HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans
HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans
复制标题
DOI：
10.1172/jci42442
复制
发表时间：
2010-10-01
影响因子：
15.9
通讯作者：
Levine, Ross L.
中科院分区：
文献类型：
--
作者：
Marubayashi, Sachie;Koppikar, Priya;Levine, Ross L.
JAK 2激酶抑制剂是在发现大多数骨髓增生性肿瘤（MPN）患者存在激活JAK 2突变后开发的，用于治疗MPN。然而，迄今为止，JAK 2抑制剂治疗在临床试验中显示出有限的疗效和明显的毒性。我们在这里报告，热休克蛋白90抑制剂，PU-H71，表现出有效性的细胞系和小鼠模型的MPN真性红细胞增多症（PV）和原发性血小板增多症（ET）破坏JAK 2蛋白的稳定性。JAK 2与HSP 90和PU-H71物理结合，并在体外和体内被PU-H71降解，表明JAK 2是HSP 90伴侣客户。PU-H71处理在JAK 2突变细胞系和原代MPN患者样品中引起细胞生长和信号传导的强效、剂量依赖性抑制。PU-H71处理小鼠导致JAK 2降解，JAK-STAT信号传导的抑制，外周血细胞计数的正常化，以及在不降解正常组织中的JAK 2或引起实质性毒性的剂量下改善MPN模型中的存活率。重要的是，PU-H71治疗还降低了小鼠中的突变等位基因负荷。这些数据建立了我们认为是一种新的治疗原理，在JAK 2依赖性MPN的治疗中抑制HSP 90。
JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the MPN polycythemia vera (PV) and essential thrombocytosis (ET) by disrupting JAK2 protein stability. JAK2 physically associated with both HSP90 and PU-H71 and was degraded by PU-H71 treatment in vitro and in vivo, demonstrating that JAK2 is an HSP90 chaperone client. PU-H71 treatment caused potent, dose-dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity. Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2-dependent MPN.