Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B cells

Fabio Ghiotto, Paolo Marcatili, Claudya Tenca, Maria Grazia Calevo, Xiao Jie Yan, Emilia Albesiano, Davide Bagnara, Monica Colombo, Giovanna Cutrona, Charles C. Chu, Fortunato Morabito, Silvia Bruno, Manlio Ferrarini, Anna Tramontano, Franco Fais, Nicholas Chiorazzi

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1188-1195
Number of pages8
JournalMolecular medicine (Cambridge, Mass.)
Volume17
Issue number11
DOIs
Publication statusPublished - Nov 2011

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B-Cell Chronic Lymphocytic Leukemia
Immunoglobulins
Light
Complementarity Determining Regions
Mutation
Mutation Rate
Clone Cells
Immunoglobulin Variable Region
B-Lymphocytes
Immunoglobulin Genes
Amino Acids

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B cells. / Ghiotto, Fabio; Marcatili, Paolo; Tenca, Claudya; Calevo, Maria Grazia; Yan, Xiao Jie; Albesiano, Emilia; Bagnara, Davide; Colombo, Monica; Cutrona, Giovanna; Chu, Charles C.; Morabito, Fortunato; Bruno, Silvia; Ferrarini, Manlio; Tramontano, Anna; Fais, Franco; Chiorazzi, Nicholas.

In: Molecular medicine (Cambridge, Mass.), Vol. 17, No. 11, 11.2011, p. 1188-1195.

Research output: Contribution to journalArticle

Ghiotto, F, Marcatili, P, Tenca, C, Calevo, MG, Yan, XJ, Albesiano, E, Bagnara, D, Colombo, M, Cutrona, G, Chu, CC, Morabito, F, Bruno, S, Ferrarini, M, Tramontano, A, Fais, F & Chiorazzi, N 2011, 'Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B cells', Molecular medicine (Cambridge, Mass.), vol. 17, no. 11, pp. 1188-1195. https://doi.org/10.2119/molmed.2011.00104
Ghiotto, Fabio ; Marcatili, Paolo ; Tenca, Claudya ; Calevo, Maria Grazia ; Yan, Xiao Jie ; Albesiano, Emilia ; Bagnara, Davide ; Colombo, Monica ; Cutrona, Giovanna ; Chu, Charles C. ; Morabito, Fortunato ; Bruno, Silvia ; Ferrarini, Manlio ; Tramontano, Anna ; Fais, Franco ; Chiorazzi, Nicholas. / Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B cells. In: Molecular medicine (Cambridge, Mass.). 2011 ; Vol. 17, No. 11. pp. 1188-1195.
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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 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.",
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AU - Bagnara, Davide

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