title: EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.
abstract: Epstein-Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.|Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Honami
authors.initials: H
authors.lastname: Takada
authors.affiliation: Division of Advanced Medicine for Virus Infections, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Imadome
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.|Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Shibayama
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.|Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yoshimori
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Ludan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Virology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saitoh
authors.affiliation: Department of Molecular Virology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Uota
authors.affiliation: Department of Molecular Virology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.|Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Virus Research Unit, Division of Medical Science, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Fujiwara
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Miura
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Ayako
authors.identifier: http://orcid.org/0000-0002-8275-5372
authors.initials: A
authors.lastname: Arai
mesh_terms: D000293:Adolescent; D000328:Adult; D045744:Cell Line, Tumor; D002470:Cell Survival; D002908:Chronic Disease; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000821:virology*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology*; D014763:Viral Matrix Proteins / Q000276:immunology; D055815:Young Adult
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins