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

G. Varano; S. Lonardi; P. Sindaco; I. Pietrini; G. Morello; P. Balzarini; F. Vit; H. Neuman; G. Bertolazzi; S. Brambillasca; N. C. Parr; M. Chiarini; S. Bellesi; E. Maiolo; S. Giampaolo; F. Mainoldi; V. Selvarasa; H. Arima; V. Pellegrini; C. Pagani; M. Bugatti; C. Ranise; T. M. Taddei; T. Sonoki; H. Thanasi; E. Morlacchi; D. Segura-Garzon; E. Albertini; R. Daffini; A. Sivacegaram; H. Yang; Y. Li; V. Cancila; G. Cicio; M. Robusto; B. Leuzzi; A. Andronache; P. Trifiro; M. Riboni; S. P. Minardi; R. J. P. Bonnal; Lopez C. Gonzalez; E. Visco; P. Capaccio; S. Torretta; L. Pignataro; C. Almici; M. Varasi; L. M. Larocca; R. Siebert; B. Falini; A. J. M. Ferreri; A. Tucci; D. Lorenzini; A. D. Cabras; G. Pruneri; Napoli A. Di; M. Ungari; M. Pizzi; Stefan Hohaus; C. Mercurio; J. Y. Song; W. C. Chan; L. Lorenzi; R. Bomben; M. Ponzoni; R. Mehr; C. Tripodo; F. Facchetti; S. 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

G. Varano
, S. Lonardi
, P. Sindaco
, I. Pietrini
, G. Morello
, P. Balzarini
, F. Vit
, H. Neuman
, G. Bertolazzi
, S. Brambillasca
, N. C. Parr
, M. Chiarini
, S. Bellesi
, E. Maiolo
, S. Giampaolo
, F. Mainoldi
, V. Selvarasa
, H. Arima
, V. Pellegrini
, C. Pagani

M. Bugatti, C. Ranise, T. M. Taddei, T. Sonoki, H. Thanasi, E. Morlacchi, D. Segura-Garzon, E. Albertini, R. Daffini, A. Sivacegaram, H. Yang, Y. Li, V. Cancila, G. Cicio, M. Robusto, B. Leuzzi, A. Andronache, P. Trifiro, M. Riboni, S. P. Minardi, R. J. P. Bonnal, Lopez C. Gonzalez, E. Visco, P. Capaccio, S. Torretta, L. Pignataro, C. Almici, M. Varasi, L. M. Larocca, R. Siebert, B. Falini, A. J. M. Ferreri, A. Tucci, D. Lorenzini, A. D. Cabras, G. Pruneri, Napoli A. Di, M. Ungari, M. Pizzi, Stefan Hohaus, C. Mercurio, J. Y. Song, W. C. Chan, L. Lorenzi, R. Bomben, M. Ponzoni, R. Mehr, C. Tripodo, F. Facchetti, S. Casola^*

^*Corresponding author

FIRC Institute of Molecular Oncology
University of Brescia
University of Palermo
IRCCS Centro di Riferimento Oncologico - Aviano PN
Bar-Ilan University
Kore University of Enna
Spedali Civili Di Brescia
Wakayama Medical University
University of Milan
National University of Singapore
August Pi i Sunyer Biomedical Research Institute
Vita-Salute San Raffaele University
IRCCS San Raffaele Scientific Institute
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
Ulm University
University of Perugia
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
Sant'Andrea Hospital
Fondazione Poliambulanza Hospital Institute
University of Padua

Research output: Contribution to journal › 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-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)+ GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.Significance: 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. 284Significance: 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

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
Publication status	Published - 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

General Medicine

Keywords

lymphoma

Access to Document

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{7abab59b485e41059bafb4e18d3243c3,

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-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)+ GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.Significance: 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. 284Significance: 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",

keywords = "lymphoma, lymphoma",

author = "G. Varano and S. Lonardi and P. Sindaco and I. Pietrini and G. Morello and P. Balzarini and F. Vit and H. Neuman and G. Bertolazzi and S. Brambillasca and Parr, \{N. C.\} and M. Chiarini and S. Bellesi and E. Maiolo and S. Giampaolo and F. Mainoldi and V. Selvarasa and H. Arima and V. Pellegrini and C. Pagani and M. Bugatti and C. Ranise and Taddei, \{T. M.\} and T. Sonoki and H. Thanasi and E. Morlacchi and D. Segura-Garzon and E. Albertini and R. Daffini and A. Sivacegaram and H. Yang and Y. Li and V. Cancila and G. Cicio and M. Robusto and B. Leuzzi and A. Andronache and P. Trifiro and M. Riboni and Minardi, \{S. P.\} and Bonnal, \{R. J. P.\} and Gonzalez, \{Lopez C.\} and E. Visco and P. Capaccio and S. Torretta and L. Pignataro and C. Almici and M. Varasi and Larocca, \{L. M.\} and R. Siebert and B. Falini and Ferreri, \{A. J. M.\} and A. Tucci and D. Lorenzini and Cabras, \{A. D.\} and G. Pruneri and Di, \{Napoli A.\} and M. Ungari and M. Pizzi and Stefan Hohaus and C. Mercurio and Song, \{J. Y.\} and Chan, \{W. C.\} and L. Lorenzi and R. Bomben and M. Ponzoni and R. Mehr and C. Tripodo and F. Facchetti and S. Casola",

year = "2025",

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

language = "English",

volume = "6",

pages = "364--393",

journal = "Blood cancer discovery",

issn = "2643-3249",

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, LC, 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, NA, 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, G.

AU - Lonardi, S.

AU - Sindaco, P.

AU - Pietrini, I.

AU - Morello, G.

AU - Balzarini, P.

AU - Vit, F.

AU - Neuman, H.

AU - Bertolazzi, G.

AU - Brambillasca, S.

AU - Parr, N. C.

AU - Chiarini, M.

AU - Bellesi, S.

AU - Maiolo, E.

AU - Giampaolo, S.

AU - Mainoldi, F.

AU - Selvarasa, V.

AU - Arima, H.

AU - Pellegrini, V.

AU - Pagani, C.

AU - Bugatti, M.

AU - Ranise, C.

AU - Taddei, T. M.

AU - Sonoki, T.

AU - Thanasi, H.

AU - Morlacchi, E.

AU - Segura-Garzon, D.

AU - Albertini, E.

AU - Daffini, R.

AU - Sivacegaram, A.

AU - Yang, H.

AU - Li, Y.

AU - Cancila, V.

AU - Cicio, G.

AU - Robusto, M.

AU - Leuzzi, B.

AU - Andronache, A.

AU - Trifiro, P.

AU - Riboni, M.

AU - Minardi, S. P.

AU - Bonnal, R. J. P.

AU - Gonzalez, Lopez C.

AU - Visco, E.

AU - Capaccio, P.

AU - Torretta, S.

AU - Pignataro, L.

AU - Almici, C.

AU - Varasi, M.

AU - Larocca, L. M.

AU - Siebert, R.

AU - Falini, B.

AU - Ferreri, A. J. M.

AU - Tucci, A.

AU - Lorenzini, D.

AU - Cabras, A. D.

AU - Pruneri, G.

AU - Di, Napoli A.

AU - Ungari, M.

AU - Pizzi, M.

AU - Hohaus, Stefan

AU - Mercurio, C.

AU - Song, J. Y.

AU - Chan, W. C.

AU - Lorenzi, L.

AU - Bomben, R.

AU - Ponzoni, M.

AU - Mehr, R.

AU - Tripodo, C.

AU - Facchetti, F.

AU - Casola, S.

PY - 2025

Y1 - 2025

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-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)+ GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.Significance: 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. 284Significance: 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

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-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)+ GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.Significance: 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. 284Significance: 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

KW - lymphoma

UR - https://publicatt.unicatt.it/handle/10807/325580

UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=105010232528&origin=inward

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105010232528&origin=inward

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

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

M3 - Article

SN - 2643-3249

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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