Antigen selection reflected in the subclonal architecture of the B-cell receptor immunoglobulin gene repertoire in splenic marginal zone lymphoma

Abstract

Almost one-third of all splenic marginal zone lymphoma (SMZL) cases express B-cell receptor immunoglobulin (BcR IG) encoded by the IGHV1-2*04 gene, implicating antigen selection in disease ontogeny. Evidence supporting this notion mostly derives from low-throughput sequencing approaches, which have limitations in capturing the full complexity of the BcR IG gene repertoire. This hinders the comprehensive assessment of the subclonal architecture of SMZL as shaped by antigen selection. To address this, we conducted a high-throughput immunogenetic investigation of SMZL aimed at the comprehensive characterization of the somatic hypermutation (SHM) and intraclonal diversification within the IG genes. We identified significant differences in the SHM and ID profiles between cases expressing the IGHV1-2*04 gene and those expressing other IGHV genes. Specifically, IGHV1-2*04 cases displayed (i) targeted SHM resulting in recurrent replacement SHMs, and (ii) significantly more pronounced intraclonal diversification, reflecting ongoing antigen selection. Overall, our findings suggest that SMZL cases expressing the IGHV1-2*04 gene have a distinct immunogenetic signature shaped by microenvironmental pressure on the clonotypic BcR IG, corroborating the idea that this group may represent a distinct molecular variant of SMZL.