Mutation Pattern of Paired Immunoglobulin Heavy and Light Variable Domains in Chronic Lymphocytic Leukemia B Cells
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 hypermutation 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.
This work was supported in part by grants to G Cutrona and F Fais from Compagnia di San Paolo 4824 SD/CV, 2007.2880; to F Fais from Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG-10698) and Associazione “Davide Ciavattini” Onlus; to F Ghiotto from Fondazione Maria Piaggio Casarsa; to A Tramontano from the King Abdullah University of Science and Technology (KAUST), award number KUK-I1-012-43; to F Morabito from AIRC progetto RG6432, cofinanced by Carical, Fondazione “A. Scorza, Provincia di Cosenza”; and to N Chiorazzi from the National Cancer Institute (RO1 CA81554), from the National Center for Research Resources (M01 General Clinical Research Center grant RR018535), and from The Karches Foundation, The Prince Family Foundation, The Marks Foundation, The Jerome Levy Foundation, The Leon Levy Foundation and the Joseph Eletto Leukemia Research Fund. G Cutrona and F Fais would like to thank the Fondazione Internazionale in Medicina Sperimentale (FIRMS) for financial and administrative assistance.
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