Stereotyped CLL-like immunoglobulin rearrangements in healthy repertoires: implications for leukemogenesis

Chronic lymphocytic leukemia (CLL) is characterized by a highly biased B-cell receptor (BcR) immunoglobulin repertoire and by recurrent stereotyped receptors defined as quasi-identical BcR recurring in unrelated patients. High-throughput sequencing studies have shown that immunoglobulin rearrangements resembling these CLL stereotypes can also be detected in healthy individuals. Beyond their relevance to leukemogenesis, these findings provide a distinctive opportunity to investigate how recurrent BcR configurations are generated, selected, and maintained during normal B-cell development. In this review, we examine the occurrence of CLL-like stereotyped immunoglobulin rearrangements in healthy repertoires and discuss their implications for normal B-cell biology. Available studies indicate that these rearrangements are physiological components of the repertoire, detectable in cord blood, bone marrow, spleen, and peripheral blood, and distributed across transitional, naïve, marginal zone-like, and memory B-cell compartments. Their representation is non-random and subset specific, suggesting that different receptor configurations are subject to distinct developmental, tolerance, and antigen-driven selection pressures. Some rearrangements are preferentially associated with antigen-inexperienced compartments, whereas others are more frequently found in post-germinal-center populations, partially recapitulating the mutational context of their leukemic counterparts. However, healthy B cells generally lack the stringent light-chain restriction observed in established CLL subsets, indicating that leukemic stereotypy results from additional receptor refinement and clonal selection. Overall, the study of CLL-like stereotypes in healthy individuals extends beyond the identification of putative leukemic precursors. It reveals how convergent receptor architectures arise within physiological immunity, how autoreactive or polyreactive configurations may escape complete censoring, and how normal B-cell repertoires accommodate recurrent immunogenetic solutions without necessarily progressing to malignancy.