title: Molecular evidence for antigen drive in the natural history of mantle cell lymphoma.
abstract: 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.
authors.affiliation: 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.
authors.forename: Aliki
authors.initials: A
authors.lastname: Xochelli
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: lesley.sutton@igp.uu.se.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Laboratory of B cell Neoplasia and Lymphoma Unit, Division of Molecular Oncology and Department of Onco-Hematology, Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Andreas
authors.initials: A
authors.lastname: Agathangelidis
authors.affiliation: Institute of Applied Biosciences, CERTH, Center for Research and Technology Hellas, Thessaloniki, Greece; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Stalika
authors.affiliation: Institute of Applied Biosciences, CERTH, Center for Research and Technology Hellas, Thessaloniki, Greece; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karypidou
authors.affiliation: Hematology Department, Nikea General Hospital, Piraeus, Greece.
authors.forename: Fotini
authors.initials: F
authors.lastname: Marantidou
authors.affiliation: Insititut d'investigacions biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Alba Navarro
authors.initials: AN
authors.lastname: Lopez
authors.affiliation: Information Technologies Institute, CERTH, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Papadopoulos
authors.affiliation: Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Supikova
authors.affiliation: Department of Pathology, Radboud University, Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Patricia
authors.initials: P
authors.lastname: Groenen
authors.affiliation: Biological Hematology Service, Hopital Pitie-Salpetriere, and UPMC Univ Paris 06, UMRS 1138, Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Boudjogra
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Sundstrom
authors.affiliation: Pathology Unit and Unit of Lymphoid Malignancies, Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Hana Skuhrova
authors.initials: HS
authors.lastname: Francova
authors.affiliation: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: Hematopathology Department, Evangelismos Hospital, Athens, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Papadaki
authors.affiliation: Information Technologies Institute, CERTH, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tzovaras
authors.affiliation: Laboratory of B cell Neoplasia and Lymphoma Unit, Division of Molecular Oncology and Department of Onco-Hematology, Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: II. Medizinische Klinik und Poliklinik, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.affiliation: Biological Hematology Service, Hopital Pitie-Salpetriere, and UPMC Univ Paris 06, UMRS 1138, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Davi
authors.affiliation: Insititut d'investigacions biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Institute of Applied Biosciences, CERTH, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hadzidimitriou
authors.affiliation: Hematology Department, Nikea General Hospital, Piraeus, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
authors.affiliation: Institute of Applied Biosciences, CERTH, Center for Research and Technology Hellas, Thessaloniki, Greece; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003564:Cytidine Deaminase / Q000378:metabolism*; D006801:Humans; D007135:Immunoglobulin Variable Region; D020522:Lymphoma, Mantle-Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D027041:Somatic Hypermutation, Immunoglobulin; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007135:Immunoglobulin Variable Region; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase