title: Analysis of IgV gene mutations in B cell chronic lymphocytic leukaemia according to antigen-driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery.
abstract: Cases of B-cell chronic lymphocytic leukaemia (B-CLL) with mutated (M) IgV(H) genes have a better prognosis than unmutated (UM) cases. We analysed the IgV(H) mutational status of B-CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B-CLLs, 124 cases were examined for IgV(H) gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity-determining regions as evidence of antigen-driven selection; this identified three B-CLL subsets: significantly mutated (sM), with evidence of antigen-driven selection, not significantly mutated (nsM) and UM, without such evidence and IgV(H) gene per cent mutations above or below the 2% cut-off. sM B-CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgV(H) genes. sM, nsM and UM B-CLL were also characterized for the biased usage of IgV(H) families, intraclonal IgV(H) gene diversification, preference of mutations to target-specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase zeta and eta and activation-induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B-CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B-CLL.
authors.affiliation: Clinical and Experimental Haematology Research Unit, De Gironcoli Hospital, Conegliano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Degan
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
authors.forename: Michele Dal
authors.initials: MD
authors.lastname: Bo
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.forename: Paola
authors.initials: P
authors.lastname: Nanni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rupolo
authors.forename: Agostino
authors.initials: A
authors.lastname: Steffan
authors.forename: Vincenza
authors.initials: V
authors.lastname: Attadia
authors.forename: Pier Ferruccio
authors.initials: PF
authors.lastname: Ballerini
authors.forename: Daniela
authors.initials: D
authors.lastname: Damiani
authors.forename: Carlo
authors.initials: C
authors.lastname: Pucillo
authors.forename: Giovanni Del
authors.initials: GD
authors.lastname: Poeta
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D027041:Somatic Hypermutation, Immunoglobulin; D015996:Survival Rate
chemical_list: D007135:Immunoglobulin Variable Region; D004259:DNA-Directed DNA Polymerase