Alox5 Blockade Eradicates JAK2V617F-Induced Polycythemia Vera in Mice.
Alox5 Blockade Eradicates JAK2V617F-Induced Polycythemia Vera in Mice.
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Alox5 阻断可根除 JAK2V617F 诱导的小鼠真性红细胞增多症
DOI：
10.1158/0008-5472.can-15-2933
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发表时间：
2017-01-01
期刊：
影响因子：
11.2
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Chen Y;Shan Y;Lu M;DeSouza N;Guo Z;Hoffman R;Liang A;Li S
与JAK突变V617F相关的骨髓增生性肿瘤，如真性红细胞增多症(PV)，尽管在使用JAK2抑制剂治疗其中一些疾病方面取得了进展，但仍无法治愈。在这项研究中，我们使用接受JAK2V617F诱导的PV的小鼠作为工具来探索新的候选治疗靶点。我们的研究集中在脂代谢酶花生四烯酸5-脂氧合酶(ALOX5)，我们发现JAK2V617F在体外和体内的造血细胞中强烈上调该酶。值得注意的是，Alox5基因的缺失或用生物活性小分子抑制剂抑制小鼠的Alox5足以抑制PV的发展。这种治疗作用与诱导细胞周期进程受阻有关，也与PV细胞的凋亡有关。基因缺失对PV启动细胞有抑制作用。同样，ALOX5抑制足以抑制表达JAK2V617F的人CD34+细胞的克隆形成。机制研究表明，ALOX5抑制JAK2V617F表达细胞的AKT活性，降低β-连环蛋白的表达。综上所述，我们的结果将ALOX5定义为JAK2V617F驱动PV的关键遗传效应因子，并将该酶确定为治疗这种难治性骨髓增殖性肿瘤的候选治疗靶点。
Myeloproliferative neoplasms such as polycythemia vera (PV) which are associated with the JAK mutation V617F remain uncurable, despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo. Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+ cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased β-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm.