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
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., Pagani, C., Bugatti, M., Ranise, C., Taddei, T. M., 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, S. P., Bonnal, R. J. P., Gonzalez Lopez, C., Visco, E., Capaccio, P., Torretta, S., Pignataro, L., Almici, C., Varasi, M., Larocca, L. M., Siebert, R., Falini, B., Ferreri, A. J. M., Tucci, A., Lorenzini, D., Cabras, A. D., Pruneri, G., Di Napoli, A., Ungari, M., Pizzi, M., Hohaus, S., Mercurio, C., Song, J. Y., Chan, W. C., Lorenzi, L., Bomben, R., Ponzoni, M., Mehr, R., Tripodo, C., Facchetti, F., Casola, S., B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements, <<BLOOD CANCER DISCOVERY>>, 2025; 6 (4): 364-393. [doi:10.1158/2643-3230.BCD-25-0099] [https://hdl.handle.net/10807/325580]
B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements
Bellesi, Silvia;Maiolo, Elena;Larocca, Luigi Maria;Hohaus, Stefan;
2025
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
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