Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2

AlQarni, S. et al. (2018) Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2. Oncogene, 37, pp. 3998-4012. (doi:10.1038/s41388-018-0147-x) (PMID:29691476)

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Abstract

Epstein-Barr virus (EBV)-associated Burkitt's lymphoma is characterised by the deregulation of c-Myc expression and a restricted viral gene expression pattern in which the EBV nuclear antigen-1 (EBNA1) is the only viral protein to be consistently expressed. EBNA1 is required for viral genome propagation and segregation during latency. However, it has been much debated whether the protein plays a role in viral-associated tumourigenesis. We show that the lymphomas which arise in EµEBNA1 transgenic mice are unequivocally linked to EBNA1 expression and that both C-Myc and Mdm2 deregulation are central to this process. Tumour cell survival is supported by IL-2 and there is a skew towards CD8-positive T cells in the tumour environment, while the immune check-point protein PD-L1 is upregulated in the tumours. Additionally, several isoforms of Mdm2 are upregulated in the EµEBNA1 tumours, with increased phosphorylation at ser166, an expression pattern not seen in Eµc-Myc transgenic tumours. Concomitantly, E2F1, Xiap, Mta1, C-Fos and Stat1 are upregulated in the tumours. Using four independent inhibitors of Mdm2 we demonstrate that the EµEBNA1 tumour cells are dependant upon Mdm2 for survival (as they are upon c-Myc) and that Mdm2 inhibition is not accompanied by upregulation of p53, instead cell death is linked to loss of E2F1 expression, providing new insight into the underlying tumourigenic mechanism. This opens a new path to combat EBV-associated disease.

Item Type:Articles
Additional Information:Funding contribution to the work includes former LRF (now Bloodwise) grants. AH was supported by a Wellcome Trust PhD studentship while at GU, KA is supported by a PhD BBSRC studentship. SA is, and YA was, supported by Saudi Arabian PhD scholarships.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tsimbouri, Dr Penelope and Wilson, Dr Joanna and Campbell, Mr Donald and Armfield, Kate and Alqarni, Sana and Herzyk, Dr Pawel and Drotar, Mr Mark
Authors: AlQarni, S., Al-Sheikh, Y., Campbell, D., Drotar, M., Hannigan, A., Boyle, S., Herzyk, P., Kossenkov, A., Armfield, K., Jamieson, L., Bailo, M., Lieberman, P. M., Tsimbouri, P., and Wilson, J. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Oncogene
Publisher:Nature Publishing Group
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:25 April 2018
Copyright Holders:Copyright © 2018 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Oncogene 37:3998-4012
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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