B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements

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-Garzón; Emma Albertini; Rosa Daffini; Anojan Sivacegaram

doi:10.1158/2643-3230.bcd-25-0099

Cancer BiologyBlood Cancer DiscoveryMay 22, 2025

Peer-reviewed journal article

B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements

Gabriele Varano iD, Silvia Lonardi iD, Paola Sindaco iD, Ilaria Pietrini iD, Gaia Morello iD, Piera Balzarini iD, Filippo Vit iD, Hadas Neuman iD, Giorgio Bertolazzi iD, Silvia Brambillasca iD, Nicara C. Parr iD, Marco Chiarini iD, Silvia Bellesi iD, Elena Maiolo iD, Sabrina Giampaolo iD, Federica Mainoldi iD, Viveka Selvarasa iD, Hiroshi Arima iD, Vilma Pellegrini iD, Chiara Pagani iD, Mattia Bugatti iD, Cecilia Ranise iD, Tommaso M. Taddei iD, Takashi Sonoki iD, Hajdica Thanasi iD, , Stefano S Casola iD

Abstract

The B cell receptor (BCR) is essential for mature B cell lymphomas, serving as therapeutic target. Here, 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. HGBCL-DH-BCL2 with undetectable IGH (IGHUND) differ from IGH-expressing counterparts for germinal center-zone gene programs, MYC expression and T cell infiltration. While IGH+ HGBCL-DH-BCL2 prefer IGM/IG-Kappa expression, IGHUND counterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGHUND HGBCL-DH-BCL2 preserve IGHV gene integrity, overcoming antigen-driven selection. IGH silencing precedes onset and shapes evolution of HGBCL-DH-BCL2 from Follicular Lymphoma (FL) or FL/HGBCL-DH-BCL2 common precursor. In FL/HGBCL-DH-BCL2 pairs and HGBCL-DH-BCL2 models, BCR silencing promoted RAG1/2-dependent IG light chain editing, causing t(8;22)(q24;q11)/IGL::MYC. IGH silencing protected HGBCL-DH-BCL2 models from killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, HGBCL-DH-BCL2 primarily originate from BCR-silenced isotype-switched t(14;18)/IGH::BCL2-positive (pre)FL cells acquiring IGL::MYC translocations during IG light chain revision, with clinical implications. SignificanceThese findings link BCR silencing in isotype-switched t(14;18)+ Follicular Lymphoma cells (or their precursors) to RAG1/2 re-expression, promoting IGL::MYC translocations responsible for transformation into high-grade B cell lymphomas (HGBCL). Predominant silencing of the BCR complex in HGBCL with MYC and BCL2 rearrangements protects tumor cells from CD79B-directed Polatuzumab-Vedotin killing.

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