Gabriele Varano, Silvia Lonardi, Paola Sindaco, Ilaria Pietrini, Gaia Morello, Piera Balzarini, Filippo Vit, Hadas Neuman, Giorgio Bertolazzi, Silvia Brambillasca, Nicara C Parr, Marco Chiarini, Silvia Bellesi, Elena Maiolo, Sabrina Giampaolo, Federica Mainoldi, Viveka Selvarasa, Hiroshi Arima, Vilma Pellegrini, Chiara Pagani, Mattia Bugatti, Cecilia Ranise, Tommaso M Taddei, Takashi Sonoki, Hajdica Thanasi, Elena Morlacchi, Daniel Segura-Garzon, Emma Albertini, Rosa Daffini, Anojan Sivacegaram, Henry Yang, Ying Li, Valeria Cancila, Giada Cicio, Michela Robusto, Brian Leuzzi, Adrian Andronache, Paolo Trifiro, Mirko Riboni, Simone P Minardi, Raoul Jp Bonnal, Cristina Lopez Gonzalez, Euplio Visco, Pasquale Capaccio, Sara Torretta, Lorenzo Pignataro, Camillo Almici, Mario Varasi, Luigi M Larocca, Reiner Siebert, Brunangelo Falini, Andrés J M Ferreri, Alessandra Tucci, Daniele Lorenzini, Antonello D Cabras, Giancarlo Pruneri, Arianna Di Napoli, Marco Ungari, Marco Pizzi, Stefan Hohaus, Ciro Mercurio, Joo Y Song, Wing C Chan, Luisa Lorenzi, Riccardo Bomben, Maurilio Ponzoni, Ramit Mehr, Claudio Tripodo, Fabio Facchetti, Stefano Casola
{"title":"B细胞受体沉默揭示MYC和BCL2重排的高级别B细胞淋巴瘤的起源和依赖性。","authors":"Gabriele Varano, Silvia Lonardi, Paola Sindaco, Ilaria Pietrini, Gaia Morello, Piera Balzarini, Filippo Vit, Hadas Neuman, Giorgio Bertolazzi, Silvia Brambillasca, Nicara C Parr, Marco Chiarini, Silvia Bellesi, Elena Maiolo, Sabrina Giampaolo, Federica Mainoldi, Viveka Selvarasa, Hiroshi Arima, Vilma Pellegrini, Chiara Pagani, Mattia Bugatti, Cecilia Ranise, Tommaso M Taddei, Takashi Sonoki, Hajdica Thanasi, Elena Morlacchi, Daniel Segura-Garzon, Emma Albertini, Rosa Daffini, Anojan Sivacegaram, Henry Yang, Ying Li, Valeria Cancila, Giada Cicio, Michela Robusto, Brian Leuzzi, Adrian Andronache, Paolo Trifiro, Mirko Riboni, Simone P Minardi, Raoul Jp Bonnal, Cristina Lopez Gonzalez, Euplio Visco, Pasquale Capaccio, Sara Torretta, Lorenzo Pignataro, Camillo Almici, Mario Varasi, Luigi M Larocca, Reiner Siebert, Brunangelo Falini, Andrés J M Ferreri, Alessandra Tucci, Daniele Lorenzini, Antonello D Cabras, Giancarlo Pruneri, Arianna Di Napoli, Marco Ungari, Marco Pizzi, Stefan Hohaus, Ciro Mercurio, Joo Y Song, Wing C Chan, Luisa Lorenzi, Riccardo Bomben, Maurilio Ponzoni, Ramit Mehr, Claudio Tripodo, Fabio Facchetti, Stefano Casola","doi":"10.1158/2643-3230.BCD-25-0099","DOIUrl":null,"url":null,"abstract":"<p><p>The B cell receptor (BCR) is critical for mature B cell lymphomas, serving as a therapeutic target. We show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) differ from IGH+ counterparts in germinal center-zone programs, MYC expression, and immune infiltrate. While IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IGH isotype switching and IG-Lambda 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)+ germinal center B cells, which edit IG light chains, fueling intra-clonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5000,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements.\",\"authors\":\"Gabriele Varano, Silvia Lonardi, Paola Sindaco, Ilaria Pietrini, Gaia Morello, Piera Balzarini, Filippo Vit, Hadas Neuman, Giorgio Bertolazzi, Silvia Brambillasca, Nicara C Parr, Marco Chiarini, Silvia Bellesi, Elena Maiolo, Sabrina Giampaolo, Federica Mainoldi, Viveka Selvarasa, Hiroshi Arima, Vilma Pellegrini, Chiara Pagani, Mattia Bugatti, Cecilia Ranise, Tommaso M Taddei, Takashi Sonoki, Hajdica Thanasi, Elena Morlacchi, Daniel Segura-Garzon, Emma Albertini, Rosa Daffini, Anojan Sivacegaram, Henry Yang, Ying Li, Valeria Cancila, Giada Cicio, Michela Robusto, Brian Leuzzi, Adrian Andronache, Paolo Trifiro, Mirko Riboni, Simone P Minardi, Raoul Jp Bonnal, Cristina Lopez Gonzalez, Euplio Visco, Pasquale Capaccio, Sara Torretta, Lorenzo Pignataro, Camillo Almici, Mario Varasi, Luigi M Larocca, Reiner Siebert, Brunangelo Falini, Andrés J M Ferreri, Alessandra Tucci, Daniele Lorenzini, Antonello D Cabras, Giancarlo Pruneri, Arianna Di Napoli, Marco Ungari, Marco Pizzi, Stefan Hohaus, Ciro Mercurio, Joo Y Song, Wing C Chan, Luisa Lorenzi, Riccardo Bomben, Maurilio Ponzoni, Ramit Mehr, Claudio Tripodo, Fabio Facchetti, Stefano Casola\",\"doi\":\"10.1158/2643-3230.BCD-25-0099\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The B cell receptor (BCR) is critical for mature B cell lymphomas, serving as a therapeutic target. We show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) differ from IGH+ counterparts in germinal center-zone programs, MYC expression, and immune infiltrate. While IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IGH isotype switching and IG-Lambda 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. 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B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements.
The B cell receptor (BCR) is critical for mature B cell lymphomas, serving as a therapeutic target. We show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) differ from IGH+ counterparts in germinal center-zone programs, MYC expression, and immune infiltrate. While IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IGH isotype switching and IG-Lambda 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)+ germinal center B cells, which edit IG light chains, fueling intra-clonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.
期刊介绍：
The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes.
The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence.
Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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