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Journal of Virology, January 2007, p. 248-260, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01096-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells{triangledown}

Maria Leao,{dagger} Emma Anderton, Mark Wade,{ddagger} Kiran Meekings, and Martin J. Allday*

Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom

Received 29 May 2006/ Accepted 4 October 2006

Epstein-Barr virus (EBV) is associated with a number of human cancers, and latent EBV gene expression has been reported to interfere with cell cycle checkpoints and cell death pathways. Here we show that latent EBV can compromise the mitotic spindle assembly checkpoint and rescue Burkitt's lymphoma (BL)-derived cells from caspase-dependent cell death initiated in aberrant mitosis. This leads to unscheduled mitotic progression, resulting in polyploidy and multi- and/or micronucleation. The EBV latent genes responsible for this phenotype are expressed from the P3HR1 strain of virus and several viruses with similar genomic deletions that remove the EBNA2 gene. Although EBNA2 and the latent membrane proteins are not expressed, the EBNA3 proteins are present in these BL cells. Survival of the EBV-positive cells is not consistently associated with EBV lytic gene expression or with the genes that are expressed in EBV latency I BL cells (i.e., EBNA1, EBERs, and BARTs) but correlates with reduced expression of the cellular proapoptotic BH3-only protein Bim. These data suggest that a subset of latent EBV gene products may increase the likelihood of damaged DNA being inherited because of the impaired checkpoint and enhanced survival capacity. This could lead to greater genetic diversity in progeny cells and contribute to tumorigenesis. Furthermore, since it appears that this restricted latent EBV expression interferes with the responses of Burkitt's lymphoma-derived cells to cytotoxic drugs, the results of this study may have important therapeutic implications in the treatment of some BL.

* Corresponding author. Mailing address: Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44 (0) 2075943836. Fax: 44 (0) 2075943973. E-mail: m.allday{at}imperial.ac.uk.

{triangledown} Published ahead of print on 11 October 2006.

{dagger} Present address: Ludwig Institute for Cancer Research, Cell and Molecular Biology, Courtauld Building, 91 Riding House Street, London W1 W7BS, United Kingdom.

{ddagger} Present address: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.

Journal of Virology, January 2007, p. 248-260, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01096-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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