Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models.
Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models.
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DOI：
10.1172/jci159638
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发表时间：
2023-03-15
影响因子：
15.9
通讯作者：
Ji, Peng
中科院分区：
文献类型：
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作者：
Han, Xu;Mei, Yang;Mishra, Rama K.;Bi, Honghao;Jain, Atul D.;Schiltz, Gary E.;Zhao, Baobing;Sukhanova, Madina;Wang, Pan;Grigorescu, Arabela A.;Weber, Patricia C.;Piwinski, John J.;Prado, Miguel A.;Paulo, Joao A.;Stephens, Len;Anderson, Karen E.;Abrams, Charles S.;Yang, Jing;Ji, Peng
骨髓增生性肿瘤（mpn）以JAK2/STAT通路激活为特征。Pleckstrin-2 （Plek2）是JAK2/STAT5通路的下游靶点，在mpn患者中过表达。我们之前发现Plek2在jak2突变的mpn的发病机制中起关键作用。Plek2在生理条件下的非必需作用使其成为MPN治疗的理想靶点。在这里，我们通过硅高通量筛选方法和基于细胞的测定确定了一流的Plek2抑制剂，然后合成了类似物。plek2特异性小分子抑制剂对细胞增殖有明显的抑制作用。在机制上，Plek2通过招募下游效应蛋白与Akt相互作用并增强其活性。plek2信号复合体还包括Hsp72，它可以保护Akt免受降解。这些功能通过Plek2抑制剂直接结合Plek2 disheveled、Egl-10和pleckstrin （DEP）结构域而被阻断。在造血特异性pten敲除小鼠模型中，Plek2在激活Akt信号传导中的作用得到进一步证实。接下来，我们在各种MPN小鼠模型中测试了Plek2抑制剂单独使用或与Akt抑制剂联合使用，结果显示出与Plek2基因缺失相似的显著治疗效果。Plek2抑制剂也能有效减少MPN患者cd34阳性细胞的增殖。我们的研究揭示了一个驱动细胞增殖的Plek2/Akt复合物，并且可以被一类抗增殖化合物靶向用于MPN治疗。
Myeloproliferative neoplasms (MPNs) are characterized by the activated JAK2/STAT pathway. Pleckstrin-2 (Plek2) is a downstream target of the JAK2/STAT5 pathway and is overexpressed in patients with MPNs. We previously revealed that Plek2 plays critical roles in the pathogenesis of JAK2-mutated MPNs. The nonessential roles of Plek2 under physiologic conditions make it an ideal target for MPN therapy. Here, we identified first-in-class Plek2 inhibitors through an in silico high-throughput screening approach and cell-based assays, followed by the synthesis of analogs. Plek2-specific small-molecule inhibitors showed potent inhibitory effects on cell proliferation. Mechanistically, Plek2 interacts with and enhances the activity of Akt through the recruitment of downstream effector proteins. The Plek2-signaling complex also includes Hsp72, which protects Akt from degradation. These functions were blocked by Plek2 inhibitors via their direct binding to the Plek2 dishevelled, Egl-10 and pleckstrin (DEP) domain. The role of Plek2 in activating Akt signaling was further confirmed in vivo using a hematopoietic-specific Pten-knockout mouse model. We next tested Plek2 inhibitors alone or in combination with an Akt inhibitor in various MPN mouse models, which showed significant therapeutic efficacies similar to that seen with the genetic depletion of Plek2. The Plek2 inhibitor was also effective in reducing proliferation of CD34-positive cells from MPN patients. Our studies reveal a Plek2/Akt complex that drives cell proliferation and can be targeted by a class of antiproliferative compounds for MPN therapy.