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

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.

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