Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target
Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target
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DOI：
10.1038/nm1249
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发表时间：
2005-06-01
期刊：
影响因子：
82.9
通讯作者：
Inghirami, G
中科院分区：
文献类型：
--
作者：
Chiarle, R;Simmons, WJ;Inghirami, G
间变性大细胞淋巴瘤（ALCL）是由染色体易位引起的，这种易位使间变性淋巴瘤激酶（ALK）原癌基因与一个二聚化伴侣并列，导致ALK的组成性表达以及ALK酪氨酸激酶活性。在人类ALCL中，活化的ALK的一个底物是转录因子Stat3，并且其磷酸化在一种新的淋巴瘤发生的核磷蛋白（NPM）-ALK转基因小鼠模型中得到了准确重现。在此我们通过基因打靶表明，Stat3对于体外小鼠胚胎成纤维细胞的转化、转基因小鼠中B细胞淋巴瘤的发生以及人类和小鼠NPM - ALK转化的B细胞和T细胞的生长和存活都是必需的。反义寡核苷酸对Stat3表达的消除显著（P < 0.0001）损害了人类和小鼠NPM - ALK肿瘤在体内的生长。Stat3的药理消除代表了一种治疗人类淋巴瘤的新的候选方法。
Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly ( P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma.