Antigen selection reflected in the subclonal architecture of the B‐cell receptor immunoglobulin gene repertoire in splenic marginal zone lymphoma
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.
Authors
- Georgios Karakatsoulis (ORCID: https://orcid.org/0000-0002-8496-3087)
- Alessio Bruscaggin (ORCID: https://orcid.org/0009-0004-9938-0396)
- Alexandra Traverse‐Glehen (ORCID: https://orcid.org/0000-0002-3934-0120)
- Andreas Agathangelidis (ORCID: https://orcid.org/0000-0002-8467-7945)
- Nikolaos Pechlivanis (ORCID: https://orcid.org/0000-0003-2502-612X)
- Davide Rossi (ORCID: https://orcid.org/0000-0002-2837-1597)
- Anastasia Iatrou (ORCID: https://orcid.org/0000-0002-8995-4454)
- Triantafyllia Κoletsa (ORCID: https://orcid.org/0000-0002-4435-3532)
- Anastasia Chatzidimitriou (ORCID: https://orcid.org/0000-0002-8106-1846)
- Κώστας Σταματόπουλος (ORCID: https://orcid.org/0000-0001-8529-640X)
- Zadie Davis (ORCID: https://orcid.org/0000-0001-6959-4853)
- Aurélie Verney
- Laura Zaragoza‐Infante (ORCID: https://orcid.org/0000-0003-0207-257X)
- Maria Papaioannou (ORCID: https://orcid.org/0000-0003-3149-6523)
- Eleftheria Polychronidou
- Fotis Psomopoulos (ORCID: https://orcid.org/0000-0002-0222-4273)
- Valentin Junet (ORCID: https://orcid.org/0000-0002-6138-0612)
- Maria Karypidou
- Paolo Ghia (ORCID: https://orcid.org/0000-0003-3750-7342)
- David Oscier (ORCID: https://orcid.org/0000-0001-8486-2051)
- Valeria Spina
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Universitat Autònoma de Barcelona (ES)
- Centre National de la Recherche Scientifique (FR)
- Vita-Salute San Raffaele University (IT)
- Inserm (FR)
- National and Kapodistrian University of Athens (GR)
- Aristotle University of Thessaloniki (GR)
- Royal Bournemouth Hospital (GB)
- Karolinska Institutet (SE)
- Hospices Civils de Lyon (FR)
- Institute of Oncology Research (CH)
- IRCCS Ospedale San Raffaele (IT)
- Centre for Research and Technology Hellas (GR)
- Centre International de Recherche en Infectiologie (FR)
- Anaxomics (Spain) (ES)
Publication Details
- Journal
- HemaSphere
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1002/hem3.70147
- Citations
- 1
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.47
Funders
- European Commission
- Hellenic Foundation for Research and Innovation