previously shown that manipulation of polyamine metabolism offers a therapeutic window to target adult leukemia, but it is not known if pediatric AML is similarly sensitive. Using pediatric AML patient-derived xenograft models, we demonstrate that polyamine metabolism is a pharmacologically targetable vulnerability of pediatric AML cells. Further, depletion of polyamines sensitizes pediatric AML cells to chemotherapy in vitro and in vivo . Mechanistically, polyamine depletion reduces protein synthesis through decreased hypusination of translational elongation factor eIF5A. Pharmacologic polyamine depletion and inhibition of eIF5A hypusination result in reduced protein synthesis and decreased expression of cell cycle regulatory proteins resulting in a G 1 cell cycle arrest and eventual cell death through apoptosis. In summary, this study reveals polyamine metabolism and hypusination of eIF5A as a vulnerability in pediatric AML that can be targeted using clinically tractable approaches.