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

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

Author information

1
Laboratory for Immunological and Molecular Cancer Research, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.

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

PMID:
25179679
PMCID:
PMC4276288
DOI:
10.1002/eji.201344421
[Indexed for MEDLINE]
Free PMC Article

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