Defective Epstein–Barr virus in chronic active infection and haematological malignancy

Yusuke Okuno, Takayuki Murata, Yoshitaka Sato, Hideki Muramatsu, Yoshinori Ito, Takahiro Watanabe, Tatsuya Okuno, Norihiro Murakami, Kenichi Yoshida, Akihisa Sawada, Masami Inoue, Keisei Kawa, Masao Seto, Koichi Ohshima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Yohei Narita, Masahiro Yoshida & 18 others Fumi Goshima, Jun ichi Kawada, Tetsuya Nishida, Hitoshi Kiyoi, Seiichi Kato, Shigeo Nakamura, Satoko Morishima, Tetsushi Yoshikawa, Shigeyoshi Fujiwara, Norio Shimizu, Yasushi Isobe, Masaaki Noguchi, Atsushi Kikuta, Keiji Iwatsuki, Yoshiyuki Takahashi, Seiji Kojima, Seishi Ogawa, Hiroshi Kimura

Research output: Contribution to journalLetter

Abstract

Epstein–Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer 1,2 . Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification 1,2 . CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms 3 . Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF1 4–7 , while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

Original languageEnglish
Pages (from-to)404-413
Number of pages10
JournalNature Microbiology
Volume4
Issue number3
DOIs
Publication statusPublished - 01-03-2019

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Defective Viruses
Hematologic Neoplasms
Viruses
Infection
Epstein-Barr Virus Infections
Infectious Mononucleosis
Natural Killer T-Cells
Lymphoproliferative Disorders
Essential Genes
Virus Diseases
Clonal Evolution
Mutation
Immediate-Early Genes
Lymphoma, Large B-Cell, Diffuse
T-Cell Lymphoma
Cell Lineage
MicroRNAs
Heterografts
Virion
Lymphoma

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Okuno, Yusuke ; Murata, Takayuki ; Sato, Yoshitaka ; Muramatsu, Hideki ; Ito, Yoshinori ; Watanabe, Takahiro ; Okuno, Tatsuya ; Murakami, Norihiro ; Yoshida, Kenichi ; Sawada, Akihisa ; Inoue, Masami ; Kawa, Keisei ; Seto, Masao ; Ohshima, Koichi ; Shiraishi, Yuichi ; Chiba, Kenichi ; Tanaka, Hiroko ; Miyano, Satoru ; Narita, Yohei ; Yoshida, Masahiro ; Goshima, Fumi ; Kawada, Jun ichi ; Nishida, Tetsuya ; Kiyoi, Hitoshi ; Kato, Seiichi ; Nakamura, Shigeo ; Morishima, Satoko ; Yoshikawa, Tetsushi ; Fujiwara, Shigeyoshi ; Shimizu, Norio ; Isobe, Yasushi ; Noguchi, Masaaki ; Kikuta, Atsushi ; Iwatsuki, Keiji ; Takahashi, Yoshiyuki ; Kojima, Seiji ; Ogawa, Seishi ; Kimura, Hiroshi. / Defective Epstein–Barr virus in chronic active infection and haematological malignancy. In: Nature Microbiology. 2019 ; Vol. 4, No. 3. pp. 404-413.
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abstract = "Epstein–Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer 1,2 . Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification 1,2 . CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms 3 . Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF1 4–7 , while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.",
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Okuno, Y, Murata, T, Sato, Y, Muramatsu, H, Ito, Y, Watanabe, T, Okuno, T, Murakami, N, Yoshida, K, Sawada, A, Inoue, M, Kawa, K, Seto, M, Ohshima, K, Shiraishi, Y, Chiba, K, Tanaka, H, Miyano, S, Narita, Y, Yoshida, M, Goshima, F, Kawada, JI, Nishida, T, Kiyoi, H, Kato, S, Nakamura, S, Morishima, S, Yoshikawa, T, Fujiwara, S, Shimizu, N, Isobe, Y, Noguchi, M, Kikuta, A, Iwatsuki, K, Takahashi, Y, Kojima, S, Ogawa, S & Kimura, H 2019, 'Defective Epstein–Barr virus in chronic active infection and haematological malignancy' Nature Microbiology, vol. 4, no. 3, pp. 404-413. https://doi.org/10.1038/s41564-018-0334-0

Defective Epstein–Barr virus in chronic active infection and haematological malignancy. / Okuno, Yusuke; Murata, Takayuki; Sato, Yoshitaka; Muramatsu, Hideki; Ito, Yoshinori; Watanabe, Takahiro; Okuno, Tatsuya; Murakami, Norihiro; Yoshida, Kenichi; Sawada, Akihisa; Inoue, Masami; Kawa, Keisei; Seto, Masao; Ohshima, Koichi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Narita, Yohei; Yoshida, Masahiro; Goshima, Fumi; Kawada, Jun ichi; Nishida, Tetsuya; Kiyoi, Hitoshi; Kato, Seiichi; Nakamura, Shigeo; Morishima, Satoko; Yoshikawa, Tetsushi; Fujiwara, Shigeyoshi; Shimizu, Norio; Isobe, Yasushi; Noguchi, Masaaki; Kikuta, Atsushi; Iwatsuki, Keiji; Takahashi, Yoshiyuki; Kojima, Seiji; Ogawa, Seishi; Kimura, Hiroshi.

In: Nature Microbiology, Vol. 4, No. 3, 01.03.2019, p. 404-413.

Research output: Contribution to journalLetter

TY - JOUR

T1 - Defective Epstein–Barr virus in chronic active infection and haematological malignancy

AU - Okuno, Yusuke

AU - Murata, Takayuki

AU - Sato, Yoshitaka

AU - Muramatsu, Hideki

AU - Ito, Yoshinori

AU - Watanabe, Takahiro

AU - Okuno, Tatsuya

AU - Murakami, Norihiro

AU - Yoshida, Kenichi

AU - Sawada, Akihisa

AU - Inoue, Masami

AU - Kawa, Keisei

AU - Seto, Masao

AU - Ohshima, Koichi

AU - Shiraishi, Yuichi

AU - Chiba, Kenichi

AU - Tanaka, Hiroko

AU - Miyano, Satoru

AU - Narita, Yohei

AU - Yoshida, Masahiro

AU - Goshima, Fumi

AU - Kawada, Jun ichi

AU - Nishida, Tetsuya

AU - Kiyoi, Hitoshi

AU - Kato, Seiichi

AU - Nakamura, Shigeo

AU - Morishima, Satoko

AU - Yoshikawa, Tetsushi

AU - Fujiwara, Shigeyoshi

AU - Shimizu, Norio

AU - Isobe, Yasushi

AU - Noguchi, Masaaki

AU - Kikuta, Atsushi

AU - Iwatsuki, Keiji

AU - Takahashi, Yoshiyuki

AU - Kojima, Seiji

AU - Ogawa, Seishi

AU - Kimura, Hiroshi

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Epstein–Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer 1,2 . Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification 1,2 . CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms 3 . Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF1 4–7 , while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

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