Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Blood Cancer J. 2020 Jan 31;10(1):12. doi: 10.1038/s41408-020-0277-6.
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.
MYD88 突变激活促进生存信号，通过 BTK 和 HCK，这两者都是伊布替尼的靶点。尽管反应率很高，但伊布替尼缺乏完全反应，其他 MYD88 触发的生存途径可能导致原发性耐药。在 MYD88 突变驱动的淋巴瘤中观察到 B 细胞受体 (BCR) 信号，即使没有激活 BCR 途径突变也是如此。我们鉴定出激活的 SYK（p-SYK），这是 MYD88 突变 WM 和 ABC DLBCL 淋巴瘤细胞中与 MYD88 结合的 BCR 的一个组成部分。共聚焦显微镜证实了 MYD88 与 MYD88 突变细胞中的 SYK 共定位。敲低 MYD88 或使用 MYD88 信号抑制剂可消除 SYK 激活，而表达突变而非野生型 MYD88 可在 MYD88 突变和野生型淋巴瘤细胞中放大 p-SYK。敲低 SYK 或使用靶向 SYK 的抑制剂可阻断 MYD88 突变细胞中的 p-STAT3 和 p-AKT 信号。细胞活力分析表明，伊布替尼和 SYK 抑制剂联合使用可引发 MYD88 突变淋巴瘤细胞的合成杀伤。我们的研究结果将突变 MYD88 的生存信号扩展到包括 MYD88 突变淋巴瘤中的 SYK 定向 BCR 串扰。SYK 与伊布替尼联合靶向治疗可产生合成致死性，为在 MYD88 突变淋巴瘤中用伊布替尼联合 SYK 抑制剂进行临床研究提供了框架。
