BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK cell lymphoma

Nenad Sejic, Lindsay George, Rosemary Tierney, Catherine Chang, Olga Kondrashova, Ruth N. MacKinnon, Ping Lan, Andrew Bell, Guillaume Lessene, Heather Long, Andreas Strasser, Claire Shannon-Lowe, Gemma L. Kelly

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Epstein-Barr virus (EBV)-associated T and NK cell malignancies, such as extra-nodal NK/T cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have poor prognosis. The rare nature of such cancers and non-malignant T/NK lymphoproliferative disorders, such as Chronic Active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases, including the contribution of EBV infection. Here we characterise a panel of ENKTL and CAEBV derived cell lines that had been established from human tumours to be used as pre-clinical models of these diseases. These cell lines were IL-2-dependent and found to carry EBV in a latency II infection state, which involves expression of the key viral oncogenic protein LMP1. All cell lines demonstrated resistance to cell death induction by DNA-damage inducing agents, the current standard of care for patients with these malignancies. This resistance was not correlated with the function of the multi-drug efflux pump, P-glycoprotein. However, apoptotic cell death could be consistently induced following treatment with A-1331852, a BH3-mimetic drug that specifically inhibits the pro-survival protein BCL-XL. A-1331852-induced apoptosis was most efficacious when pro-survival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL and CAEBV cell lines provided evidence that A1331852 treatment would be therapeutically beneficial in vivo. The data here suggest that therapeutic targeting of BCL-XL would be effective for patients with EBV-driven T/NK proliferative diseases, however, MCL-1 could be a resistance factor.
Original languageEnglish
Pages (from-to)4775-4787
Number of pages13
JournalBlood Advances
Issue number19
Early online date5 Oct 2020
Publication statusPublished - 13 Oct 2020

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Not yet published as of 30/09/2020.


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