title: Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases.
abstract: We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases.
authors.affiliation: Institute of Agrobiotechnology, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hadzidimitriou
authors.forename: Andreas
authors.initials: A
authors.lastname: Agathangelidis
authors.forename: Nikos
authors.initials: N
authors.lastname: Darzentas
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Delfau-Larue
authors.forename: Lone Bredo
authors.initials: LB
authors.lastname: Pedersen
authors.forename: Alba Navarro
authors.initials: AN
authors.lastname: Lopez
authors.forename: Antonis
authors.initials: A
authors.lastname: Dagklis
authors.forename: Paul
authors.initials: P
authors.lastname: Rombout
authors.forename: Kheira
authors.initials: K
authors.lastname: Beldjord
authors.forename: Arne
authors.initials: A
authors.lastname: Kolstad
authors.forename: Martin H
authors.initials: MH
authors.lastname: Dreyling
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: Athanasios
authors.initials: A
authors.lastname: Tsaftaris
authors.forename: Penelope
authors.initials: P
authors.lastname: Mavragani-Tsipidou
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Patricia
authors.initials: P
authors.lastname: Groenen
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.forename: Theodora
authors.initials: T
authors.lastname: Papadaki
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Christian
authors.initials: C
authors.lastname: Geisler
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Frederic
authors.initials: F
authors.lastname: Davi
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D000595:Amino Acid Sequence; D016000:Cluster Analysis; D015331:Cohort Studies; D000939:Epitopes / Q000235:genetics* / Q000502:physiology; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics / Q000502:physiology; D005803:Genes, Immunoglobulin / Q000235:genetics / Q000502:physiology; D006801:Humans; D007125:Immunogenetics / Q000379:methods; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data
chemical_list: D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region