SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas.,Blood Cancer Journal

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SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas.
Blood Cancer Journal ( IF 12.9 ) Pub Date : 2020-01-31 , DOI: 10.1038/s41408-020-0277-6
Manit Munshi ₁ , Xia Liu ₁ , Jiaji G Chen ₁ , Lian Xu ₁ , Nickolas Tsakmaklis ₁ , Maria G Demos ₁ , Amanda Kofides ₁ , Maria Luisa Guerrera ₁ , Cristina Jimenez ₁ , Gloria G Chan ₁ , Zachary R Hunter _{1,

2} , M Lia Palomba ₃ , Kimon V Argyropoulos ₃ , Kirsten Meid ₁ , Andrew Keezer ₁ , Joshua Gustine ₁ , Toni Dubeau _{1,

2} , Jorge J Castillo _{1,

2} , Christopher J Patterson ₁ , Jinhua Wang ₄ , Sara J Buhrlage ₄ , Nathanael S Gray ₄ , Steven P Treon _{1,

2} , Guang Yang _{1,

2}

Affiliation

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.

中文翻译：

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传导。

激活 MYD88 突变可通过 BTK 和 HCK（依鲁替尼的两个靶点）促进促生存信号传导。尽管应答率很高，但对依鲁替尼缺乏完全应答，并且其他 MYD88 触发的促生存途径可能导致原发性耐药。即使没有激活 BCR 通路突变，在突变 MYD88 驱动的淋巴瘤中也观察到了 B 细胞受体 (BCR) 信号传导。我们在 MYD88 突变的 WM 和 ABC DLBCL 淋巴瘤细胞中鉴定出活化的 SYK (p-SYK)，它是与 MYD88 复合的 BCR 成分。共聚焦显微镜证实了 MYD88 与 SYK 在 MYD88 突变细胞中的共定位。敲除 MYD88 或使用 MYD88 信号抑制剂可消除 SYK 激活，而在 MYD88 突变型和野生型淋巴瘤细胞中，突变型而非野生型 MYD88 的表达会扩增 p-SYK。敲除 SYK 或使用针对 SYK 的抑制剂可阻断 MYD88 突变细胞中的 p-STAT3 和 p-AKT 信号传导。细胞活力分析表明，依鲁替尼和 SYK 抑制剂的组合可触发对 MYD88 突变淋巴瘤细胞的合成杀伤。我们的研究结果扩展了突变 MYD88 促生存信号的范围，包括 MYD88 突变淋巴瘤中 SYK 定向的 BCR 串扰。靶向 SYK 与依鲁替尼联合产生合成致死率，为伊布替尼与 SYK 抑制剂在 MYD88 突变淋巴瘤中的临床研究提供了框架。

更新日期：2020-01-31

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