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Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma

Oncogene volume 26, pages 5115–5123 (2007)Cite this article

Abstract

Epstein–Barr virus (EBV) has been implicated in the pathogenesis of human malignancies but the mechanisms of oncogenesis remain largely unknown. Genomic instability and chromosomal aberrations are hallmarks of malignant transformation. We report that EBV carriage promotes genomic instability in Burkitt's lymphoma (BL). Cytogenetic analysis of EBV− and EBV+ BL lines and their sublines derived by EBV conversion or spontaneous loss of the viral genome revealed a significant increase in dicentric chromosomes, chromosome fragments and chromatid gaps in EBV-carrying cells. Expression of EBV latency I was sufficient for this effect, whereas a stronger effect was observed in cells expressing latency III. Telomere analysis by fluorescent in situ hybridization revealed an overall increase of telomere size and prevalence of telomere fusion and double strand-break fusion in dicentric chromosomes from EBV+ cells. Phosphorylated H2AX, a reporter of DNA damage and ongoing repair, was increased in virus-carrying cells in the absence of exogenous stimuli, whereas efficient activation of DNA repair was observed in both EBV+ and EBV− cells following treatment with etoposide. These findings point to induction of telomere dysfunction and DNA damage as important mechanisms for EBV oncogenesis.

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Abbreviations

BL:

Burkitt's lymphoma

EBV:

Epstein–Barr virus

LCL EBV:

immortalized lymphoblastoid cell line

CIN:

chromosomal instability

DSB:

double-strand DNA breaks

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Acknowledgements

This study was supported by grants from the Swedish Cancer Society, the Swedish Medical Research Council and the Karolinska Institute, Stockholm, Sweden. SAK is supported by a PhD fellowship awarded by the Iranian Government. AS was supported by personal fellowship awarded by the Cancer Research Institute/Cancer Foundation, New York, USA.

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Author notes

  1. S A Kamranvar and B Gruhne: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

    S A Kamranvar, B Gruhne, A Szeles & M G Masucci

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  1. S A Kamranvar
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  2. B Gruhne
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  3. A Szeles
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  4. M G Masucci
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Correspondence to M G Masucci.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kamranvar, S., Gruhne, B., Szeles, A. et al. Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma. Oncogene 26, 5115–5123 (2007). https://doi.org/10.1038/sj.onc.1210324

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