Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.

Jane R Noble,Sonja Frölich,Eugene H Y Choi,Ted Wong,Roger D Everett,Roger R Reddel,Mingqi Han,Christine E Napier,Anthony J Cesare,Erdahl Teber

doi:10.1242/jcs.222349

Abstract

ABSTRACTCancers 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 promyelocytic leukemia nuclear bodies (PML NBs) that 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 infecting ATRX-deficient cells than wild-type ATRX-expressing cells. Infection of co-cultured primary and ATRX-deficient cancer cells revealed that mutant HSV-1 selectively killed ATRX-deficient 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.

Highlights

Healthy cells can divide a limited number of times, whereas cancer cell populations usually acquire an unlimited proliferative capacity
We found that expression of viral proteins, including immediate early proteins involved in replication compartment assembly (ICP4, ICP8 and ICP27) and the capsid protein expressed at late stage (VP5), was strongly limited in ATRX-expressing cells infected with mutant herpes simplex virus type 1 (HSV-1) as compared to WT HSV-1 (Fig. 1C,D, left panels)
promyelocytic leukemia nuclear bodies (PML NBs) count correlates with resistance to mutant HSV-1 Because ATRX is a constitutive component of PML NBs, we examined these nuclear structures in the cell line panel

Summary

Introduction

Healthy cells can divide a limited number of times, whereas cancer cell populations usually acquire an unlimited proliferative capacity. Most human tumors activate a telomere lengthening mechanism, either telomerase (TEL) or alternative lengthening of telomeres (ALT), to counteract telomere shortening and thereby enable unlimited cellular proliferation (Kim et al, 1994; Bryan et al, 1995). ALT is activated in many of the remaining 10–15% of cancers, and is common in various cancers including osteosarcomas, several soft tissue sarcoma subtypes, and astrocytomas including pediatric glioblastoma (Bryan et al, 1997; Henson et al, 2005; Heaphy et al, 2011b). Loss of the chromatin remodeling protein α-thalassemia/mental retardation syndrome Xlinked (ATRX) or its heterodimeric binding partner, death domainassociated protein 6 (DAXX) have been identified in a significant proportion of tumors and cell lines that utilize ALT (Heaphy et al, 2011a; Bower et al, 2012; Jiao et al, 2012; Lovejoy et al, 2012)

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