Oncogenesis of CAEBV revealed: Intragenic deletions in the viral genome and leaky expression of lytic genes

Takayuki Murata, Yusuke Okuno, Yoshitaka Sato, Takahiro Watanabe, Hiroshi Kimura

Research output: Contribution to journalReview article

Abstract

Epstein-Barr virus (EBV) is a causative agent of infectious mononucleosis and several malignancies involving lymphocytes and epithelial cells. We recently reported genomic analyses of chronic active EBV infection (CAEBV), a proliferative disorder of T and/or NK cells, as well as other lymphoid malignancies. We found that T and/or NK cells undergoing clonal expansion in CAEBV patients gain somatic driver mutations as the disorder progresses. Investigation of the viral genome revealed viral genomes harboring intragenic deletions in the BamHI-rightward transcripts (BART) region and in essential lytic genes. Interestingly, we observed that these deletions resulted in leaky expression of viral lytic genes. This increased expression of viral lytic genes is reminiscent of the “pre-latent abortive lytic” state, in which a substantial number of lytic genes are produced for weeks in the absence of progeny production, which contributes to cell survival upon de novo infection. It has been known that EBV can choose either latent or lytic state, but this dualistic concept may need to be reconsidered, as our data suggest the presence of the third, intermediate state; leaky expression of lytic genes that does not lead to completion of the full lytic amplification cycle. Leaky expression of lytic genes likely contributes to the formation and maintenance of several types of EBV-associated tumors. We also presented significant circumstantial evidence suggesting that EBV infects lymphoid progenitor cells in CAEBV before differentiation into T and NK cells. Taken together, our new data shed light on oncogenesis of CAEBV and other EBV-associated malignancies.

Original languageEnglish
Article numbere2095
JournalReviews in Medical Virology
DOIs
Publication statusAccepted/In press - 01-01-2019

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Epstein-Barr Virus Infections
Viral Genome
Human Herpesvirus 4
Carcinogenesis
Gene Expression
Natural Killer Cells
Viral Genes
T-Lymphocytes
Neoplasms
Lymphoid Progenitor Cells
Infectious Mononucleosis
Essential Genes
Cell Survival
Epithelial Cells
Maintenance
Lymphocytes
Mutation
Infection
Genes

All Science Journal Classification (ASJC) codes

  • Virology
  • Infectious Diseases

Cite this

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title = "Oncogenesis of CAEBV revealed: Intragenic deletions in the viral genome and leaky expression of lytic genes",
abstract = "Epstein-Barr virus (EBV) is a causative agent of infectious mononucleosis and several malignancies involving lymphocytes and epithelial cells. We recently reported genomic analyses of chronic active EBV infection (CAEBV), a proliferative disorder of T and/or NK cells, as well as other lymphoid malignancies. We found that T and/or NK cells undergoing clonal expansion in CAEBV patients gain somatic driver mutations as the disorder progresses. Investigation of the viral genome revealed viral genomes harboring intragenic deletions in the BamHI-rightward transcripts (BART) region and in essential lytic genes. Interestingly, we observed that these deletions resulted in leaky expression of viral lytic genes. This increased expression of viral lytic genes is reminiscent of the “pre-latent abortive lytic” state, in which a substantial number of lytic genes are produced for weeks in the absence of progeny production, which contributes to cell survival upon de novo infection. It has been known that EBV can choose either latent or lytic state, but this dualistic concept may need to be reconsidered, as our data suggest the presence of the third, intermediate state; leaky expression of lytic genes that does not lead to completion of the full lytic amplification cycle. Leaky expression of lytic genes likely contributes to the formation and maintenance of several types of EBV-associated tumors. We also presented significant circumstantial evidence suggesting that EBV infects lymphoid progenitor cells in CAEBV before differentiation into T and NK cells. Taken together, our new data shed light on oncogenesis of CAEBV and other EBV-associated malignancies.",
author = "Takayuki Murata and Yusuke Okuno and Yoshitaka Sato and Takahiro Watanabe and Hiroshi Kimura",
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Oncogenesis of CAEBV revealed : Intragenic deletions in the viral genome and leaky expression of lytic genes. / Murata, Takayuki; Okuno, Yusuke; Sato, Yoshitaka; Watanabe, Takahiro; Kimura, Hiroshi.

In: Reviews in Medical Virology, 01.01.2019.

Research output: Contribution to journalReview article

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T1 - Oncogenesis of CAEBV revealed

T2 - Intragenic deletions in the viral genome and leaky expression of lytic genes

AU - Murata, Takayuki

AU - Okuno, Yusuke

AU - Sato, Yoshitaka

AU - Watanabe, Takahiro

AU - Kimura, Hiroshi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Epstein-Barr virus (EBV) is a causative agent of infectious mononucleosis and several malignancies involving lymphocytes and epithelial cells. We recently reported genomic analyses of chronic active EBV infection (CAEBV), a proliferative disorder of T and/or NK cells, as well as other lymphoid malignancies. We found that T and/or NK cells undergoing clonal expansion in CAEBV patients gain somatic driver mutations as the disorder progresses. Investigation of the viral genome revealed viral genomes harboring intragenic deletions in the BamHI-rightward transcripts (BART) region and in essential lytic genes. Interestingly, we observed that these deletions resulted in leaky expression of viral lytic genes. This increased expression of viral lytic genes is reminiscent of the “pre-latent abortive lytic” state, in which a substantial number of lytic genes are produced for weeks in the absence of progeny production, which contributes to cell survival upon de novo infection. It has been known that EBV can choose either latent or lytic state, but this dualistic concept may need to be reconsidered, as our data suggest the presence of the third, intermediate state; leaky expression of lytic genes that does not lead to completion of the full lytic amplification cycle. Leaky expression of lytic genes likely contributes to the formation and maintenance of several types of EBV-associated tumors. We also presented significant circumstantial evidence suggesting that EBV infects lymphoid progenitor cells in CAEBV before differentiation into T and NK cells. Taken together, our new data shed light on oncogenesis of CAEBV and other EBV-associated malignancies.

AB - Epstein-Barr virus (EBV) is a causative agent of infectious mononucleosis and several malignancies involving lymphocytes and epithelial cells. We recently reported genomic analyses of chronic active EBV infection (CAEBV), a proliferative disorder of T and/or NK cells, as well as other lymphoid malignancies. We found that T and/or NK cells undergoing clonal expansion in CAEBV patients gain somatic driver mutations as the disorder progresses. Investigation of the viral genome revealed viral genomes harboring intragenic deletions in the BamHI-rightward transcripts (BART) region and in essential lytic genes. Interestingly, we observed that these deletions resulted in leaky expression of viral lytic genes. This increased expression of viral lytic genes is reminiscent of the “pre-latent abortive lytic” state, in which a substantial number of lytic genes are produced for weeks in the absence of progeny production, which contributes to cell survival upon de novo infection. It has been known that EBV can choose either latent or lytic state, but this dualistic concept may need to be reconsidered, as our data suggest the presence of the third, intermediate state; leaky expression of lytic genes that does not lead to completion of the full lytic amplification cycle. Leaky expression of lytic genes likely contributes to the formation and maintenance of several types of EBV-associated tumors. We also presented significant circumstantial evidence suggesting that EBV infects lymphoid progenitor cells in CAEBV before differentiation into T and NK cells. Taken together, our new data shed light on oncogenesis of CAEBV and other EBV-associated malignancies.

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