The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-κB activation in anaplastic large cell lymphoma
The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-κB activation in anaplastic large cell lymphoma
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DOI：
10.1016/s1535-6108(04)00084-4
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发表时间：
2004-04-01
期刊：
影响因子：
50.3
通讯作者：
Watanabe, T
中科院分区：
文献类型：
--
作者：
Horie, R;Watanabe, M;Watanabe, T
NPM-ALK是间变性大细胞淋巴瘤（ALCL）的特征，CD 30的高表达也是如此，这是经典霍奇金淋巴瘤的H-RS细胞共有的特征。在H-RS细胞中，过表达的CD 30的配体非依赖性信号传导驱动组成性NF-B-K活化，这在ALCL细胞中不存在。在这里，我们发现NPM-ALK阻碍CD 30信号传导和NF-B-K活化，这取决于ALK激酶活性和N-末端NPM结构域。将NPM-ALK转导至H-RS细胞系中可消除TRAF蛋白的募集和聚集，诱导ALCL样形态和表型。TRAF 2与NPM-ALK在位于激酶结构域的共有结合基序处结合。因此，NPM-ALK消除了CD 30驱动的NF-B-K活化，也可以诱导ALCL表型，将ALCL细胞与T细胞来源的H-RS细胞区分开来。
NPM-ALK characterizes anaplastic large cell lymphoma (ALCL), as does the high expression of CD30, a feature shared with H-RS cells of classic Hodgkin's lymphoma. In H-RS cells, ligand-independent signaling by overexpressed CD30 drives constitutive NF-B-K activation, which is absent in ALCL cells. Here we show that NPM-ALK impedes CD30 signaling and NF-B-K activation, dependent on both ALK kinase activity and the N-terminal NPM domain. NPM-ALK transduction into H-RS cell lines abrogates recruitment and aggregation of TRAF proteins, inducing an ALCL-like morphology and phenotype. TRAF2 associates with NPM-ALK at a consensus binding motif located in the kinase domain. Thus, NPM-ALK abrogates CD30-driven NF-B-K activation and can also induce an ALCL phenotype, distinguishing ALCL cells from H-RS cells of T cell origin.