Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis
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<sup>...
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MDPI AG
2021-10-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/12/10/1630 |
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| author | Marla C. Glass Justin M. Smith Hans H. Cheng Mary E. Delany |
| author_facet | Marla C. Glass Justin M. Smith Hans H. Cheng Mary E. Delany |
| author_sort | Marla C. Glass |
| collection | DOAJ |
| description | 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<sup>+</sup>) 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<sup>+</sup> 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. |
| first_indexed | 2024-03-10T06:32:56Z |
| format | Article |
| id | doaj.art-99ef0caa834246f6b5806515cf0f5c0b |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T06:32:56Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-99ef0caa834246f6b5806515cf0f5c0b2023-11-22T18:23:01ZengMDPI AGGenes2073-44252021-10-011210163010.3390/genes12101630Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during TumorigenesisMarla C. Glass0Justin M. Smith1Hans H. Cheng2Mary E. Delany3Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Animal Science, University of California Davis, Davis, CA 95616, USAAvian Disease and Oncology Laboratory, United States Department of Agriculture, Agricultural Research Service, East Lansing, MI 48823, USADepartment of Animal Science, University of California Davis, Davis, CA 95616, USAThe 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<sup>+</sup>) 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<sup>+</sup> 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.https://www.mdpi.com/2073-4425/12/10/1630herpesvirusMarek’s disease virus (MDV)viral integrationchickenavian genomicsFISH |
| spellingShingle | Marla C. Glass Justin M. Smith Hans H. Cheng Mary E. Delany Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis Genes herpesvirus Marek’s disease virus (MDV) viral integration chicken avian genomics FISH |
| title | Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis |
| title_full | Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis |
| title_fullStr | Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis |
| title_full_unstemmed | Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis |
| title_short | Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis |
| title_sort | marek s disease virus telomeric integration profiles of neoplastic host tissues reveal unbiased chromosomal selection and loss of cellular diversity during tumorigenesis |
| topic | herpesvirus Marek’s disease virus (MDV) viral integration chicken avian genomics FISH |
| url | https://www.mdpi.com/2073-4425/12/10/1630 |
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