Multiomics analysis reveals the genetic and epigenetic features of high-risk NK cell–type chronic active EBV infection
Abstract
Abstract Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an orphan disease characterized by the proliferation and infiltration of EBV-infected T/natural killer (NK) cells into multiple organs. Although CAEBV is a heterogeneous disease with diverse clinical courses, its pathogenesis remains poorly understood. In this study, we explored the molecular mechanisms underlying CAEBV by performing a comprehensive multiomics analysis, including genome, transcriptome, epigenome, and single-cell transcriptome and surface proteome analyses, of 65 patients with CAEBV. Methylation analysis identified 2 distinct subtypes of NK cell–type CAEBV based on the CpG island methylator phenotype (CIMP). In CIMP-positive CAEBV, regions associated with enhancer of zeste homolog 2 binding sites and histone H3 lysine 27 trimethylation exhibited increased DNA hypermethylation, resulting in downregulation of tumor suppressor and antiherpesvirus genes. CIMP-positive CAEBV had a particularly poor prognosis and displayed a “neoplastic” phenotype with a DNA methylation pattern similar to that of extranodal NK/T-cell lymphoma, a higher tumor mutation burden, and frequent copy number alterations. In addition, both in vitro and in vivo functional assays demonstrated that 5-azacytidine, a hypomethylating agent, was a potentially effective agent for high-risk CIMP-positive CAEBV. Finally, we established a method to effectively detect EBV-infected cells in single-cell analysis, suggesting that EBV-infected NK cells have tissue-resident properties and that innate and adaptive immunity to EBV is compromised in patients with CAEBV. The present findings provide insight into the complex molecular features of CAEBV and suggest potential molecular therapies.
Article Details
Authors (43)
Ryo Akazawa
1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Takashi Mikami
Masaki Yamada
Itaru Kato
Hirohito Kubota
Satoshi Saida
1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Yoshinori Uchihara
Yuriko Ishikawa
3Department of Advanced Medicine for Virus Infections, National Center for Child Health and Development, Tokyo, Japan
Tatsuya Kamitori
Keiji Tasaka
Kiyotaka Isobe
1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Tomoya Isobe
Kazushi Izawa
Katsutsugu Umeda
1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Hidefumi Hiramatsu
1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Keita Jinnouchi
9Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
Masahiro Hirata
9Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
Masakazu Fujimoto
Tomoo Daifu
10Department of Pediatrics, Japanese Red Cross Otsu Hospital, Otsu, Japan
Hiroo Ueno
16Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Seishiro Nodomi
5Department of Pediatrics, Kurashiki Central Hospital, Okayama, Japan
Machiko Sawada
Hisanori Fujino
12Department of Pediatrics, Osaka Red Cross Hospital, Osaka, Japan
Katsuyoshi Koh
23Japan Children’s Cancer Group ALL Committee, Nagoya, Japan
Mitsuteru Hiwatari
14Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Motohiro Kato
6Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Hiroaki Goto
Ikumi Katano
17Laboratory Animal Research Department, Central Institute for Experimental Medicine and Life Science, Kawasaki, Japan
Ryoji Ito
17Laboratory Animal Research Department, Central Institute for Experimental Medicine and Life Science, Kawasaki, Japan
Mamoru Ito
Nobuyuki Kakiuchi
Masahiro M. Nakagawa
Yuichi Shiraishi
Yoshitaka Honda
Hiroyuki Yoshitomi
21Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan
Hideki Ueno
Department of Immunology, Graduate School of Medicine, Kyoto University
Maho Sato
23Department of Hematology/Oncology, Osaka Women’s and Children’s Hospital, Osaka, Japan
Satoru Miyano
Hironori Haga
9Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
Akihisa Sawada
23Department of Hematology/Oncology, Osaka Women’s and Children’s Hospital, Osaka, Japan
Ken-Ichi Imadome
Seishi Ogawa
Junko Takita