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.

EBV-miR-BHRF1-1 Targets p53 Gene: Potential Role in Epstein-Barr Virus Associated Chronic Lymphocytic Leukemia

“…The study reported by Li et al [11] has described p53 as a functionally relevant target of EBV-BHRF1-1 to potentiate lytic replication of EBV in nasopharyngeal carcinoma. Furthermore, several studies have demonstrated that lymphomas driven by EBV are dependent upon MDM2 which can further regulate p53 gene [15,16]. We also found that higher expressions of EBV-BHRF1-1 were associated with lower p53 and p53 protein which can reflect the functional role of p53 gene in our CLL patients.…”

Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomas

“…Curiously, αDEC-E1 plus Adeno-E1-LMP vaccination led to only a modest increase in EBNA1-specific CD8 + T cells. In recent studies, it was shown that mice with primary BL-E1 tumors had an imbalanced CD4 + /CD8 + T cell ratio in the spleen, which was lower compared with mice without tumors (36). We observed a slight decrease of both CD4 + and CD8 + T cells in tumor-bearing spleens compared with spleens in tumor-free mice, and this was most visible in the PBS-treated mice (Supplemental Figure 4B).…”

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

“…However, its host chromatin binding activity also mediates some growth transforming activity 39 . Accordingly, EBNA1 expression in murine B cells induces tumors with some similarities to Burkitt's lymphoma 40 . EBNA2 induces the transcription of the cellular oncogene MYC and compromises lytic EBV replication by inducing Tet methylcytosine dioxygenase 2 (TET2) expression, thereby blocking methylation sites for BZLF1 binding 16,17,41 .…”