Extra-telomeric functions of telomerase in the pathogenesis of Epstein-Barr virus-driven B-cell malignancies and potential therapeutic implications

Abstract

The Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus causally linked to a broad spectrum of both lymphoid and epithelial malignancies. In order to maintain its persistence in host cells and promote tumorigenesis, EBV must restrict its lytic cycle, which would ultimately lead to cell death, selectively express latent viral proteins, and establish an unlimited proliferative potential. The latter step depends on the maintenance of telomere length provided by telomerase. The viral oncoprotein LMP-1 activates TERT, the catalytic component of telomerase. In addition to its canonical role in stabilizing telomeres, TERT may promote EBV-driven tumorigenesis through extra-telomeric functions. TERT contributes toward preserving EBV latency; in fact, through the NOTCH2/BATF pathway, TERT negatively affects the expression of BZLF1, the master regulator of the EBV lytic cycle. In contrast, TERT inhibition triggers a complete EBV lytic cycle, leading to the death of EBV-infected cells. Interestingly, short-term TERT inhibition causes cell cycle arrest and apoptosis, partly by inducing telomere-independent activation of the ATM/ATR/TP53 pathway. Importantly, TERT inhibition also sensitizes EBV-positive tumor cells to antiviral therapy and enhances the pro-apoptotic effects of chemotherapeutic agents. We provide here an overview on how the extra-telomeric functions of TERT contribute to EBV-driven tumorigenesis. We also discuss the potential therapeutic approach of TERT inhibition in EBV-driven malignancies.

Keywords: B-cell malignancies; Epstein-Barr virus; Latent/lytic viral cycle; TERT extra-telomeric functions; Telomerase.

Fig. 1

TERT levels affect EBV latent/lytic status. A, cross-talk between EBV and TERT to sustain viral latency program: in EBV-infected primary B lymphocytes, activation of TERT occurs concomitantly with induction of latent EBV proteins and down-regulation of EBV lytic gene expression. EBV-encoded LMP-1 activates TERT at transcriptional level via NF-κB and MAPK/ERK1/2 pathways. In turn, TERT expression activates NOTCH2 at transcriptional level via NF-κB pathway. NOTCH2 activates BATF, which negatively affects the expression of BZLF1, a master regulator of viral lytic cycle, thus favouring induction and maintenance of EBV latency program, essential for EBV-driven transformation. Immunohistochemical image: TERT (a, b) and BZLF1 (c, d) protein expression in early- (a, c) and late- (b, d) infected B lymphocytes (X40). B, TERT or NOTCH inhibition triggers EBV lytic cycle: TERT silencing by shRNA (shTERT) or inhibition of NOTCH signaling by γ-secretase inhibitors lead to NOTCH2-dependent down-regulation of BATF and up-regulation of BZLF1, inducing a complete EBV lytic cycle. Immunohistochemical image: EBV lytic gp350 protein expression in EBV-positive BL cells untreated (a) and treated (b) for 72 h with shTERT (X20). Scale bar, 100 μm. See the text for details