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AID induces intraclonal diversity and genomic damage in CD86(+) chronic lymphocytic leukemia cells
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Huemer, Michael, Rebhandl, Stefan, Zaborsky, Nadja, Gassner, Franz, Hainzl, Stefan, Weiss, Lukas, Hebenstreit, Daniel, Greil, Richard and Geisberger, Roland (2014) AID induces intraclonal diversity and genomic damage in CD86(+) chronic lymphocytic leukemia cells. European Journal of Immunology, Volume 44 (Number 12). pp. 3747-3757. doi:10.1002/eji.201344421 ISSN 0014-2980.
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Official URL: http://dx.doi.org/10.1002/eji.201344421
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.
| Item Type: | Journal Article | ||||||||||
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| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||
| Library of Congress Subject Headings (LCSH): | Chronic lymphocytic leukemia -- Treatment | ||||||||||
| Journal or Publication Title: | European Journal of Immunology | ||||||||||
| Publisher: | Wiley - V C H Verlag GmbH & Co. KGaA | ||||||||||
| ISSN: | 0014-2980 | ||||||||||
| Official Date: | December 2014 | ||||||||||
| Dates: |
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| Volume: | Volume 44 | ||||||||||
| Number: | Number 12 | ||||||||||
| Number of Pages: | 11 | ||||||||||
| Page Range: | pp. 3747-3757 | ||||||||||
| DOI: | 10.1002/eji.201344421 | ||||||||||
| Status: | Peer Reviewed | ||||||||||
| Publication Status: | Published | ||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||
| Date of first compliant deposit: | 29 December 2015 | ||||||||||
| Date of first compliant Open Access: | 29 December 2015 | ||||||||||
| Funder: | Fonds zur Förderung der Wissenschaftlichen Forschung (Austria) (FWF), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Paracelsus Medical University, SCRI-LIMCR, Salzburg (Austria) | ||||||||||
| Grant number: | P24619(FWF), SFB021 (FWF), T516-B13 (FWF), BB/L006340/1 (BBSRC), PMU-FFF E-12/16/084-EGG (PMU), |
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