B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements
- Autori: Varano, G.; Lonardi, S.; Sindaco, P.; Pietrini, I.; Morello, G.; Balzarini, P.; Vit, F.; Neuman, H.; Bertolazzi, G.; Brambillasca, S.; Parr, N.C.; Chiarini, M.; Bellesi, S.; Maiolo, E.; Giampaolo, S.; Mainoldi, F.; Selvarasa, V.; Arima, H.; Pellegrini, V.; Pagani, C.; Bugatti, M.; Ranise, C.; Taddei, T.M.; Sonoki, T.; Thanasi, H.; Morlacchi, E.; Segura-Garzon, D.; Albertini, E.; Daffini, R.; Sivacegaram, A.; Yang, H.; Li, Y.; Cancila, V.; Cicio, G.; Robusto, M.; Leuzzi, B.; Andronache, A.; Trifiro, P.; Riboni, M.; Minardi, S.P.; Bonnal, R.J.P.; Gonzalez, C.L.; Visco, E.; Capaccio, P.; Torretta, S.; Pignataro, L.; Almici, C.; Varasi, M.; Larocca, L.M.; Siebert, R.; Falini, B.; Ferreri, A.J.M.; Tucci, A.; Lorenzini, D.; Cabras, A.D.; Pruneri, G.; Di Napoli, A.; Ungari, M.; Pizzi, M.; Hohaus, S.; Mercurio, C.; Song, J.Y.; Chan, W.C.; Lorenzi, L.; Bomben, R.; Ponzoni, M.; Mehr, R.; Tripodo, C.; Facchetti, F.; Casola, S.
- Anno di pubblicazione: 2025
- Tipologia: Articolo in rivista
- OA Link: http://hdl.handle.net/10447/692417
Abstract
The B-cell receptor (BCR) is critical for mature B-cell lymphomas (BCL), serving as a therapeutic target. We show that high-grade BCLs with MYC and BCL2 rearrangements [HGBCL–double-hit (DH)–BCL2] predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) tumors differ from IGH+ counterparts in germinal center (GC) zone programs, MYC expression, and immune infiltrate. Whereas IGH+ HGBCL-DH-BCL2 tumors favor IGM/IG-κ expression, IGHUND counterparts complete IGH isotype switching and IG-λ rearrangements. IGHUND lymphomas retain productive IGHV rearrangements and require IGH for optimal fitness. BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and facilitating t(8;22)/IGL::MYC translocations. IGHUND HGBCL-DH-BCL2 models exhibit reduced sensitivity to the CD79B-targeting antibody–drug conjugate polatuzumab vedotin. Collectively, HGBCL-DH-BCL2 commonly arises from isotype-switched t(14;18)+ GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.