7月22日,，Nature雜志在線報道,，JAK-STAT二聚體的活化是骨髓增生性腫瘤細胞在JAK2抑制劑治療情況下持續(xù)存在的原因。
在大多數(shù)骨髓增生性腫瘤（MPN）患者體內(nèi),，研究者證實存在JAK2基因和血小板生成素受體基因（MPL）的體細胞激活突變,，促使JAK2激酶抑制劑的臨床研發(fā),。 JAK2抑制劑治療可改善MPN相關的脾腫大和全身癥狀，但并不顯著減少或消除在大多數(shù)患者體內(nèi)的MPN克隆,。因此,，研究者試圖揭開在長期抑制JAK2基因活性的情況下，MPN細胞持續(xù)不消退的機制,。
本研究發(fā)現(xiàn),，持續(xù)性給予JAK2抑制劑與JAK-STAT信號恢復活化以及激活的JAK2和JAK1或TYK2形成異二聚體相關。與之相一致的是,，JAK2可被其他JAK激酶反式激活,。此外，這種現(xiàn)象是可逆的：撤除JAK2抑制劑,，與細胞恢復對JAK2激酶抑制劑的敏感性,，以及與JAK2表達的可逆變化有關。
研究者發(fā)現(xiàn),，在小鼠模型和JAK2抑制劑治療的患者中,，JAK2異二聚體增加，在細胞株中JAK2持續(xù)性激活,。RNA干擾和藥理研究表明,，應用JAK2抑制劑的持續(xù)存在的MPN細胞仍然依賴于JAK2蛋白的表達。因此,，導致JAK2退化的治療方法對于持續(xù)存在的MPN細胞仍有療效,，而且對于JAK2依賴性惡性腫瘤患者，JAK2抑制劑還可帶來額外的益處,。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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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.
