Abstract
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 Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q–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 JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype.
Highlights
Myeloproliferative neoplasms (MPNs) are clonal myeloid malignancies characterized by somatic mutations acquired in hematopoietic stem/progenitor cells, which drive the expansion of 1 or more myeloid lineages
IDH1R132H and Idh2R140Q mice had elevated serum levels of 2HG (Figure 1, C and G), and 2HG levels were higher in mice with concurrent IDH1R132H and Jak2V617F mutations compared with mice with the IDH1R132H mutation alone (P = 0.0024), suggesting that Jak2 and isocitrate dehydrogenase 1 (IDH1) mutations interact to promote higher 2HG levels through either increased 2HG production or higher isocitrate dehydrogenase (IDH)-mutant cell burden
Expression of mutant IDH1 or Idh2 in concert with Jak2V617F resulted in disruption of the splenic architecture beyond that observed in Jak2V617F mice, including the expansion of blast-like cells with open chromatin and large nucleoli in JAK2/IDH-mutant mice, which was not observed in Jak2V617F mice
Summary
Myeloproliferative neoplasms (MPNs) are clonal myeloid malignancies characterized by somatic mutations acquired in hematopoietic stem/progenitor cells, which drive the expansion of 1 or more myeloid lineages. Previous studies have identified recurrent somatic mutations in epigenetic regulators in patients whose disease has transformed from MPN to AML, including mutations in isocitrate dehydrogenase 1 (IDH1), IDH2, and TET2 [9, 10]. These studies are underscored by candidate gene studies in patients with chronic MPN, which have shown that mutations in epigenetic regulators are associated with poor overall survival [11, 12]. We sought to establish and characterize murine models of accelerated-phase MPN with concomitant JAK/STAT activation and IDH mutations to identify the disease mechanism and test novel mechanism-based combination therapies
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