文章：

SYK由突变的MYD88激活，并在MYD88驱动的B细胞淋巴瘤中驱动促生存信号

SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas

原文发布日期：2020-01-31

DOI: 10.1038/s41408-020-0277-6

类型: Article

开放获取: 是

英文摘要：

Activating MYD88 mutations promote pro-survival signaling through BTK and HCK, both targets of ibrutinib. Despite high response rates, complete responses to ibrutinib are lacking, and other MYD88 triggered pro-survival pathways may contribute to primary drug resistance. B-cell receptor (BCR) signaling has been observed in lymphomas driven by mutated MYD88, even without activating the BCR pathway mutations. We identified activated SYK (p-SYK), a component of BCR in complex with MYD88 in MYD88-mutated WM and ABC DLBCL lymphoma cells. Confocal microscopy confirmed co-localization of MYD88 with SYK in MYD88-mutated cells. Knockdown of MYD88 or use of a MYD88 signaling inhibitor abrogated SYK activation, while expression of mutated but not wild-type MYD88 amplified p-SYK in MYD88-mutated and wild-type lymphoma cells. Knockdown of SYK or use of inhibitors targeting SYK blocked p-STAT3 and p-AKT signaling in MYD88-mutated cells. Cell viability analysis showed that combining ibrutinib and SYK inhibitors triggered synthetic killing of MYD88-mutated lymphoma cells. Our findings extend the spectrum of mutated MYD88 pro-survival signaling to include SYK directed BCR cross talk in MYD88-mutated lymphomas. Targeting SYK in combination with ibrutinib produces synthetic lethality, providing a framework for the clinical investigation of ibrutinib with SYK inhibitors in MYD88-mutated lymphomas.
 

摘要翻译： 

激活的MYD88突变通过BTK和HCK（二者均为伊布替尼的靶点）促进促生存信号传导。尽管初始应答率较高，但患者对伊布替尼的完全应答仍显不足，其他由MYD88触发的促生存通路可能导致原发性耐药。在MYD88突变驱动的淋巴瘤中，即使没有激活BCR通路突变，仍可观察到B细胞受体信号传导。我们发现，在MYD88突变的WM和ABC DLBCL淋巴瘤细胞中，活化的SYK（p-SYK）作为BCR组分与MYD88形成复合物。共聚焦显微镜证实MYD88与SYK在突变细胞中的共定位。敲低MYD88或使用MYD88信号抑制剂可消除SYK活化，而在MYD88突变型和野生型淋巴瘤细胞中，突变型（非野生型）MYD88的表达会增强p-SYK。敲低SYK或使用SYK抑制剂能阻断突变细胞中的p-STAT3和p-AKT信号传导。细胞活力分析表明，伊布替尼与SYK抑制剂联用可引发MYD88突变淋巴瘤细胞的合成性杀伤。我们的研究将突变MYD88的促生存信号传导范围扩展至SYK导向的BCR交叉对话，靶向SYK与伊布替尼联用可产生合成致死效应，为伊布替尼联合SYK抑制剂在MYD88突变淋巴瘤中的临床研究提供了理论框架。

原文链接：

SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas