1. Defective Epstein–Barr virus in chronic active infection and haematological malignancy
- Author
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Norio Shimizu, Yoshinori Ito, Masahiro Yoshida, Satoko Morishima, Masao Seto, Atsushi Kikuta, Keiji Iwatsuki, Yusuke Okuno, Kenichi Yoshida, Jun-ichi Kawada, Yasushi Isobe, Kenichi Chiba, Hiroko Tanaka, Koichi Ohshima, Seiji Kojima, Shigeyoshi Fujiwara, Masaaki Noguchi, Hideki Muramatsu, Keisei Kawa, Hiroshi Kimura, Takayuki Murata, Seishi Ogawa, Norihiro Murakami, Akihisa Sawada, Masami Inoue, Yoshitaka Sato, Seiichi Kato, Tetsuya Nishida, Satoru Miyano, Shigeo Nakamura, Fumi Goshima, Yoshiyuki Takahashi, Tatsuya Okuno, Tetsushi Yoshikawa, Yohei Narita, Hitoshi Kiyoi, Yuichi Shiraishi, and Takahiro Watanabe
- Subjects
Male ,Microbiology (medical) ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Immunology ,Lymphoproliferative disorders ,DNA-Directed DNA Polymerase ,Biology ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Microbiology ,Immediate early protein ,Immediate-Early Proteins ,Mice ,Viral Proteins ,03 medical and health sciences ,Chronic active EBV infection ,hemic and lymphatic diseases ,Genetics ,medicine ,Animals ,Humans ,Epstein–Barr virus infection ,Neoplastic Processes ,030304 developmental biology ,0303 health sciences ,030306 microbiology ,Cell Biology ,Middle Aged ,medicine.disease ,Epstein–Barr virus ,Virology ,Lymphoproliferative Disorders ,BZLF1 ,Lymphoma ,DNA-Binding Proteins ,MicroRNAs ,Lytic cycle ,Hematologic Neoplasms ,Mutation ,Trans-Activators ,Heterografts ,Female ,Gene Deletion - Abstract
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.
- Published
- 2019