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
- 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 suppressorThe 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.…
