title: Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B cells.
abstract: B-cell chronic lymphocytic leukemia (CLL) patients display leukemic clones bearing either germline or somatically mutated immunoglobulin heavy variable (IGHV ) genes. Most information on CLL immunoglobulins (Igs), such as the definition of stereotyped B-cell receptors (BCRs), was derived from germline unmutated Igs. In particular, detailed studies on the distribution and nature of mutations in paired heavy- and light-chain domains of CLL clones bearing mutated Igs are lacking. To address the somatic hyper-mutation dynamics of CLL Igs, we analyzed the mutation pattern of paired IGHV-diversity-joining (IGHV-D-J ) and immunoglobulin kappa/lambda variable-joining (IGK/LV-J ) rearrangements of 193 leukemic clones that displayed ≥ 2% mutations in at least one of the two immunoglobulin variable (IGV ) genes (IGHV and/or IGK/LV ). The relationship between the mutation frequency in IGHV and IGK/LV complementarity determining regions (CDRs) and framework regions (FRs) was evaluated by correlation analysis. Replacement (R) mutation frequency within IGK/LV chain CDRs correlated significantly with mutation frequency of paired IGHV CDRs in λ but not κ isotype CLL clones. CDRs of IGKV-J rearrangements displayed a lower percentage of R mutations than IGHVs. The frequency/pattern of mutations in kappa CLL Igs differed also from that in κ-expressing normal B cells described in the literature. Instead, the mutation frequency within the FRs of IGHV and either IGKV or IGLV was correlated. Notably, the amount of diversity introduced by replaced amino acids was comparable between IGHVs and IGKVs. The data indicate a different mutation pattern between κ and λ isotype CLL clones and suggest an antigenic selection that, in κ samples, operates against CDR variation.
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ghiotto
authors.forename: Paolo
authors.initials: P
authors.lastname: Marcatili
authors.forename: Claudya
authors.initials: C
authors.lastname: Tenca
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Calevo
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.forename: Emilia
authors.initials: E
authors.lastname: Albesiano
authors.forename: Davide
authors.initials: D
authors.lastname: Bagnara
authors.forename: Monica
authors.initials: M
authors.lastname: Colombo
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cutrona
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.forename: Fortunato
authors.initials: F
authors.lastname: Morabito
authors.forename: Silvia
authors.initials: S
authors.lastname: Bruno
authors.forename: Manlio
authors.initials: M
authors.lastname: Ferrarini
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.forename: Franco
authors.initials: F
authors.lastname: Fais
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology*; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D017434:Protein Structure, Tertiary
chemical_list: D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region