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

Sindaco, P.; Lonardi, S.; Varano, G.; Pietrini, I.; Morello, G.; Balzarini, P.; Neuman, H.; Vit, F.; Bertolazzi, G.; Arima, H.; Chiarini, M.; Lorenzi, L.; Pellegrini, V.; Giampaolo, S.; Garzon, D.; Ranise, C.; Bugatti, M.; Pagani, C.; Daffini, R.; Mainoldi, F.; Selvarasa, V.; Sivacegaram, A.; Yang, H.; Ying, L.; Cancila, V.; Bonnal, R.; Visco, E.; Gonzalez, C. L.; Capaccio, P.; Ferreri, A. J. M.; Tucci, A.; Cabras, A. D.; Pruneri, G.; di Napoli, A.; Siebert, R.; Bomben, R.; Falini, B.; Pizzi, M.; Song, J. Y.; Chan, W. C.; Ponzoni, M.; Mehr, R.; Tripodo, C.; Facchetti, F.; Casola, S.

doi:10.1101/2024.07.13.603066

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bioRxiv · 10.1101/2024.07.13.603066

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

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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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Sindaco, P., Lonardi, S., Varano, G., Pietrini, I., Morello, G., Balzarini, P., Neuman, H., Vit, F., Bertolazzi, G., Arima, H., Chiarini, M., Lorenzi, L., Pellegrini, V., Giampaolo, S., Garzon, D., Ranise, C., Bugatti, M., Pagani, C., Daffini, R., Mainoldi, F., Selvarasa, V., Sivacegaram, A., Yang, H., Ying, L., Cancila, V., Bonnal, R., Visco, E., Gonzalez, C. L., Capaccio, P., Ferreri, A. J. M., Tucci, A., Cabras, A. D., Pruneri, G., di Napoli, A., Siebert, R., Bomben, R., Falini, B., Pizzi, M., Song, J. Y., Chan, W. C., Ponzoni, M., Mehr, R., Tripodo, C., Facchetti, F., Casola, S.. 2024-07-17. B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements. https://doi.org/10.1101/2024.07.13.603066

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