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

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 (IGH UND ) 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, IGH UND counterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGH UND 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 I GL::MYC translocations during IG light chain revision, with clinical implications. Significance These 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.