Marek’s Disease Virus-Induced T-Cell Lymphomas

Parcells, Mark S.; Burnside, Joan; Morgan, Robin

doi:10.1007/978-1-4614-0016-5_13

Cited by 15 publications

(9 citation statements)

References 135 publications

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“…MD serves as an excellent model for studying virus-induced T-cell lymphomas. Among the more than 100 genes carried by the MDV (17, 18), the gene encoding the basic leucine zipper protein Meq ( M DV E coRI Q ), which is undisputedly expressed in both lytic and latent infections, is the most important viral gene associated with MD oncogenicity (19, 20). Deletion of the Meq gene or inhibition of its important interactions with host proteins such as c-Jun, c-Fos, and C-terminal binding protein (CtBP) can affect the oncogenicity of the virus (21–23).…”

Section: Introductionmentioning

confidence: 99%

Marek's Disease Virus-Encoded MicroRNA 155 Ortholog Critical for the Induction of Lymphomas Is Not Essential for the Proliferation of Transformed Cell Lines

Zhang

Tang

Luo

et al. 2019

J Virol

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MicroRNAs (miRNAs) are small noncoding RNAs with profound regulatory roles in many areas of biology, including cancer. MicroRNA 155 (miR-155), one of the extensively studied multifunctional miRNAs, is important in several human malignancies such as diffuse large B cell lymphoma and chronic lymphocytic leukemia. Moreover, miR-155 orthologs KSHV-miR-K12-11 and MDV-miR-M4, encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV) and Marek’s disease virus (MDV), respectively, are also involved in oncogenesis. In MDV-induced T-cell lymphomas and in lymphoblastoid cell lines derived from them, MDV-miR-M4 is highly expressed. Using excellent disease models of infection in natural avian hosts, we showed previously that MDV-miR-M4 is critical for the induction of T-cell lymphomas as mutant viruses with precise deletions were significantly compromised in their oncogenicity. However, those studies did not elucidate whether continued expression of MDV-miR-M4 is essential for maintaining the transformed phenotype of tumor cells. Here using an in situ CRISPR/Cas9 editing approach, we deleted MDV-miR-M4 from the MDV-induced lymphoma-derived lymphoblastoid cell line MDCC-HP8. Precise deletion of MDV-miR-M4 was confirmed by PCR, sequencing, quantitative reverse transcription-PCR (qRT-PCR), and functional analysis. Continued proliferation of the MDV-miR-M4-deleted cell lines demonstrated that MDV-miR-M4 expression is not essential for maintaining the transformed phenotype, despite its initial critical role in the induction of lymphomas. Ability to examine the direct role of oncogenic miRNAs in situ in tumor cell lines is valuable in delineating distinct determinants and pathways associated with the induction or maintenance of transformation in cancer cells and will also contribute significantly to gaining further insights into the biology of oncogenic herpesviruses. IMPORTANCE Marek’s disease virus (MDV) is an alphaherpesvirus associated with Marek’s disease (MD), a highly contagious neoplastic disease of chickens. MD serves as an excellent model for studying virus-induced T-cell lymphomas in the natural chicken hosts. Among the limited set of genes associated with MD oncogenicity, MDV-miR-M4, a highly expressed viral ortholog of the oncogenic miR-155, has received extensive attention due to its direct role in the induction of lymphomas. Using a targeted CRISPR-Cas9-based gene editing approach in MDV-transformed lymphoblastoid cell lines, we show that MDV-miR-M4, despite its critical role in the induction of tumors, is not essential for maintaining the transformed phenotype and continuous proliferation. As far as we know, this was the first study in which precise editing of an oncogenic miRNA was carried out in situ in MD lymphoma-derived cell lines to demonstrate that it is not essential in maintaining the transformed phenotype.

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Section: Introductionmentioning

confidence: 99%

Marek's Disease Virus-Encoded MicroRNA 155 Ortholog Critical for the Induction of Lymphomas Is Not Essential for the Proliferation of Transformed Cell Lines

Zhang

Tang

Luo

et al. 2019

J Virol

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“…Among the more than 100 genes encoded by the MDV [ 40 , 41 ], Meq protein, which is expressed both in lytic and latent infections undisputedly, is the most important viral gene associated with MD oncogenicity [ 42 , 43 ]. pp38 , another important gene in MDV pathogenesis, is a unique phosphoprotein and is necessary for cytolytic infection of B cells, maintenance of the transformed state but not for cytolytic infection of the feather follicle epithelium, and horizontal spread of MDV [ 44 , 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

Application of CRISPR/Cas9 Gene Editing System on MDV-1 Genome for the Study of Gene Function

Zhang

Tang

Sadigh

et al. 2018

Viruses

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Marek’s disease virus (MDV) is a member of alphaherpesviruses associated with Marek’s disease, a highly contagious neoplastic disease in chickens. Complete sequencing of the viral genome and recombineering techniques using infectious bacterial artificial chromosome (BAC) clones of Marek’s disease virus genome have identified major genes that are associated with pathogenicity. Recent advances in CRISPR/Cas9-based gene editing have given opportunities for precise editing of the viral genome for identifying pathogenic determinants. Here we describe the application of CRISPR/Cas9 gene editing approaches to delete the Meq and pp38 genes from the CVI988 vaccine strain of MDV. This powerful technology will speed up the MDV gene function studies significantly, leading to a better understanding of the molecular mechanisms of MDV pathogenesis.

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“…MDV, also known as gallid herpesvirus type 2 (GaHV-2), causes a variety of clinical symptoms including neurological disorders and immunosuppression, but is most renowned for its oncogenic potential [ 2 ]. The virus efficiently induces malignant T-cell lymphomas and is considered to be the most prevalent clinically-diagnosed cancer in animals [ 3 ]. MDV infection of susceptible chickens can result in a mortality rate of up to 100%.…”

Section: Introductionmentioning

confidence: 99%

Telomeres and Telomerase: Role in Marek’s Disease Virus Pathogenesis, Integration and Tumorigenesis

Kheimar

Previdelli

Wight

et al. 2017

Viruses

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Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG)n that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek’s disease virus (MDV), harbor telomeric repeats (TMR) identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR) that shares 88% sequence identity with the telomerase RNA in chicken (chTR). vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis.

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Marek’s Disease Virus-Induced T-Cell Lymphomas

Cited by 15 publications

References 135 publications

Marek's Disease Virus-Encoded MicroRNA 155 Ortholog Critical for the Induction of Lymphomas Is Not Essential for the Proliferation of Transformed Cell Lines

Marek's Disease Virus-Encoded MicroRNA 155 Ortholog Critical for the Induction of Lymphomas Is Not Essential for the Proliferation of Transformed Cell Lines

Application of CRISPR/Cas9 Gene Editing System on MDV-1 Genome for the Study of Gene Function

Telomeres and Telomerase: Role in Marek’s Disease Virus Pathogenesis, Integration and Tumorigenesis

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