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
N1 - Funding Information:
S.Kojima was supported by a grant from Sanofi K.K. All other authors declare no competing interests.
Funding Information:
The authors would like to thank all of the subjects and families for participating in this study. The authors would like to thank N. Yoshida, M. Okada, H. Moriuchi, K. Yamamoto, S. Kamimura, Y. Horikoshi and T. Kinoshita for providing samples. The authors would also like to thank Y. Miura, Y. Imanishi, F. Ando, S. Kumagai, T. Kunogi, H. Matsuda, H.M.A. Masud and H. Namizaki for their valuable assistance. The authors acknowledge M. Nakatochi for valuable comments. The authors acknowledge the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine for technical support of cell sorting and next-generation sequencing. The authors acknowledge the Human Genome Center, the Institute of Medical Science, the University of Tokyo (http://sc.hgc.jp/shirokane.html) for providing super-computing resources. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.K. (grant nos 25293109 and 17H04081), grants from Japan Agency for Medical Research and Development to H.K. (grant no. JP17ek0109286) and T.M. (grant no. JP17fm0208016), a grant from the Hori Sciences and Arts Foundation and from the Ministry of Health, Labor, and Welfare of Japan to H.K. (grant no. H29-Nanchi-016).
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 cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. 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 BRLF14–7, 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 cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. 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 BRLF14–7, 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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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 -