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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 \u223c50% 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>We describe the identification of a previously unrecognized ubiquitin ligase\u2013substrate (FBXO45\u2013GEF-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 cancers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-0442","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T03:46:58Z","timestamp":1737085618000},"page":"838-861","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The FBXO45\u2013GEF-H1 Axis Controls Germinal Center Formation and B-cell Lymphomagenesis"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3040-0019","authenticated-orcid":false,"given":"Anagh A.","family":"Sahasrabuddhe","sequence":"first","affiliation":[{"name":"1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"2Human Oncology Pathogenesis Program, Memorial Sloan Kettering 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