The FBXO45–GEF-H1 axis controls germinal center formation and B-cell lymphomagenesis Journal Article
| Authors: | Sahasrabuddhe, A. A.; Chen, X.; Ma, K.; Wu, R.; Liang, H. C.; Kapoor, R.; Chhipa, R. R.; Onder, O.; McFetridge, C.; Van Arnam, J. S.; Zhang, X.; Morrissette, J. J. D.; Pillai, V.; Li, M. M.; Szankasi, P.; Basrur, V.; Conlon, K. P.; Raabe, T. D.; Bailey, N. G.; Hogaboam, C. M.; Rottapel, R.; Kim, J.; López, C.; Schlesner, M.; Siebert, R.; Dreval, K.; Morin, R. D.; Moro, L.; Pagano, M.; Staudt, L. M.; Lim, M. S.; Elenitoba-Johnson, K. S. J. |
| Article Title: | The FBXO45–GEF-H1 axis controls germinal center formation and B-cell lymphomagenesis |
| 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 mu-tually 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 cancers. © 2025 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | genetics; mouse; animal; metabolism; animals; mice; pathology; b cell lymphoma; germinal center; lymphoma, b-cell; f-box proteins; guanine nucleotide exchange factors; guanine nucleotide exchange factor; f box protein; humans; human |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 4 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-04-01 |
| Start Page: | 838 |
| End Page: | 861 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-0442 |
| PUBMED: | 39820335 |
| PROVIDER: | scopus |
| PMCID: | PMC11962402 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding authors are Kojo Elenitoba-Johnson and Megan Lim -- Source: Scopus |
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