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

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

Development of therapeutic approaches to target Epstein Barr virus related disease

Abstract not currently available

Therapeutic Approaches to Targeting EBV Related Disease

Epstein-Barr virus infection is associated with several lymphoid and epithelial malignancies. The replication and persistence of the EBV genome in latently infected cells is dependent on the homodimer formation of EBV nuclear antigen 1 (EBNA1) and it’s binding to the cognate EBV OriP element. Current chemotherapeutic treatments of EBV-positive malignancies are not specific to the EBV status of the disease. EBNA1 has been considered as a driver for oncogenesis and is consistently detected in all EBVV-associated tumours. However, EBNA1 is able to regulate it’s own expression, both at transcriptional and translational levels. Our work focuses on controlling EBV-associated disease through the inhibition of EBNA1 expression or function. In order to inhibit function, the aim is to disrupt EBNA1 homodimer formation. To do this, we have designed and synthesised small peptides aimed to prevent EBNA1 homodimer formation and destabilise existing homodimers. These putative dimer inhibitory peptides (DIP), designed to mimic the proline-rich loop of the protein (which is thought to stabilise the dimer) are attached to the cell penetrating peptide TAT, to act as competitive inhibitors in the nucleus of infected cells. Data will be presented on the effect of these peptides in multiple EBV dependent and independent tumour B cell lines, with respect to cell penetration, cell viability and protein dimerisation. We have also been investigating agents that interfere with the unique self-regulatory mechanism of EBNA1 expression, and their potential as therapeutic drugs. These data will be presented. These studies may underpin novel approaches to treating EBV positive and dependent disease by inhibiting viral persistence, and possibly the cell survival properties of EBNA1

Development of Therapeutic Approaches to Targeting EBV Related Disease

No abstract available

Therapeutic Approaches to Targeting EBV Related Disease

Epstein-Barr virus infection is associated with several lymphoid and epithelial malignancies. The replication and persistence of the EBV genome in latently infected cells is dependent on the homodimer formation of EBV nuclear antigen 1 (EBNA1) and it’s binding to the cognate EBV OriP element. Current chemotherapeutic treatments of EBV-positive malignancies are not specific to the EBV status of the disease. EBNA1 has been considered as a driver for oncogenesis and is consistently detected in all EBVV-associated tumours. However, EBNA1 is able to regulate it’s own expression, both at transcriptional and translational levels. Our work focuses on controlling EBV-associated disease through the inhibition of EBNA1 expression or function. In order to inhibit function, the aim is to disrupt EBNA1 homodimer formation. To do this, we have designed and synthesised small peptides aimed to prevent EBNA1 homodimer formation and destabilise existing homodimers. These putative dimer inhibitory peptides (DIP), designed to mimic the proline-rich loop of the protein (which is thought to stabilise the dimer) are attached to the cell penetrating peptide TAT, to act as competitive inhibitors in the nucleus of infected cells. Data will be presented on the effect of these peptides in multiple EBV dependent and independent tumour B cell lines, with respect to cell penetration, cell viability and protein dimerisation. We have also been investigating agents that interfere with the unique self-regulatory mechanism of EBNA1 expression, and their potential as therapeutic drugs. These data will be presented. These studies may underpin novel approaches to treating EBV positive and dependent disease by inhibiting viral persistence, and possibly the cell survival properties of EBNA1

Development of Therapeutic Approaches to Targeting EBV Related Disease

No abstract available

Therapeutic Approaches to Targetting Epstein-Barr Virus Related Disease

Epstein-Barr virus infection is associated with several lymphoid and epithelial malignancies. The replication and persistence of the EBV genome in latently infected cells is dependent on the homodimer formation of EBV nuclear antigen 1 (EBNA1) and it’s binding to the cognate EBV OriP element. Current chemotherapeutic treatments of EBV-positive malignancies are non-specific to the EBV status of the disease. We have designed and synthesised eight small peptides using Solid Phase Peptide Synthesis, aimed to prevent EBNA1 homodimer formation and destabilise existing homodimers. These putative dimer inhibitory peptides (DIP), designed to mimic the proline loop of the protein (which stabilises the dimer) are attached to the cell penetrating peptide TAT, to act as competitive inhibitors in the nucleus of infected cells. Data will be presented on the effect of these peptides on multiple EBV dependent and independent tumour B cell lines, with respect to cell penetration, cell viability and protein dimerisation. These peptides may provide a novel approach to treating EBV positive and dependent disease by inhibiting viral persistence, and possibly the cell survival properties of EBNA1

Development of Therapeutic Approaches to Targeting Epstein-Barr virus Related Malignancies

No abstract available

Therapeutic Approaches to Targetting Epstein-Barr Virus Related Disease

Epstein-Barr virus infection is associated with several lymphoid and epithelial malignancies. The replication and persistence of the EBV genome in latently infected cells is dependent on the homodimer formation of EBV nuclear antigen 1 (EBNA1) and it’s binding to the cognate EBV OriP element. Current chemotherapeutic treatments of EBV-positive malignancies are non-specific to the EBV status of the disease. We have designed and synthesised eight small peptides using Solid Phase Peptide Synthesis, aimed to prevent EBNA1 homodimer formation and destabilise existing homodimers. These putative dimer inhibitory peptides (DIP), designed to mimic the proline loop of the protein (which stabilises the dimer) are attached to the cell penetrating peptide TAT, to act as competitive inhibitors in the nucleus of infected cells. Data will be presented on the effect of these peptides on multiple EBV dependent and independent tumour B cell lines, with respect to cell penetration, cell viability and protein dimerisation. These peptides may provide a novel approach to treating EBV positive and dependent disease by inhibiting viral persistence, and possibly the cell survival properties of EBNA1

Development of Therapeutic Approaches to Targeting Epstein-Barr virus Related Malignancies

No abstract available