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) (PMCID:PMC6054874)

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: Wilson, Professor Joanna and Campbell, Mr Donald and Tsimbouri, Dr Monica and Armfield, Kate and Herzyk, Dr Pawel and Drotar, Mr Mark and Alqarni, Sana
• 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 > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; 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