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

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.

• Authors: Sana AlQarni, Yazeed Al-Sheikh, Donald Campbell, Mark Drotar, Adele Hannigan, Shelagh Boyle, Pawel Herzyk, Andrew Kossenkov, Kate Armfield, Lauren Jamieson, Mariarca Bailo, Paul M Lieberman, Penelope Tsimbouri, Joanna B Wilson
• Journal: Oncogene (Oncogene) Vol. 37 Issue 29 Pg. 3998-4012 (07 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29691476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• E2F1 Transcription Factor
• Epstein-Barr Virus Nuclear Antigens
• Interleukin-2
• Proto-Oncogene Proteins c-myc
• Tumor Suppressor Protein p53
• Mdm2 protein, mouse
• Proto-Oncogene Proteins c-mdm2
• EBV-encoded nuclear antigen 1

Topics

• Animals
• B7-H1 Antigen (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Cell Death (physiology)
• Cell Line
• E2F1 Transcription Factor (metabolism)
• Epstein-Barr Virus Infections (metabolism, virology)
• Epstein-Barr Virus Nuclear Antigens (metabolism)
• Gene Expression Regulation, Viral (physiology)
• Herpesvirus 4, Human (metabolism)
• Humans
• Interleukin-2 (metabolism)
• Lymphoma (metabolism, virology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation (physiology)