SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.

IF 12.6 1区医学 Q1 IMMUNOLOGY

Journal of Experimental Medicine Pub Date : 2024-10-07 Epub Date: 2024-09-05 DOI:10.1084/jem.20231143

Ana Portelinha, Shenqiu Wang, Sara Parsa, Man Jiang, Alexander N Gorelick, Sagarajit Mohanty, Soumya Sharma, Elisa de Stanchina, Marjan Berishaj, Chunying Zhao, James Heward, Neeraj K Aryal, Omid Tavana, Jiayu Wen, Jude Fitzgibbon, Ahmet Dogan, Anas Younes, Ari M Melnick, Hans-Guido Wendel

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引用次数: 0

Abstract

The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.

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SETD1B 突变使 B 细胞淋巴瘤具有抗凋亡性和 BCL2 独立性。

t(14;18)易位可激活BCL2，被认为是大多数滤泡性淋巴瘤（FL）的始发基因病变。令人惊讶的是，FL 患者对 BCL2 抑制剂 Venetoclax 没有反应。我们的研究表明，影响组蛋白赖氨酸甲基转移酶 SETD1B (KMT2G) 的突变和缺失发生在 7% 的 FL 和 16% 的弥漫大 B 细胞淋巴瘤（DLBCL）中。SETD1B 的缺乏使患者对 Venetoclax 和一种实验性 MCL-1 抑制剂产生明显的抗药性。SETD1B 还是一种肿瘤抑制因子，在体内淋巴瘤的发展过程中与 KMT2D 的缺失相互配合。一致的是，人类淋巴瘤中 SETD1B 的缺失通常与 KMT2D 的缺失同时发生。从机理上讲，SETD1B 是多种促凋亡 BCL2 家族蛋白表达所必需的。相反，在 SETD1B 缺失的淋巴瘤中，KDM5 组蛋白 H3K4 去甲基化酶抑制剂可恢复 BIM 和 BIK 的表达，并与 Venetoclax 起协同作用。这些结果确立了 SETD1B 是细胞死亡的表观遗传调节因子，并揭示了增强 Venetoclax 对淋巴瘤敏感性的药理学策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental Medicine 医学-免疫学

CiteScore

26.60

自引率

1.30%

发文量

189

审稿时长

3-8 weeks

期刊介绍： Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.