RAG1/2 expression in IGH-switched follicular lymphoma associated with transformation to high-grade B-cell lymphoma.

High-grade B-cell lymphomas with MYC and BCL2 rearrangements (HGBCL-MYC/BCL2 or DLBCL/HGBCL-MYC/BCL2, hereafter referred to as DLBCL/HGBCL-MYC/BCL2) are highly aggressive malignancies that originate from germinal center (GC)-experienced B cells [1,2,3,4]. By performing in situ RNA hybridization, Varano et al. recently showed that approximately one third of DLBCL/HGBCL-MYC/BCL2 cases express transcripts for the Recombination Activating Genes RAG1 and RAG2 [5]. Reactivation of immunoglobulin (IG) V(D)J recombination in these GC-derived tumors promoted B-cell receptor (BCR) revision (also called receptor editing) through secondary IG light chain variable (V) region gene rearrangements, driving intraclonal BCR diversification and, in some instances, BCR extinction via accumulation of non-productive secondary IG light chain V gene rearrangements [5]. Sequencing of chromosomal breakpoints in DLBCL/HGBCL-MYC/BCL2 uncovered a subset of t(8;22) translocations causally linked to aberrant RAG-dependent IG-lambda (IGL) V gene editing [5]. These findings support the existence of a GC-experienced t(14;18)+ DLBCL/HGBCL-MYC/BCL2 precursor cell that, upon RAG1/2 re-expression and BCR receptor editing, becomes vulnerable to IGL::MYC rearrangements (and possibly also to other MYC translocations), ultimately driving lymphoma emergence. However, the presence of RAG-expressing DLBCL/HGBCL-MYC/BCL2 precursor cells remains unproven.