Insights into mechanisms of resistance to apoptosis in Epstein-Barr virus-associated T and NK cell lymphomas

Sejic, Nenad (2019). Insights into mechanisms of resistance to apoptosis in Epstein-Barr virus-associated T and NK cell lymphomas. University of Birmingham. Ph.D.

Sejic2019PhD.pdf Text - Accepted Version Restricted to Repository staff only until 23 July 2024. Available under License All rights reserved. Download (10MB)

Abstract

Ectopic Epstein-Barr virus (EBV) infection of T or NK cells is associated with several aggressive diseases including extra-nodal NK/T cell lymphoma (ENKTL) and chronic active EBV (CAEBV). Resistance to standard chemotherapy results in extremely poor patient prognosis. This thesis aimed to uncover the cellular and viral mechanisms behind such resistance, and to identify vulnerabilities for therapeutic targeting. An extensive collection of patient-derived cell lines demonstrated an EBV latency II phenotype and exhibited resistance to clinically administered genotoxic compounds. Importantly, apoptotic cell death could be consistently induced following treatment with the BH3 mimetic, A-1331852, that inhibits the BCL-2 pro-survival protein, BCL-XL. Furthermore, A 1331852 proved effective in 1 of 3 newly developed xenograft NSG mouse models. In the two non-responder cell lines, it was shown that BCL-XL dependency was potentially maintained by viral LMP1 in an IL-2-dependent manner. IL-2 withdrawal in vitro, emulating the in vivo environment, led to a survival dependency switch from BCL-XL to MCL-1, and ultimately a reduced response to A-1331852. Finally, to identify novel cytotoxic drugs for ENKTL and CAEBV, a high-throughput screen of 4079 compounds was performed. This identified a shortlist of effective hits for further study in these severe diseases where targeted treatment options are unexplored.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Shannon-Lowe, Claire UNSPECIFIED UNSPECIFIED Long, Heather UNSPECIFIED UNSPECIFIED Kelly, Gemma UNSPECIFIED UNSPECIFIED Strasser, Andreas UNSPECIFIED UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department:	Institute of Immunology and Immunotherapy
Funders:	Other
Other Funders:	Universitas 21
Subjects:	Q Science > QR Microbiology > QR355 Virology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
URI:	http://etheses.bham.ac.uk/id/eprint/9322

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