JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma
JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma
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DOI：
10.1038/leu.2013.157
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发表时间：
2014-02-01
期刊：
影响因子：
11.4
通讯作者：
Coppo, P.
中科院分区：
文献类型：
--
作者：
Bouchekioua, A.;Scourzic, L.;Coppo, P.
结外鼻型自然杀伤（NK）/T细胞淋巴瘤（NKCL）是一种预后不良的侵袭性恶性肿瘤，其中信号转导和转录激活因子3（STAT 3）通常被组成性激活并致癌。在这里，我们证明，STAT 3激活主要是由于组成性Janus激酶（JAK）3磷酸化酪氨酸980，观察到在三个四个测试的NKCL细胞系和20的23个NKCL肿瘤样本的研究。在其中一个细胞系和19个NKCL原发性肿瘤样品中的4个（21%）中，组成性JAK 3活化与JAK 3假激酶结构域中的获得性突变（A573 V或V722 I）相关。然后，我们表明，JAK 3/STAT 3通路的组成性激活在NKCL细胞生长和存活以及侵袭性表型中具有重要作用。事实上，通过用化学抑制剂或小干扰RNA靶向JAK 3，NKCL细胞生长在体外减慢。在人NKCL异种移植小鼠模型中，JAK 3抑制剂CP-690550显著延迟了肿瘤生长。总之，JAK 3的组成性激活（可能由JAK 3激活突变引起）是NKCL的常见特征，值得作为治疗靶点进行测试。
Extranodal, nasal-type natural killer (NK)/T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. Here, we demonstrate that STAT3 activation mostly results from constitutive Janus kinase (JAK) 3 phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples under study. In one of the cell lines and in 4 of 19 (21%) NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. We then show that constitutive activation of the JAK3/STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor CP-690550. Altogether, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL that deserves to be tested as a therapeutic target.