B-cell Receptor Silencing Reveals the Origin and Dependencies 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-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 Gonzalez Lopez; 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

doi: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

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 Gonzalez Lopez, 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

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

FIRC Institute of Molecular Oncology
University of Brescia
University of Palermo
IRCCS Centro di Riferimento Oncologico - Aviano PN
Kore University of Enna
Brescia Civil Hospital
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Sant'Anna School of Advanced Studies
Wakayama Medical University
University of Milan
National University of Singapore
Cogentech Società Benefit S.R.L.
August Pi i Sunyer Biomedical Research Institute
San Raffaele Scientific Institute
Vita-Salute San Raffaele University
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
Saint Camillus International University of Health and Medical Sciences
Ulm University
University of Perugia
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
Sant'Andrea Hospital
Fondazione Poliambulanza Hospital
University of Padua
Catholic University of the Sacred Heart
City of Hope National Med Center

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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 (IGH^UND) 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, IGH^UND counterparts complete IGH isotype switching and IG-λ rearrangements. IGH^UND 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. IGH^UND 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.

Original language	English
Pages (from-to)	364-393
Number of pages	30
Journal	Blood cancer discovery
Volume	6
Issue number	4
DOIs	https://doi.org/10.1158/2643-3230.BCD-25-0099
State	Published - 1 Jul 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors.

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10.1158/2643-3230.BCD-25-0099

Cite this

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., ... Casola, S. (2025). B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements. Blood cancer discovery, 6(4), 364-393. https://doi.org/10.1158/2643-3230.BCD-25-0099

@article{1c54a329212b4d9892d181ab4400db55,

title = "B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements",

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.",

author = "Gabriele Varano and Silvia Lonardi and Paola Sindaco and Ilaria Pietrini and Gaia Morello and Piera Balzarini and Filippo Vit and Hadas Neuman and Giorgio Bertolazzi and Silvia Brambillasca and Parr, \{Nicara C.\} and Marco Chiarini and Silvia Bellesi and Elena Maiolo and Sabrina Giampaolo and Federica Mainoldi and Viveka Selvarasa and Hiroshi Arima and Vilma Pellegrini and Chiara Pagani and Mattia Bugatti and Cecilia Ranise and Taddei, \{Tommaso M.\} and Takashi Sonoki and Hajdica Thanasi and Elena Morlacchi and Daniel Segura-Garzon and Emma Albertini and Rosa Daffini and Anojan Sivacegaram and Henry Yang and Ying Li and Valeria Cancila and Giada Cicio and Michela Robusto and Brian Leuzzi and Adrian Andronache and Paolo Trifiro and Mirko Riboni and Minardi, \{Simone P.\} and Bonnal, \{Raoul J.P.\} and \{Gonzalez Lopez\}, Cristina and Euplio Visco and Pasquale Capaccio and Sara Torretta and Lorenzo Pignataro and Camillo Almici and Mario Varasi and Larocca, \{Luigi M.\} and Reiner Siebert and Brunangelo Falini and Ferreri, \{Andres J.M.\} and Alessandra Tucci and Daniele Lorenzini and Cabras, \{Antonello D.\} and Giancarlo Pruneri and \{Di Napoli\}, Arianna and Marco Ungari and Marco Pizzi and Stefan Hohaus and Ciro Mercurio and Song, \{Joo Y.\} and Chan, \{Wing C.\} and Luisa Lorenzi and Riccardo Bomben and Maurilio Ponzoni and Ramit Mehr and Claudio Tripodo and Fabio Facchetti and Stefano Casola",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

year = "2025",

month = jul,

day = "1",

doi = "10.1158/2643-3230.BCD-25-0099",

language = "אנגלית",

volume = "6",

pages = "364--393",

journal = "Blood cancer discovery",

issn = "2643-3230",

publisher = "American Association for Cancer Research Inc.",

number = "4",

}

Varano, G, Lonardi, S, Sindaco, P, Pietrini, I, Morello, G, Balzarini, P, Vit, F, Neuman, H, Bertolazzi, G, Brambillasca, S, Parr, NC, Chiarini, M, Bellesi, S, Maiolo, E, Giampaolo, S, Mainoldi, F, Selvarasa, V, Arima, H, Pellegrini, V, Pagani, C, Bugatti, M, Ranise, C, Taddei, TM, 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, SP, Bonnal, RJP, Gonzalez Lopez, C, Visco, E, Capaccio, P, Torretta, S, Pignataro, L, Almici, C, Varasi, M, Larocca, LM, Siebert, R, Falini, B, Ferreri, AJM, Tucci, A, Lorenzini, D, Cabras, AD, Pruneri, G, Di Napoli, A, Ungari, M, Pizzi, M, Hohaus, S, Mercurio, C, Song, JY, Chan, WC, Lorenzi, L, Bomben, R, Ponzoni, M, Mehr, R, Tripodo, C, Facchetti, F & Casola, S 2025, 'B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements', Blood cancer discovery, vol. 6, no. 4, pp. 364-393. https://doi.org/10.1158/2643-3230.BCD-25-0099

TY - JOUR

T1 - B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements

AU - Varano, Gabriele

AU - Lonardi, Silvia

AU - Sindaco, Paola

AU - Pietrini, Ilaria

AU - Morello, Gaia

AU - Balzarini, Piera

AU - Vit, Filippo

AU - Neuman, Hadas

AU - Bertolazzi, Giorgio

AU - Brambillasca, Silvia

AU - Parr, Nicara C.

AU - Chiarini, Marco

AU - Bellesi, Silvia

AU - Maiolo, Elena

AU - Giampaolo, Sabrina

AU - Mainoldi, Federica

AU - Selvarasa, Viveka

AU - Arima, Hiroshi

AU - Pellegrini, Vilma

AU - Pagani, Chiara

AU - Bugatti, Mattia

AU - Ranise, Cecilia

AU - Taddei, Tommaso M.

AU - Sonoki, Takashi

AU - Thanasi, Hajdica

AU - Morlacchi, Elena

AU - Segura-Garzon, Daniel

AU - Albertini, Emma

AU - Daffini, Rosa

AU - Sivacegaram, Anojan

AU - Yang, Henry

AU - Li, Ying

AU - Cancila, Valeria

AU - Cicio, Giada

AU - Robusto, Michela

AU - Leuzzi, Brian

AU - Andronache, Adrian

AU - Trifiro, Paolo

AU - Riboni, Mirko

AU - Minardi, Simone P.

AU - Bonnal, Raoul J.P.

AU - Gonzalez Lopez, Cristina

AU - Visco, Euplio

AU - Capaccio, Pasquale

AU - Torretta, Sara

AU - Pignataro, Lorenzo

AU - Almici, Camillo

AU - Varasi, Mario

AU - Larocca, Luigi M.

AU - Siebert, Reiner

AU - Falini, Brunangelo

AU - Ferreri, Andres J.M.

AU - Tucci, Alessandra

AU - Lorenzini, Daniele

AU - Cabras, Antonello D.

AU - Pruneri, Giancarlo

AU - Di Napoli, Arianna

AU - Ungari, Marco

AU - Pizzi, Marco

AU - Hohaus, Stefan

AU - Mercurio, Ciro

AU - Song, Joo Y.

AU - Chan, Wing C.

AU - Lorenzi, Luisa

AU - Bomben, Riccardo

AU - Ponzoni, Maurilio

AU - Mehr, Ramit

AU - Tripodo, Claudio

AU - Facchetti, Fabio

AU - Casola, Stefano

PY - 2025/7/1

Y1 - 2025/7/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105010232528

U2 - 10.1158/2643-3230.BCD-25-0099

DO - 10.1158/2643-3230.BCD-25-0099

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C2 - 40402557

AN - SCOPUS:105010232528

SN - 2643-3230

VL - 6

SP - 364

EP - 393

JO - Blood cancer discovery

JF - Blood cancer discovery

IS - 4

ER -

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

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