Metabolic Alterations in JAK2 Mutant Hematopoietic Cells Represent Therapeutic Vulnerabilities for Myeloproliferative Neoplasms

Increased energy requirement and metabolic reprograming is a hallmark of cancer cells. We found that mouse models of myeloproliferative neoplasms (MPN) expressing mutant JAK2 displayed systemic metabolic changes including hypoglycemia and adipose atrophy. Modulation of nutrient availability modified MPN manifestations and survival. Hypoglycemia in MPN mice correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Transcriptomic and metabolomic analyses together with functional assays in hematopoietic stem and progenitor cells identified vulnerable metabolic nodes for therapeutic targeting. Inhibition of Pfkfb3, a key regulatory enzyme of glycolysis, increased blood glucose levels, improved blood counts and reduced splenomegaly. We observed additive efficacy with ruxolitinib. Mechanistically, altered redox homeostasis promoted apoptosis of susceptible MPN cells. Overall design: Triplicates for each genotype