B cell receptor silencing reveals the origin of high-grade B cell lymphomas withMYCandBCL2rearrangements

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 withMYCandBCL2rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. HGBCL-DH-BCL2with undetectable IGH (IGHUND) differ from IGH-expressing counterparts for germinal center-zone gene programs,MYCexpression and T cell infiltration. While IGH+HGBCL-DH-BCL2prefer IGM/IG-Kappa expression, IGHUNDcounterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGHUNDHGBCL-DH-BCL2preserveIGHVgene integrity, overcoming antigen-driven selection. IGH silencing precedes onset and shapes evolution of HGBCL-DH-BCL2from Follicular Lymphoma (FL) or FL/HGBCL-DH-BCL2common precursor. In FL/HGBCL-DH-BCL2pairs and HGBCL-DH-BCL2models, BCR silencing promoted RAG1/2-dependent IG light chain editing, causing t(8;22)(q24;q11)/IGL::MYC. IGH silencing protected HGBCL-DH-BCL2models from killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, HGBCL-DH-BCL2primarily originate from BCR-silenced isotype-switched t(14;18)/IGH::BCL2-positive (pre)FL cells acquiring IGL::MYCtranslocations 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, promotingIGL::MYCtranslocations responsible for transformation into high-grade B cell lymphomas (HGBCL). Predominant silencing of the BCR complex in HGBCL withMYCandBCL2rearrangements protects tumor cells from CD79B-directed Polatuzumab-Vedotin killing.