CLL‐like stereotyped BCRs are equally produced in young and old healthy adults, share features of public clonotypes and may be stuck at a pre‐germinal centre stage

Summary Chronic lymphocytic leukaemia (CLL) is a B‐cell lymphoproliferative disorder with ~40% of cases harbouring stereotyped B‐cell receptors (BCRs), defined by common features in their immunoglobulin sequences. Major CLL stereotypes are associated with specific genetic abnormalities that may influence prognosis. To explore their physiological counterparts, we analyzed total circulating BCR repertoires from 69 healthy volunteers (HVs) aged 18–78 years. In healthy repertoires, mean abundances of ‘typical’ CLL‐like stereotyped immunoglobulins (CLS‐IG) and ‘non‐typical’ CLS‐IG (expected CDR3 sequences but different IGHV or IGHJ genes) were 0.053% and 0.46%, respectively, suggesting that CLL may arise from B cells expressing BCR patterns frequently shared between individuals. Stereotype distribution differed markedly from CLL cases: as an example, subset #2 was found in over 60% of HVs, while subset #1, the second most common in CLL, was absent. While typical CLS‐IGs were rare in HVs, they dominated in CLL. Then, we longitudinally analyzed BCR repertoires within sorted circulating B‐cell subpopulations in a second dataset. This revealed that the vast majority of healthy B cells carrying major CLS‐IGs appeared to be stuck at pre‐germinal centre stages. Similar to t(14;18) translocations in healthy individuals, stereotyped BCRs may lack intrinsic oncogenic potential and require additional selection events to drive CLL transformation.