Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia

Anastasia Hadzidimitriou, Nikos Darzentas, Fiona Murray, Tanja Smilevska, Eleni Arvaniti, Cristina Tresoldi, Athanasios Tsaftaris, Nikolaos Laoutaris, Achilles Anagnostopoulos, Frederic Davi, Paolo Ghia, Richard Rosenquist, Kostas Stamatopoulos, Chrysoula Belessi

Research output: Contribution to journalArticlepeer-review

Abstract

We analyzed somatic hypermutation (SHM) patterns and secondary rearrangements involving the immunoglobulin (IG) light chain (LC) gene loci in 725 patients with chronic lymphocytic leukemia (CLL). Important differences regarding mutational load and targeting were identified in groups of sequences defined by IGKV/ IGLV gene usage and/or K/LCDR3 features. Recurrent amino acid (AA) changes in the IGKV/IGLV sequences were observed in subsets of CLL cases with stereotyped B-cell receptors (BCRs), especially those expressing IGHV3-21/ IGLV3-21 and IGHV4-34/IGKV2-30 BCRs. Comparison with CLL LC sequences carrying heterogeneous K/LCDR3s or non-CLL LC sequences revealed that distinct amino acid changes appear to be "CLL-biased." Finally, a significant proportion of CLL cases with monotypic LC expression were found to carry multiple potentially functional LC rearrangements, alluding to active, (auto)antigen-driven receptor editing. In conclusion, SHM targeting in CLL LCs is just as precise and, likely, functionally driven as in heavy chains. Secondary LC gene rearrangements and subset-biased mutations in CLL LC genes are strong indications that LCs are crucial in shaping the specificity of leukemic BCRs, in association with defined heavy chains. Therefore, CLL is characterized not only by stereotyped HCDR3 and heavy chains but, rather, by stereotyped BCRs involving both chains, which generate distinctive antigen-binding grooves.

Original languageEnglish
Pages (from-to)403-411
Number of pages9
JournalBlood
Volume113
Issue number2
DOIs
Publication statusPublished - Jan 8 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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