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.
B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements / Varano, Gabriele; Lonardi, Silvia; Sindaco, Paola; Pietrini, Ilaria; Morello, Gaia; Balzarini, Piera; Vit, Filippo; Neuman, Hadas; Bertolazzi, Giorgio; Brambillasca, Silvia; Parr, Nicara C; Chiarini, Marco; Bellesi, Silvia; Maiolo, Elena; Giampaolo, Sabrina; Mainoldi, Federica; Selvarasa, Viveka; Arima, Hiroshi; Pellegrini, Vilma; Pagani, Chiara; Bugatti, Mattia; Ranise, Cecilia; Taddei, Tommaso M; Sonoki, Takashi; Thanasi, Hajdica; Morlacchi, Elena; Segura-Garzon, Daniel; Albertini, Emma; Daffini, Rosa; Sivacegaram, Anojan; Yang, Henry; Li, Ying; Cancila, Valeria; Cicio, Giada; Robusto, Michela; Leuzzi, Brian; Andronache, Adrian; Trifiro, Paolo; Riboni, Mirko; Minardi, Simone P; Bonnal, Raoul J P; Gonzalez, Cristina Lopez; Visco, Euplio; Capaccio, Pasquale; Torretta, Sara; Pignataro, Lorenzo; Almici, Camillo; Varasi, Mario; Larocca, Luigi M; Siebert, Reiner; Falini, Brunangelo; Ferreri, Andres J M; Tucci, Alessandra; Lorenzini, Daniele; Cabras, Antonello D; Pruneri, Giancarlo; Di Napoli, Arianna; Ungari, Marco; Pizzi, Marco; Hohaus, Stefan; Mercurio, Ciro; Song, Joo Y; Chan, Wing C; Lorenzi, Luisa; Bomben, Riccardo; Ponzoni, Maurilio; Mehr, Ramit; Tripodo, Claudio; Facchetti, Fabio; Casola, Stefano. - In: BLOOD CANCER DISCOVERY. - ISSN 2643-3249. - 6:4(2025), pp. 364-393. [10.1158/2643-3230.BCD-25-0099]
B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements
Di Napoli, Arianna;
2025
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
