Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen

Lesley-Ann Sutton, Efterpi Kostareli, Anastasia Hadzidimitriou, Nikos Darzentas, Athanasios Tsaftaris, Achilles Anagnostopoulos, Richard Rosenquist, Kostas Stamatopoulos

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

Abstract

Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen recognition through the clonotypic B-cell receptors (BCRs). However, it is still unclear whether antigen involvement is restricted to the malignant transformation phase or whether the putative antigen(s) may continuously trigger the CLL clone and affect not only the progenitor cell but also the leukemic cells themselves. To address this issue, we conducted a large-scale subcloning study of rearranged immunoglobulin heavy variable (IGHV) genes of diverse mutational status from 71 CLL cases (total, 1496 subcloned sequences), belonging to both the common IgM/IgD variant and the rare IgG-positive variant. Although most cases showed no or low levels of intraclonal diversification (ID), we report intense ID in the IGHV genes of selected cases, especially a subgroup of 13 IgG-switched cases expressing stereotyped, mutated IGHV4-34 rearrangements (subset 4). We demonstrate that the ID evident in subset 4 cases cannot be attributed to IGHV4-34 usage, IGHV gene-mutated status, class-switch recombination, or BCR stereotypy in general; rather, it represents a unique phenomenon strongly correlated with the distinctive BCR of subset 4. In such cases, the observed ID patterns may imply a stereotyped response to an active, ongoing interaction with antigen(s).

Original languageEnglish
Pages (from-to)4460-8
Number of pages9
JournalBlood
Volume114
Issue number20
DOIs
Publication statusPublished - 12 Nov 2009

Keywords

  • Amino Acid Sequence
  • Antigens/immunology
  • Base Sequence
  • Clone Cells
  • Genes, Immunoglobulin Heavy Chain/genetics
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell/genetics
  • Molecular Sequence Data
  • Polymerase Chain Reaction

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