Marek's Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis.

Marla C Glass,Hans H Cheng,Mary E Delany,Justin M Smith

doi:10.3390/genes12101630

Abstract

The avian α-herpesvirus known as Marek’s disease virus (MDV) linearly integrates its genomic DNA into host telomeres during infection. The resulting disease, Marek’s disease (MD), is characterized by virally-induced lymphomas with high mortality. The temporal dynamics of MDV-positive (MDV+) transformed cells and expansion of MD lymphomas remain targets for further understanding. It also remains to be determined whether specific host chromosomal sites of MDV telomere integration confer an advantage to MDV-transformed cells during tumorigenesis. We applied MDV-specific fluorescence in situ hybridization (MDV FISH) to investigate virus-host cytogenomic interactions within and among a total of 37 gonad lymphomas and neoplastic splenic samples in birds infected with virulent MDV. We also determined single-cell, chromosome-specific MDV integration profiles within and among transformed tissue samples, including multiple samples from the same bird. Most mitotically-dividing cells within neoplastic samples had the cytogenomic phenotype of ‘MDV telomere-integrated only’, and tissue-specific, temporal changes in phenotype frequencies were detected. Transformed cell populations composing gonad lymphomas exhibited significantly lower diversity, in terms of heterogeneity of MDV integration profiles, at the latest stages of tumorigenesis (>50 days post-infection (dpi)). We further report high interindividual and lower intraindividual variation in MDV integration profiles of lymphoma cells. There was no evidence of integration hotspots into a specific host chromosome(s). Collectively, our data suggests that very few transformed MDV+ T cell populations present earlier in MDV-induced lymphomas (32–50 dpi), survive, and expand to become the dominant clonal population in more advanced MD lymphomas (51–62 dpi) and establish metastatic lymphomas.

Highlights

IntroductionMarek’s disease virus (MDV) is a ubiquitous oncogenic avian α-herpesvirus that induces MD, which is characterized by visceral tumors and nerve enlargement in susceptible host chicken populations
Marek’s disease virus (MDV) is a ubiquitous oncogenic avian α-herpesvirus that induces MD, which is characterized by visceral tumors and nerve enlargement in susceptible host chicken populations.The severe form of MD often leads to mortality in susceptible birds
Through analyses of host chromosome-specific MDV integration profiles for MD gonad lymphomas, we discovered that the transformed-cell populations composing lymphomas exhibit significantly lower diversity at later stages of tumorigenesis

Summary

Introduction

MDV is a ubiquitous oncogenic avian α-herpesvirus that induces MD, which is characterized by visceral tumors and nerve enlargement in susceptible host chicken populations. The severe form of MD often leads to mortality in susceptible birds. MDV-infected birds serve as an important disease model system for human oncogenic herpesvirusassociated health conditions. Chicken MD research is of critical, global agricultural importance and directly impacts food production, animal health and welfare, and economic sustainability of commercial production systems. In MDV infection, oncogenic strains transition from a cytolytic replicative stage consisting of circularized extra-chromosomal MDV in host cells, peaking around 1 week after infection, to a latent infection stage wherein the virus is no longer replicating and evades host immune detection and responses [1,2,3,4,5,6]. MDV latency has significant temporal overlap with viral linear-integration events into the telomeres of host chromosome [7,8]

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