title: An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Bikos
authors.affiliation: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karypidou
authors.affiliation: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Stalika
authors.affiliation: 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: Panagiotis
authors.initials: P
authors.lastname: Baliakas
authors.affiliation: Institute of Applied Biosciences, CERTH, 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.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Information Technologies Institute, CERTH, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Papadopoulos
authors.affiliation: Division of Experimental Oncology and Department of Onco-Hematology, Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Andreas
authors.initials: A
authors.lastname: Agathangelidis
authors.affiliation: Information Technologies Institute, CERTH, Thessaloniki, Greece.
authors.forename: Evdoxia
authors.initials: E
authors.lastname: Papadopoulou
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.
authors.forename: Zadie
authors.initials: Z
authors.lastname: Davis
authors.affiliation: Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Algara
authors.affiliation: Hematopathology Department, Evangelismos Hospital, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kanellis
authors.affiliation: Department of Pathology and Hematology, Hospices Civils de Lyon, Universite Lyon, Lyon, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Traverse-Glehen
authors.affiliation: Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mollejo
authors.affiliation: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Pathology Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Section of Haemato-Oncology, Institute of Cancer Research, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: Section of Haemato-Oncology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.affiliation: Hospital Universitario Marques de Valdecilla, Santander, Cantabria, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Hematopathology Department, Evangelismos Hospital, Athens, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Papadaki
authors.affiliation: Division of Experimental Oncology and Department of Onco-Hematology, Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
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: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Nikos
authors.initials: N
authors.lastname: Darzentas
authors.affiliation: Information Technologies Institute, CERTH, Thessaloniki, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tzovaras
authors.affiliation: Hematology Department, Nikea General Hospital, Pireaus, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
authors.affiliation: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hadzidimitriou
authors.affiliation: 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. kostas.stamatopoulos@gmail.com.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000941:Antigens / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D020869:Gene Expression Profiling; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D013160:Splenic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D059467:Transcriptome
chemical_list: D000941:Antigens; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell