Ther Adv Hematol. 2011 Feb;2(1):11-9. doi: 10.1177/2040620710393391.
Aberrant JAK-STAT signaling is a hallmark of myeloproliferative neoplasms (MPNs). These hyperproliferative disorders are classically associated with activating mutations in tyrosine kinases such as JAK2 and the thrombopoietin (TPO) receptor MPL. Activation of JAK-STAT signaling and responses to JAK2 inhibitors have been observed in MPN patients lacking JAK2 or MPL mutations, suggesting that other regulatory elements in the JAK-STAT pathway are altered. However, the molecular basis for this observation has been unclear. Recently, the role of inhibitory regulators of JAK-STAT signaling in MPN pathogenesis has been increasingly recognized. LNK is an adaptor protein that forms a negative feedback loop by binding to MPL and JAK2 and inhibiting downstream STAT activation. Murine models indicate that loss of LNK function can promote the development of a MPN phenotype. Several recent studies have identified novel LNK mutations in MPNs, thus validating this notion in humans. These findings represent a novel genetic paradigm of loss of negative feedback regulation of JAK-STAT activation in MPNs and have implications for the future development of targeted therapies in MPNs.
异常的 JAK-STAT 信号是骨髓增殖性肿瘤（MPN）的标志。这些过度增殖性疾病通常与酪氨酸激酶的激活突变有关，如 JAK2 和血小板生成素（TPO）受体 MPL。在缺乏 JAK2 或 MPL 突变的 MPN 患者中，观察到 JAK-STAT 信号的激活和对 JAK2 抑制剂的反应，这表明 JAK-STAT 通路中的其他调节元件发生了改变。然而，这一观察结果的分子基础尚不清楚。最近，JAK-STAT 信号抑制调节因子在 MPN 发病机制中的作用越来越受到重视。LNK 是一种衔接蛋白，通过与 MPL 和 JAK2 结合并抑制下游 STAT 激活形成负反馈环。小鼠模型表明，LNK 功能缺失可促进 MPN 表型的发展。最近的几项研究在 MPN 中鉴定出了新型 LNK 突变，从而在人类中验证了这一观点。这些发现代表了 MPN 中 JAK-STAT 激活负反馈调节丧失的一种新的遗传模式，对 MPN 靶向治疗的未来发展具有重要意义。
