IgG-Switched cll has a distinct immunogenetic signature from the common md variant: Ontogenetic implications

Anna Vardi, Andreas Agathangelidis, Lesley Ann Sutton, Maria Chatzouli, Lydia Scarfòo, Larry Mansouri, Vassiliki Douka, Achilles Anagnostopoulos, Nikos Darzentas, Richard Rosenquist, Paolo Ghia, Chrysoula Belessi, Kostas Stamatopoulos

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Immunoglobulin G-switched chronic lymphocytic leukemia (G-CLL) is a rare variant of CLL, whose origin and ontogenetic relationship to the common IgM/IgD (MD-CLL) variant remains undefined. Here, we sought for clues about the ontogeny of G-CLL versus MD-CLL by profiling the relevant IG gene repertoires. Experimental Design: Using purpose-built bioinformatics methods, we performed detailed immunogenetic profiling of a multinational CLL cohort comprising 1,256 cases, of which 1,087 and 169 expressed IG mu/delta and gamma heavy chains, respectively. Results: G-CLL has a highly skewed IG gene repertoire that is distinct from MD-CLL, especially in terms of (i) overuse of the IGHV4-34 and IGHV4-39 genes and (ii) differential somatic hypermutation (SHM) load. Repertoire differences were also found when comparing subgroups with similarSHMstatus and were mainly attributed to the exclusive representation in G-CLL of two major subsets with quasi-identical (stereotyped) B-cell receptors. These subsets, namely #4 (IGHV4-34/IGKV2-30) and #8 (IGHV4-39/IGKV1(D)-39), were found to display sharply contrasting SHM and clinical behavior. Conclusions: G-CLL exhibits an overall distinct immunogenetic signature from MD-CLL, prompting speculations about distinct ontogenetic derivation and/or immune triggering. The reasons underlying the differential regulation of SHM among G-CLL cases remain to be elucidated. Clin Cancer Res; 20(2); 323-30.

Original languageEnglish
Pages (from-to)323-330
Number of pages8
JournalClinical Cancer Research
Volume20
Issue number2
DOIs
Publication statusPublished - Jan 15 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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