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Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.
Journal of Cell Science 2019 Februrary 12
Cancers that utilize the Alternative Lengthening of Telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of PML nuclear bodies (PML NBs) which are required for intrinsic immunity to various viruses. Here we asked whether ATRX-deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in killing ATRX-deficient cells. Infection of co-cultured primary and ATRX-null cancer cells revealed that mutant HSV-1 selectively killed ATRX-null cells. Sensitivity to mutant HSV-1 infection also correlated inversely with PML protein levels, and we showed that ATRX upregulates PML expression at both the transcriptional and post-transcriptional levels. These data provide a basis for predicting, based on ATRX or PML levels, which tumors will respond to a selective oncolytic herpesvirus.
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