The FBXO45–GEF-H1 Axis Controls Germinal Center Formation and B-cell Lymphomagenesis

作者：Anagh A. Sahasrabuddhe, Xiaofei Chen, Kaiyu Ma, Rui Wu, Huan-Chang Liang, Richa Kapoor, Rishi Raj Chhipa, Özlem Önder, Courtney McFetridge, John S. Van Arnam, Xiao Zhang, Jennifer J.D. Morrissette, Vinodh Pillai, Marilyn M. Li, Philippe Szankasi, Venkatesha Basrur, Kevin Conlon, Tobias 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 · 发表于：Cancer Discovery · 年份：2025 · DOI：10.1158/2159-8290.cd-24-0442 · 被引用次数：4 · 研究领域：Ubiquitin and proteasome pathways、Lymphoma Diagnosis and Treatment、Viral-associated cancers and disorders

Abstract The role of ubiquitin-mediated degradation mechanisms in the pathogenesis of diffuse large B-cell lymphoma (BCL) and follicular lymphoma 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 BCLs 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 follicular lymphoma to 45.12% in diffuse large BCL. 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 BCLs with important implications for targeted therapies. Significance: We describe the identification of a previously unrecognized ubiquitin ligase–substrate (FBXO45–GEF-H1) regulatory axis that plays an important role in germinal center formation and pathogenesis of common BCLs. These studies reveal novel insights linking dysregulated ubiquitin-mediated control to exploitable vulnerabilities and novel therapeutic strategies for these can...