AID Induces Intraclonal Diversity and Genomic Damage in CD86(+) Chronic Lymphocytic Leukemia Cells

Overview

Journal Eur J Immunol

Specialty Allergy & Immunology

Date 2014 Sep 3

PMID 25179679

Citations 16

Authors

Michael Huemer

Stefan Rebhandl

Nadja Zaborsky

Franz J Gassner

Stefan Hainzl

Lukas Weiss

Daniel Hebenstreit

Richard Greil

Roland Geisberger

Affiliations

Soon will be listed here.

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.

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