Marek’s disease virus telomeric integration profiles of neoplastic host tissues reveal unbiased chromosomal selection and loss of cellular diversity during tumorigenesis

Authors: GLASS, MARLA - University Of California, Davis; SMITH, JUSTIN - University Of California, Davis; Cheng, Hans; DELANY, MARY - University Of California, Davis

Submitted to: Genes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/14/2021
Publication Date: 10/17/2021
Citation: Glass, M.C., Smith, J.M., Cheng, H.H., Delany, M.E. 2021. Marek’s disease virus telomeric integration profiles of neoplastic host tissues reveal unbiased chromosomal selection and loss of cellular diversity during tumorigenesis. Genes. 12(10):1630. https://doi.org/10.3390/genes12101630.
DOI: https://doi.org/10.3390/genes12101630

Interpretive Summary: Marek's disease (MD) is caused by Marek's disease virus (MDV), a ubiquitous herpesvirus that induces T cell lymphomas in susceptible birds. Control of MD is through a combination of biosecurity, mass vaccination, and selection for resistant birds. Understanding how MDV induces lymphomas should provide clues for more efficient and sustainable disease control. In this submission, the dynamics of viral integration, which is necessary for the generation of tumors, was examined in individual cells. The key finding is that the MDV genome does not have a preferential integration site in the chicken genome. This suggests that other events such as epigenetic modifications or key somatic mutations are necessary for the development of gross tumors. Furthermore, the dataset should serve as a resource for future studies into the role of MDV integration, infection, and viral latency in transformation of host cells.

Technical Abstract: The avian alpha-herpesvirus known as Marek’s disease virus (MDV) linearly integrates its 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 site(s) of MDV telomere integration confer an advantage to MDV-transformed cells during tu-morigenesis. We applied MDV-specific fluorescence in situ hybridization (MDV FISH) to investigate virus-host cytogenomic interactions within and among a total of 42 gonad lymphomas and neoplastic splenic samples in birds infected with virulent pathotype MDV (vMDV). We also determined single-cell, chromosome-specific MDV integration profiles within and among trans-formed tissue samples, including multiple samples from the same bird. Most mitotical-ly-dividing cells within neoplastic samples had the MDV telomere-integrated only cytogenomic phenotype, although tissue-specific, temporal changes in phenotype frequencies were detected. Transformed cell populations composing gonad lymphomas exhibited significantly lower diver-sity, 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 trans-formed MDV+ T cells populations present early in MDV-induced oncogenesis (32-50 dpi) survive and expand to become the dominant clonal population in late-stage MD lymphomas (51-62 dpi) and to establish metastatic lymphomas.