IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK.
IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK.
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IL-2R 共同 γ 链被核磷蛋白间变性淋巴瘤激酶 (NPM-ALK) 表观遗传沉默，并通过靶向 NPM-ALK 发挥肿瘤抑制因子的作用。
DOI：
10.1073/pnas.1100319108
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发表时间：
2011
影响因子：
11.1
通讯作者：
Wasik,Mariusz
中科院分区：
文献类型：
--
作者：
Zhang,Qian;Wang,HongYi;Liu,Xiaobin;Bhutani,Gauri;Kantekure,Kanchan;Wasik,Mariusz
Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4+T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4+T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of theIL-2Rγgene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to theIL-2Rγgene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of theIL-2Rγgene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.
