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

<div>Abstract<p>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 <i>MYC</i> and <i>BCL2</i> rearrangements [HGBCL–double-hit (DH)–<i>BCL2</i>] predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-<i>BCL2</i> (IGH<sup>UND</sup>) tumors differ from IGH<sup>+</sup> counterparts in germinal center (GC) zone programs, MYC expression, and immune infiltrate. Whereas IGH<sup>+</sup> HGBCL-DH-<i>BCL2</i> tumors favor IGM/IG-κ expression, IGH<sup>UND</sup> counterparts complete IGH isotype switching and IG-λ rearrangements. IGH<sup>UND</sup> lymphomas retain productive <i>IGHV</i> rearrangements and require IGH for optimal fitness. BCR silencing, caused by accelerated IGH turnover and reduced <i>IGH</i> expression, precedes HGBCL-DH-<i>BCL2</i> onset, inducing RAG1/2-dependent IG light chain editing and facilitating t(8;22)/<i>IGL</i>::<i>MYC</i> translocations. IGH<sup>UND</sup> HGBCL-DH-<i>BCL2</i> models exhibit reduced sensitivity to the CD79B-targeting antibody–drug conjugate polatuzumab vedotin. Collectively, HGBCL-DH-<i>BCL2</i> commonly arises from isotype-switched t(14;18)<sup>+</sup> GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.</p>Significance:<p>These findings link BCR silencing in IGH isotype-switched t(14;18)<sup>+</sup> GC B cells to RAG1/2 expression, which triggers IG light chain editing and predisposes to <i>IGL</i>::<i>MYC</i> translocations, promoting HGBCL. In HGBCL with <i>MYC</i> and <i>BCL2</i> rearrangements, BCR silencing protects from polatuzumab vedotin killing.</p><p><a href="https://aacrjournals.org/bloodcancerdiscov/article-abstract/doi/10.1158/2643-3230.BCD-25-0160" target="_blank"><i>See related commentary by Shevchenko and Hodson, p. 284</i></a></p></div>