AID induces intraclonal diversity and genomic damage in CD86(+) chronic lymphocytic leukemia cells

Eur J Immunol. 2014 Dec;44(12):3747-57. doi: 10.1002/eji.201344421. Epub 2014 Oct 18.

Abstract

The activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination of the Ig genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B-cell malignancies. Although it has been shown that AID is expressed in B-cell chronic lymphocytic leukemia (CLL), a clear analysis of in vivo AID activity in this B-cell malignancy remained elusive. In this study performed on primary human CLL samples, we report that, despite the presence of a dominant VDJ heavy chain region, a substantial intraclonal diversity was observed at VDJ as well as at IgM switch regions (Sμ), showing ongoing AID activity in vivo during disease progression. This AID-mediated heterogeneity was higher in CLL subclones expressing CD86, which we identified as the proliferative CLL fraction. Finally, CD86 expression correlated with shortened time to first treatment and increased γ-H2AX focus formation. Our data demonstrate that AID is active in CLL in vivo and thus, AID likely contributes to clonal evolution of CLL.

Keywords: Activation-induced deaminase (AID) • CD86 • Chronic lymphocytic leukemia (CLL) • Clonal evolution • Mutation.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-2 Antigen / immunology*
  • Cell Proliferation*
  • Cytidine Deaminase / immunology*
  • DNA Damage / immunology*
  • Female
  • Gene Expression Regulation, Leukemic / immunology
  • Genes, Immunoglobulin Heavy Chain / immunology
  • Histones / immunology
  • Humans
  • Immunoglobulin Switch Region / immunology
  • Immunoglobulin mu-Chains / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Neoplasm Proteins / immunology*

Substances

  • B7-2 Antigen
  • CD86 protein, human
  • H2AX protein, human
  • Histones
  • Immunoglobulin mu-Chains
  • Neoplasm Proteins
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase