Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms
Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms
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DOI：
10.1182/blood-2010-02-270108
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发表时间：
2010-08-12
期刊：
影响因子：
20.3
通讯作者：
Gotlib, Jason
中科院分区：
文献类型：
--
作者：
Oh, Stephen T.;Simonds, Erin F.;Gotlib, Jason
由于酪氨酸激酶的激活导致Janus激酶信号转导和转录激活因子（JAK-STAT）信号转导失调是骨髓恶性肿瘤的常见特征。在此，我们报告了2例JAK 2 V617 F阴性骨髓增生性肿瘤（MPN）患者中接头蛋白LNK（JAK-STAT信号的负调节因子）的首次人类疾病相关突变。1例患者表现出5个碱基对缺失和错义突变，导致提前终止密码子和pleckstrin同源性（PH）和Src同源性2（SH 2）结构域的丢失。第二例患者在PH结构域中有错义突变（E208 Q）。用这些LNK突变体转导的BaF 3-MPL细胞显示增强和持续的血小板生成素依赖性生长和信号传导。来自携带LNK突变的MPN患者的原始样本显示出异常的JAK-STAT激活，并且在这两名患者中，对精氨酸应答的CD 34（+）早期祖细胞异常丰富。这些发现表明，由于LNK负反馈调节的丧失导致的JAK-STAT激活是MPN发病的新机制。（血。2010;116（6）：988-992）
Dysregulated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F-negative myeloproliferative neoplasms (MPNs). One patient exhibited a 5 base-pair deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and Src homology 2 (SH2) domains. A second patient had a missense mutation (E208Q) in the PH domain. BaF3-MPL cells transduced with these LNK mutants displayed augmented and sustained thrombopoietin-dependent growth and signaling. Primary samples from MPN patients bearing LNK mutations exhibited aberrant JAK-STAT activation, and cytokine-responsive CD34(+) early progenitors were abnormally abundant in both patients. These findings indicate that JAK-STAT activation due to loss of LNK negative feedback regulation is a novel mechanism of MPN pathogenesis. (Blood. 2010;116(6):988-992)