JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.
Damon Runyon Cancer Research Foundation (DRG-2241-15)
Howard Hughes Medical Institute (Faculty Scholars Award)
Stand Up To Cancer
National Cancer Institute (U.S.) (P50CA165962)
National Cancer Institute (U.S.) (P30CA14051)
Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project)
Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) Program
National Institutes of Health (U.S.) (grant U54OD020355-01)
National Institutes of Health (U.S.) (grant NCI R01CA172636)
National Institutes of Health (U.S.) (grant R35CA197594)
National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747).