Metabolic regulation of oxidative phosphorylation in pediatric AML relapse

PROJECT SUMMARY The overall goal of this research is to determine how lipid metabolism supports oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) stem cells. Leukemia stem cells (LSC) are responsible for relapse in AML, and a major goal in the field is identifying novel ways to eradicate AML-LSC. Recently, lipids have been identified as essential metabolic substrates for AML-LSC; however, the mechanisms linking lipids and OXPHOS are not known. To address this, I have determined relapse-specific candidate genes using RNA-Sequencing data from a cohort of pediatric AML patients characterized through the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) study. The results suggest that fatty acid oxidation (FAO) is repurposed to drive heme biosynthesis and fuel OXPHOS in AML relapse. In this K38 StAARTS application, I will test this hypothesis by studying lipid metabolism and OXPHOS in vitro with AML cell lines and in vivo using pediatric patient-derived xenografts. Aim 1 will use stable isotope metabolite tracing experiments to determine if palmitate is a key carbon source for heme in AML cells with LSC properties. Then, Aim 2 will test the effects of a high-fat diet on the growth and aggressiveness of pediatric AML-LSC xenografts obtained through St. Jude’s Public Resource Of Patient- derived and Expanded Leukemias (PROPEL) program. AML-LSC from Aim 2 will also be tested for the effects of a high-fat diet on OXPHOS activity and heme-containing protein content using comprehensive proteomic profiling through the Duke Molecular Physiology Institute’s Metabolomics and Proteomics Core. The results from these studies will provide a mechanistic link between lipid metabolism and OXPHOS in AML-LSC and have the potential to identify new therapeutic targets. My Mentor team, Institutional Environment and Career Development Plan, together with my clinical Hematology-Oncology fellowship, will provide a superb training experience that will ensure the success of this research and prepare me for a future transition to independence as a Pediatric Hematology-Oncology physician scientist.