脾脏中恶性淋巴瘤的HE染色图片（图）
来自宾夕法尼亚州大学佩雷尔曼医学院的病理学教授Mariusz A. Wasik和副教授Qian Zhang通过研究发现，在肿瘤细胞中一种新型融合蛋白通过沉默肿瘤抑制基因IL-2Rγ而引起癌症的发生。该研究的论文发表在最近的《PNAS》杂志上，这个发现为未来治疗淋巴瘤及其它癌症提供了新的靶点。
融合蛋白由两种不同的基因编码的蛋白质结合而成。它们在肿瘤细胞中比较常见。
科学家们研究锁定在一种名为NPM-ALK的融合蛋白上。间变型淋巴瘤激酶（ALK）在人胎儿时期仅仅只在神经细胞中表达，当其错误的表达在非神经组织细胞中时，会结合核磷蛋白（NPM）或其它配体蛋白形成融合蛋白，而后引发细胞病变导致癌症。融合蛋白NPM-ALK通过抑制细胞中的肿瘤抑制基因IL-2Rγ的表达发挥功能。ALK融合蛋白在其它的一些癌症中也能被检测出来，例如肺癌、甲状腺癌和肾癌。
IL-2Rγ蛋白作为很多重要的细胞因子配体，发挥着调控正常免疫细胞CD4+T细胞的生长和分化。研究小组发现在T淋巴瘤细胞中IL-2Rγ的表达会被NPM-ALK所抑制。IL-2Rγ基因的启动子由于DNA分子骨架上被加入甲基而导致化学结构上发生改变，从而无法正常的进行转录翻译。
该融合蛋白NPM-ALK的发现对之前在慢性白血病研究中发现的BCR-ABL融合蛋白是一个新的补充，也为未来治疗各种表达ALK的肿瘤细胞，如肺癌、淋巴癌等，提供了新的靶点。（生物探索 Jun译）
生物探索推荐英文论文原文摘要：
IL-2R common γ-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK
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 the IL-2Rγ gene 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 the IL-2Rγ gene 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 the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.
