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JAK2/IDH 突变驱动的骨髓增殖性肿瘤对联合靶向抑制敏感。

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

机构信息

Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York, USA.

Gerstner Sloan Kettering Graduate School of Biomedical Sciences, and.

出版信息

J Clin Invest. 2018 Feb 1;128(2):789-804. doi: 10.1172/JCI94516. Epub 2018 Jan 22.

DOI:10.1172/JCI94516
PMID:29355841
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5785272/
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.

摘要

患有骨髓增殖性肿瘤（MPN）的患者常进展为骨髓衰竭或急性髓系白血病（AML），且表观遗传调节因子（如代谢酶异柠檬酸脱氢酶（IDH））的突变与不良预后相关。在这里，我们表明 Jak2V617F 和突变型 IDH1R132H 或 Idh2R140Q 的联合表达可诱导 MPN 进展，改变干细胞/祖细胞功能，并损害小鼠的分化。Jak2V617F Idh2R140Q-突变 MPN 对 IDH 的小分子抑制敏感。Jak2 和 IDH2 的联合抑制在小鼠模型中使干细胞和祖细胞区室正常化，并比单独抑制 Jak2 更能减轻疾病负担。此外，联合 JAK2 和 IDH2 抑制剂治疗还可逆转 MPN 干细胞中的异常基因表达，并逆转由同时发生的 JAK2 和 IDH2 突变引起的代谢物扰动。联合 JAK2 和 IDH2 抑制剂治疗在具有 JAK2mut 和 IDH2mut 突变的 MPN 患者的细胞中也显示出协同疗效。总之，这些数据表明，联合 JAK 和 IDH 抑制可能为这种高风险 MPN 亚型提供治疗优势。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/a568800777ef/jci-128-94516-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/05588f9c56fa/jci-128-94516-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/7e77e5b46abb/jci-128-94516-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/a568800777ef/jci-128-94516-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/5bc34a9a377d/jci-128-94516-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/13ca52a6a42a/jci-128-94516-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/a6ada7f62722/jci-128-94516-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a665/5785272/c120c057e9e0/jci-128-94516-g004.jpg
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