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 language | English |
|---|---|
| Pages (from-to) | 404-413 |
| Number of pages | 10 |
| Journal | Nature Microbiology |
| Volume | 4 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 01-03-2019 |
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All Science Journal Classification (ASJC) codes
- Microbiology
- Immunology
- Applied Microbiology and Biotechnology
- Genetics
- Microbiology (medical)
- Cell Biology
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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 journal › Letter
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85060449822&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060449822&partnerID=8YFLogxK
U2 - 10.1038/s41564-018-0334-0
DO - 10.1038/s41564-018-0334-0
M3 - Letter
C2 - 30664667
AN - SCOPUS:85060449822
VL - 4
SP - 404
EP - 413
JO - Nature Microbiology
JF - Nature Microbiology
SN - 2058-5276
IS - 3
ER -