Department of Medicine

Oncogenic Herpesviruses - Professor Martin Allday

Group leader - Professor Martin Allday

Use of real time Quantitative-PCR to investigate gene expression in EBV-carrying tumour cells

Use of real time Quantitative-PCR to investigate gene expression in EBV-carrying tumour cells

A significant subset of viruses produce what are known as persistent infections. This means that after primary infection the host carries the virus for life, generally with no obvious symptoms and in a state of equilibrium with the immune system. Such long-term, intimate relationships between virus and host can – on rare occasions (often associated with impairment of the immune system) – result in cancer. For example in humans Epstein-Barr virus (EBV) is associated with several B cell lymphomas and carcinomas, Hepatitis B and C viruses are linked to hepatocellular carcinoma and Karposi’s Sarcoma (KS)-associated virus (KSHV) is involved in the pathogenesis of KS and two B cell lymphomas. We are interested in the circumstances that lead to the development of virus-associated cancers and specifically the contribution EBV makes to the pathogenesis of various B cell lymphomas. We are trying to understand how this relates to normal persistence of the virus in a latent form and whether the virus can provide specific targets for therapeutic intervention.

Current Research Themes:

What roles do a family of EBV nuclear proteins (EBNAs 3A, 3B and 3C) play in re-programming B cells to make them and their progeny more likely to become cancerous?

How do these proteins help overcome the ‘oncogenic stress’ and DNA damage response induced by infection of B cells by EBV in vitro?

How do EBNAs 3A, 3B and 3C interact with components of the polycomb group protein (PcG) system and other chromatin modifying complexes, to epigenetically regulate host and viral gene expression?

What roles do the EBNA3 proteins play in EBV persistence, immune surveillance and lymphomagenesis in vivo? umour cells

Funding and collaborators:

The Wellcome Trust (through a Senior Investigator Award), Leukaemia & Lymphoma Research Fund (LLRF), and Singapore Government (A*) fund our research. For the in vivo pathogenesis and immune surveillance studies, we have a close collaboration with Professor Christian Munz, University of Zurich.

Selected recent publications:

BIM promoter directly targeted by EBNA3C in polycomb-mediated repression by EBV. Paschos K, Parker GA, Watanatanasup E, White RE, Allday MJ. Nucleic Acids Res. 2012 Aug;40(15):7233-46. doi: 10.1093/nar/gks391. Epub 2012 May 14.

EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. White RE, Rämer PC, Naresh KN, Meixlsperger S, Pinaud L, Rooney C, Savoldo B, Coutinho R, Bödör C, Gribben J, Ibrahim HA, Bower M, Nourse JP, Gandhi MK, Middeldorp J, Cader FZ, Murray P, Münz C, Allday MJ.  J Clin Invest. 2012 Apr 2;122(4):1487-502. doi: 10.1172/JCI58092. Epub 2012 Mar 12.

Latent Epstein-Barr virus can inhibit apoptosis in B cells by blocking the induction of NOXA expression. Yee J, White RE, Anderton E, Allday MJ. PLoS One. 2011;6(12):e28506. Epub 2011 Dec 9.

An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells. Nikitin PA, Yan CM, Forte E, Bocedi A, Tourigny JP, White RE, Allday MJ, Patel A, Dave SS, Kim W, Hu K, Guo J, Tainter D, Rusyn E, Luftig MA. Cell Host Microbe. 2010 Dec 16;8(6):510-22.

Extensive co-operation between the Epstein-Barr virus EBNA3 proteins in the manipulation of host gene expression and epigenetic chromatin modification. White RE, Groves IJ, Turro E, Yee J, Kremmer E, Allday MJ. PLoS One. 2010 Nov 15;5(11):e13979.

Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Paschos K, Allday MJ. Trends Microbiol. 2010 Oct;18(10):439-47. Epub 2010 Aug 18. Review.

Epigenetic repression of p16(INK4A) by latent Epstein-Barr virus requires the interaction of EBNA3A and EBNA3C with CtBP.   Skalska L, White RE, Franz M, Ruhmann M, Allday MJ.   PLoS Pathog. 2010 Jun 10;6(6):e1000951.

How does Epstein-Barr virus (EBV) complement the activation of Myc in the pathogenesis of Burkitt's lymphoma? Allday MJ.   Semin Cancer Biol. 2009 Dec;19(6):366-76. Epub 2009 Jul 25. Review

 

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