Dissertation

Investigating the anti-apoptotic role of ebv in endemic burkitt lymphona

Fitzsimmons, Leah

2015

Overview

Epstein-Barr virus (EBV) has been etiologically associated with Burkitt lymphoma (BL) since its discovery 50 years ago, but despite this long-standing association the precise role of the virus in the pathogenesis of BL remains enigmatic. EBV can be lost spontaneously from EBV-positive BL cell lines, and these EBV-loss clones have been reported to exhibit increased sensitivity to apoptosis. We have confirmed and extended those observations and report that sporadic loss of EBV from BL cells is consistently associated with enhanced sensitivity to apoptosis-inducing agents and conversely, reduced tumorigenicity \\(in\\) \\(vivo\\). Importantly, reinfection of EBV-loss clones with EBV can restore apoptosis protection, although surprisingly, individual Latency I genes cannot. We also used inducible pro-apoptotic BH3 ligands to investigate Bcl-2-family dependence in BL clones as well as profiling gene expression changes in response to apoptosis induction in EBV-positive versus EBV-loss clones. We found that EBV-loss was consistently associated with enhanced sensitivity to BH3-ligand-induced death and increased activation of apoptosis signalling pathways, although no individual apoptosis-related gene was responsible. Instead we find that Latency I EBV genes co-operate to co-ordinately repress the BH3-only proteins Bim, Puma and Noxa to inhibit apoptosis in BL.

• Publisher: ProQuest Dissertations & Theses