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

Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and nonmalignant T/NK lymphoproliferative disorders, such as chronic active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases. Here, we characterize a panel of ENKTL- and CAEBV-derived cell lines that had been established from human tumors to be used as preclinical models of these diseases. These cell lines were interleukin-2 dependent and found to carry EBV in a latency II gene-expression pattern. 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 multidrug 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 prosurvival protein BCL-XL. A-1331852-induced apoptosis was most efficacious when prosurvival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL cell line SNK6 provided evidence that A-1331852 treatment could 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 potential resistance factor.

Epstein-barr virus and the pathogenesis of T and NK lymphoma: a mystery unsolved.

The potent growth-transforming properties of Epstein-Barr virus (EBV) and its role in pathogenesis of a range of B cell and epithelial malignancies are well established. By contrast, the association of this B lymphotropic virus with malignancies of T and NK cell origin was entirely unexpected. Although a number of mature T and NK lymphoma subtypes have been associated with EBV, evidence for a robust viral/tumour relationship is principally limited to extranodal NK/T lymphoma (ENKTL). Despite progress in diagnosis and classification, alongside an evolving understanding of ENKTL pathobiology, EBV's contribution to lymphomagenesis remains largely unresolved. Challenges relate to the rarity of this entity, a lack of clinical and biological correlative data and scarcity of fresh tissue for molecular and functional studies. Nonetheless, recent studies on viral and cellular gene expression have permitted new avenues of investigation into ENKTL pathobiology aiming to extend our understanding of disease biology and ultimately improve clinical outcomes.