To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-ΔE4a, AID-ΔE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.

2 Medizinische Klinik und Poliklinik University Hospital Schleswig Holstein Kiel Germany

Biological Hematology Service Hopital Pitie Salpetriere and UPMC Univ Paris 06 UMRS 1138 Paris France

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

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Pathology Radboud University Nijmegen Medical Centre Nijmegen the Netherlands

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department Nikea General Hospital Piraeus Greece

Hematopathology Department Evangelismos Hospital Athens Greece

Information Technologies Institute CERTH Center for Research and Technology Hellas Thessaloniki Greece

Insititut d'investigacions biomèdiques August Pi i Sunyer Hospital Clínic University of Barcelona Barcelona Spain

Institute of Applied Biosciences CERTH Center for Research and Technology Hellas Thessaloniki Greece

Laboratory of B cell Neoplasia and Lymphoma Unit Division of Molecular Oncology and Department of Onco Hematology Università Vita Salute San Raffaele Milan Italy

Pathology Unit and Unit of Lymphoid Malignancies Istituto Scientifico San Raffaele Milan Italy

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$a Xochelli, Aliki $u Institute of Applied Biosciences, CERTH, Center for Research and Technology Hellas, Thessaloniki, Greece; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

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$a Molecular evidence for antigen drive in the natural history of mantle cell lymphoma / $c A. Xochelli, LA. Sutton, A. Agathangelidis, E. Stalika, M. Karypidou, F. Marantidou, AN. Lopez, G. Papadopoulos, J. Supikova, P. Groenen, M. Boudjogra, C. Sundstrom, M. Ponzoni, HS. Francova, A. Anagnostopoulos, S. Pospisilova, T. Papadaki, D. Tzovaras, P. Ghia, C. Pott, F. Davi, E. Campo, R. Rosenquist, A. Hadzidimitriou, C. Belessi, K. Stamatopoulos,

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$a To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-ΔE4a, AID-ΔE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.

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