Intraclonal heterogeneity in mature B-cell malignancies: The perspective of immunogenetics.

Abstract

Intraclonal heterogeneity is increasingly recognized as a central determinant of evolutionary fitness in B-cell malignancies. Since these tumors arise from lineages that naturally diversify through V(D)J recombination, somatic hypermutation (SHM), and class switch recombination (CSR), their malignant counterparts retain and/or aberrantly reactivate these processes, generating antigen receptor repertoires with complex subclonal architectures. Advances in next-generation and single-cell immunogenetics have revealed that intraclonal heterogeneity arising from variations in IG genes is neither random nor incidental: it reflects ongoing antigenic engagement, microenvironmental pressures, and selection for functional B-cell receptor immunoglobulin (BcR IG) configurations that promote survival and, conceivably, also therapy escape. Here, we provide an overview of BcR IG intraclonal heterogeneity across malignancies of mature B cells, focusing on how it may relate to tumor evolution, immune surveillance, and treatment-induced bottlenecks. We also highlight methodological breakthroughs enabling high-resolution reconstruction of subclonal trajectories and discuss how intraclonal heterogeneity can be leveraged to refine risk stratification, measurable residual disease (MRD) assessment, and individualized treatment strategies.