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MAPK负反调节赋予了对JAK2^V617F信号传输的依赖

Meenu Kesarwani¹, Zachary Kincaid¹, Mohammad Azhar¹

¹Division of Pathology, Cincinnati Children's Hospital, Cincinnati, OH, USA.

|July 10, 2023

概括

准DUSP1可能为JAK2^V617F驱动的骨髓增殖性瘤 (MPN) 提供治疗方法. 这种方法通过恢复p53水平并诱导癌细胞中的合成致死性来克服治疗耐药性.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
血液学血液学血液学

背景情况:

由于补偿性生存途径,JAK2激酶抑制剂 (TKI) 治疗对于髓增殖性瘤 (MPN) 通常是无效的.
由炎症性细胞因子维持的MEK-ERK和PI3K通路的重新激活导致MPN的治疗失败.

研究的目的:

研究细胞因子信号在JAK2^V617F诱导的MPN中的作用及其对治疗耐药性的影响.
探索向DUSP1在JAK2^V617F驱动的MPN中治疗性反应的潜力.

主要方法:

研究了JAK2^V617F和细胞因子信号在DUSP1表达上的融合.
评估了DUSP1删除和抑制对JAK2^V617F细胞中的p53稳定和亡的影响.
通过小分子抑制剂和异位DUSP6表达,评估了DUSP1抑制的克隆选择性.

主要成果:

JAK2^V617F和细胞因子信号融合以增强DUSP1的表达,这抑制了p53稳定,并增加了亡值.
通过增加p53水平,DUSP1删除导致JAK2^V617F表达细胞中的合成致死性.
选择性DUSP1抑制与DUSP6恢复相结合,可以消除JAK2^V617F细胞,克服抗性.

结论:

炎症性细胞因子和JAK2^V617F信号诱导DUSP1,降低p53的调节,并在MPN中引起TKI耐药性.
针对DUSP1,特别是与管理DUSP6等补偿途径的策略相结合,显示出在JAK2^V617F驱动的MPN中治疗治疗的希望.

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