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 Jak2^V617F and mutant IDH1^R132H or Idh2^R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2^V617F Idh2^R140Q–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 JAK2^mut and IDH2^mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype.

中文翻译：

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JAK2 / IDH突变驱动的骨髓增生性肿瘤对联合靶向抑制敏感。

患有骨髓增生性肿瘤（MPN）的患者经常会发展为骨髓衰竭或急性髓细胞性白血病（AML），表观遗传调节剂的突变（例如代谢酶异柠檬酸脱氢酶（IDH））与不良预后相关。在这里，我们表明Jak2 ^V617F和突变IDH1 ^R132H或Idh2 ^R140Q的联合表达诱导MPN进展，改变干/祖细胞功能，并损害小鼠的分化。Jak2 ^V617F Idh2 ^R140Q–突变的MPN对IDH的小分子抑制敏感。与单独使用JAK抑制相比，对JAK2和IDH2的联合抑制使鼠模型中的干细胞和祖细胞区室正常化，并在更大程度上减轻了疾病负担。此外，联合使用JAK2和IDH2抑制剂治疗还可以逆转MPN干细胞中异常的基因表达，并逆转由并发的JAK2和IDH2突变引起的代谢物扰动。JAK2和IDH2抑制剂的联合治疗在具有JAK2 ^mut和IDH2 ^mut的MPN患者的细胞中也显示出协同疗效突变。综上所述，这些数据表明联合的JAK和IDH抑制作用可能在这种高风险的MPN亚型中提供治疗优势。