Regulation of cardiac metabolism during Leukemia

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) and cancer are the leading causes of morbidity and mortality. Leukemia is a specific type of blood cancer and among the deadliest cancers in the United States. Patients with acute myeloid leukemia (AML) are at an increased risk of heart failure even after disease remission. In the heart, cardiomyocytes are critical to maintaining the pump function, and our prior work establishes that the production of cancer-specific metabolites, or oncometabolites, impairs contractile function during leukemia. However, the mechanisms that drive structural remodeling during disease progression and after recovery have remained unknown. Analysis of AML has recently revealed recurrent mutations in several genes associated with metabolic and epigenetic processes, including TET2 and IDH2. Somatic mutations of TET2 or IDH2 cause dysregulated metabolism and clonal hematopoiesis in AML. Furthermore, both mutations have been associated with the production and release of oncometabolites, including D-2-hydroxyglutarate, which may systemically impact metabolism. We recently demonstrated that the oncometabolite D-2-hydroxyglutarate disrupts cardiac oxidative metabolism and redirects Krebs cycle intermediates. Our data support a model in which somatic mutations in clonal hematopoiesis and AML disrupt oxidative metabolism in cardiomyocytes, resulting in reduced α- ketoglutarate (α-KG) signaling, epigenetic activation, and subsequent structural remodeling. Three independent specific aims are designed to extend this emerging field of cardio-oncometabolism and test the hypothesis that myeloid TET2 and IDH2 mutations create a systemic metabolic phenotype that causes and activates the transcriptional reprogramming, culminating in cardiomyopathy and heart failure. Aim 1 will examine alterations in oxidative metabolism in the heart in response to mutations of TET2 or IDH2-mutant AML. Aim 2 will determine the impact of reductive carboxylation on epigenome remodeling in the heart. Aim 3 will determine sexual dimorphism in the development of cardiomyopathy during Idh2 and Tet2 mutations in hematopoietic stem and progenitor cells. We have established clinically relevant AML models and designed methods to study cardiac metabolism in vivo and ex vivo to realize these aims. Together, these approaches enable us to uncover how Tet2 and Idh2 mutations drive metabolic and structural remodeling in the heart and identify more effective ways to treat leukemia.