PURPOSE: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. EXPERIMENTAL DESIGN: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). RESULTS: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). CONCLUSIONS: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Haematology Royal Bournemouth Hospital Bournemouth United Kingdom

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Pathology and Hematology Hospices Civils de Lyon Universite Lyon Lyon France

Department of Pathology Hospital Virgen de la Salud Toledo Spain

Division of Experimental Oncology and Department of Onco Hematology Università Vita Salute San Raffaele and Istituto Scientifico San Raffaele Milan Italy

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece Central European Institute of Technology Masaryk University Brno Czech Republic

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece Institute of Applied Biosciences CERTH Thessaloniki Greece

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece Institute of Applied Biosciences CERTH Thessaloniki Greece Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Hematology Department Nikea General Hospital Pireaus Greece

Hematopathology Department Evangelismos Hospital Athens Greece

Hospital Universitario Marques de Valdecilla Santander Cantabria Spain

Information Technologies Institute CERTH Thessaloniki Greece

Institute of Applied Biosciences CERTH Thessaloniki Greece

Institute of Applied Biosciences CERTH Thessaloniki Greece Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Pathology Unit San Raffaele Scientific Institute Milan Italy

Section of Haemato Oncology Institute of Cancer Research London United Kingdom

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