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Nature:JAK-STAT二聚体活化支持MPN细胞抵抗JAK2抑制剂治疗

来源:生物谷 2012-07-25 22:05

7月22日,Nature杂志在线报道,JAK-STAT二聚体的活化是骨髓增生性肿瘤细胞在JAK2抑制剂治疗情况下持续存在的原因。

在大多数骨髓增生性肿瘤(MPN)患者体内,研究者证实存在JAK2基因和血小板生成素受体基因(MPL)的体细胞激活突变,促使JAK2激酶抑制剂的临床研发。 JAK2抑制剂治疗可改善MPN相关的脾肿大和全身症状,但并不显著减少或消除在大多数患者体内的MPN克隆。因此,研究者试图揭开在长期抑制JAK2基因活性的情况下,MPN细胞持续不消退的机制。

本研究发现,持续性给予JAK2抑制剂与JAK-STAT信号恢复活化以及激活的JAK2和JAK1或TYK2形成异二聚体相关。与之相一致的是,JAK2可被其他JAK激酶反式激活。此外,这种现象是可逆的:撤除JAK2抑制剂,与细胞恢复对JAK2激酶抑制剂的敏感性,以及与JAK2表达的可逆变化有关。

研究者发现,在小鼠模型和JAK2抑制剂治疗的患者中,JAK2异二聚体增加,在细胞株中JAK2持续性激活。RNA干扰和药理研究表明,应用JAK2抑制剂的持续存在的MPN细胞仍然依赖于JAK2蛋白的表达。因此,导致JAK2退化的治疗方法对于持续存在的MPN细胞仍有疗效,而且对于JAK2依赖性恶性肿瘤患者,JAK2抑制剂还可带来额外的益处。(生物谷bioon.com)

Heterodimeric JAK–STAT activation as a mechanism of persistence to JAK2 inhibitor therapy

Priya Koppikar,Neha Bhagwat,Outi Kilpivaara,Taghi Manshouri,Mazhar Adli,Todd Hricik,Fan Liu,Lindsay M. Saunders,Ann Mullally,Omar Abdel-Wahab,Laura Leung,Abby Weinstein,Sachie Marubayashi,Aviva Goel,Mithat G?nen,Zeev Estrov,Benjamin L. Ebert,Gabriela Chiosis,Stephen D. Nimer,Bradley E. Bernstein,Srdan Verstovsek& Ross L. Levine

The identification of somatic activating mutations in JAK2 (refs?1–4) and in the thrombopoietin receptor gene (MPL)5 in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors6, 7. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.

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