The FBXO45-GEF-H1 axis controls germinal center formation and B-cell lymphomagenesis

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-01-17 DOI:10.1158/2159-8290.cd-24-0442

Anagh A. Sahasrabuddhe, Xiaofei Chen, Kaiyu Ma, Rui Wu, Huan-Chang Liang, Richa Kapoor, Rishi R. Chhipa, Ozlem Onder, Courtney McFetridge, John S. Van Arnam, Xiao Zhang, Jennifer J.D. Morrissette, Vinodh Pillai, Marilyn M. Li, Philippe Szankasi, Venkatesha Basrur, Kevin P. Conlon, Tobias D. Raabe, Nathanael G. Bailey, Cory M. Hogaboam, Robert Rottapel, Junhyong Kim, Cristina López, Matthias Schlesner, Reiner Siebert, Kostiantyn Dreval, Ryan D. Morin, Loredana Moro, Michele Pagano, Louis M. Staudt, Megan S. Lim, Kojo S.J. Elenitoba-Johnson

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引用次数: 0

Abstract

The role of ubiquitin-mediated degradation mechanisms in the pathogenesis of diffuse large B cell (DLBCL) and follicular lymphoma (FL) is not completely understood. We show that conditional deletion of the E3 ubiquitin ligase Fbxo45 in germinal center B-cells results in B-cell lymphomagenesis in homozygous (100%) and heterozygous (48%) mice. Mechanistically, FBXO45 targets the RHO guanine exchange factor ARHGEF2/GEF-H1 for ubiquitin-mediated degradation. Double genetic ablation of Fbxo45 and Arhgef2 ameliorated lymphoma formation. Transgenic knock-in mice harboring a GEF-H1 mutant unable to bind FBXO45 develop B-cell lymphomas with ~50% penetrance. Genome sequencing in human lymphomas identified mutually-exclusive FBXO45 copy number losses and ARHGEF2 gains, with combined frequencies ranging from 26.32% in FL to 45.12% in DLBCL. Notably, FBXO45 silencing enhances sensitivity to MEK1/2 inhibition. These results identify FBXO45 and ARHGEF2 as a novel tumor-suppressor and oncogene pair involved in the pathogenesis of B-cell lymphomas with significant implications for targeted therapies.

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FBXO45-GEF-H1轴控制生发中心的形成和b细胞淋巴瘤的发生

泛素介导的降解机制在弥漫性大B细胞（DLBCL）和滤泡性淋巴瘤（FL）发病机制中的作用尚不完全清楚。我们发现生发中心b细胞中E3泛素连接酶Fbxo45的条件缺失导致纯合子（100%）和杂合子（48%）小鼠的b细胞淋巴瘤发生。在机制上，FBXO45靶向RHO鸟嘌呤交换因子ARHGEF2/GEF-H1进行泛素介导的降解。双基因消融Fbxo45和Arhgef2改善淋巴瘤形成。携带不能结合FBXO45的GEF-H1突变体的转基因敲入小鼠发生约50%外显率的b细胞淋巴瘤。人类淋巴瘤的基因组测序发现FBXO45拷贝数缺失和ARHGEF2增益是相互排斥的，其组合频率从FL的26.32%到DLBCL的45.12%不等。值得注意的是，FBXO45沉默增强了对MEK1/2抑制的敏感性。这些结果表明FBXO45和ARHGEF2是一种新的肿瘤抑制因子和癌基因对，参与b细胞淋巴瘤的发病机制，对靶向治疗具有重要意义。

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

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.