Activated mature B cells undergo enforced Sµ-3'RRrec in the λ-c-MYC mouse model

Abstract

The Sµ-3'RR recombination (Sµ-3'RRrec) in B cells, a genomic rearrangement occurring within the immunoglobulin heavy chain (IGH) locus is believed to lead to B cell receptor (BCR) loss. Its increased frequency in patients with chronic lymphocytic leukemia (CLL), especially those with high MYC expression, suggests c-MYC contribute to genetic instability during oncogenesis To explore c-MYC's role in enhancing Sµ-3'RRrec, the study used a λ-c-MYC transgenic (Tg) mouse model overexpressing MYC specifically in B cells, along with wild-type (WT) and activation-induced cytidine deaminase knockout (AIDKO) mice. The results show that MYC overexpression leads to a higher proportion of BCR− B cells, which undergo Sµ-3'RRrec. These BCR− B cells are sensitive to apoptosis and represent activated mature B cells that likely originate outside the germinal center (GC). Further analysis demonstrated that Sµ-3'RRrec occurs more frequently in BCR− B cells than BCR+ B cells. These BCR− cells also display a polyclonal IGHV repertoire, indicating their diverse origins. Additionally, we observed changes in the class switch recombination (CSR) junctions in BCR− B cells, hinting at DNA repair differences.