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Supplementary figure S7 from B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements

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posted on 2025-07-03, 13:40 authored by 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 J.P. Bonnal, Cristina Lopez Gonzalez, Euplio Visco, Pasquale Capaccio, Sara Torretta, Lorenzo Pignataro, Camillo Almici, Mario Varasi, Luigi M. Larocca, Reiner Siebert, Brunangelo Falini, Andres 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

IGG transcript a protein analyses in HGBCL-DH-BCL2(-BCL6) cell lines and HEK293T cells before and after complementation with IG expression vectors

Funding

Fondazione Cariplo (Cariplo Foundation)

Fondazione Spedali Civili di Brescia

US-Israel Binational Science Foundation

Ministry of University and Research

Italian Ministry of University and Research to the Department Molecular Biotechnology and Translational Medicine, University of Milan

Italian Ministry of University and Research, Investment 1.4 [CN3] SPOKE 2, lotto 5 of the National Recovery and Resilience Plan (PNRR) funded by the EU “Next Generation EU” [CUP B63C2200061.

Fondazione AIRC per la ricerca sul cancro ETS (AIRC)

Fondazione Beretta (Beretta Foundation)

American Society of Hematology (ASH)

H2020 Marie Skłodowska-Curie Actions (MSCA)

Marie Sklodowska-Curie Innovative Training Network

Bar-Ilan University President’s scholarship

Italian Ministry of University and Research

History

ARTICLE 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. These findings link BCR silencing in IGH isotype-switched t(14;18)+ GC B cells to RAG1/2 expression, which triggers IG light chain editing and predisposes to IGL::MYC translocations, promoting HGBCL. In HGBCL with MYC and BCL2 rearrangements, BCR silencing protects from polatuzumab vedotin killing.See related commentary by Shevchenko and Hodson, p. 284

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    Blood Cancer Discovery

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    Keywords

    Biological Agents & TherapiesAntibody-drug conjugatesCarcinogenesisTumor initiation and promotionHematological CancersLymphomasTumor Evolution

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