STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target

// Erika Onozawa 1, 2 , Haruna Shibayama 1, 2 , Honami Takada 1, 2 , Ken-Ichi Imadome 3 , Sho Aoki 2 , Mayumi Yoshimori 1, 2 , Norio Shimizu 4 , Shigeyoshi Fujiwara 5, 6 , Takatoshi Koyama 2 , Osamu Miura 1 and Ayako Arai 1, 2 1 Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan 2 Department of Laboratory Molecular Genetics of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan 3 Department of Advanced Medicine for Infections, National Center for Child Health and Development (NCCHD), Setagaya-ku, Tokyo, Japan 4 Center of Stem cell and Regenerative Medicine, Institute of Research, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan 5 Department of Allergy and Clinical Immunology, National Center for Child Health and Development (NCCHD), Setagaya-ku, Tokyo, Japan 6 Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan Correspondence to: Ayako Arai, email: ara.hema@tmd.ac.jp Keywords: chronic active Epstein-Barr virus infection; STAT3; T/NK-cell lymphoproliferative disorder; cytokines; ruxolitinib Received: August 03, 2017     Accepted: June 22, 2018     Published: July 24, 2018 ABSTRACT Chronic active Epstein-Barr virus infection (CAEBV) is a lymphoproliferative disorder characterized by the clonal proliferation of EBV-infected T or NK cells and is related to severe systemic inflammation. This study aims to investigate STAT3 to elucidate the mechanism underlying the CAEBV development. We determined that STAT3 was constitutively activated in EBV-positive T- or NK-cell lines. We also determined that STAT3 was activated in the peripheral blood mononuclear cells (PBMCs) containing EBV-infected clonally proliferating T or NK cells in six of seven patients with CAEBV. We conducted direct sequencing of the STAT3 Src homology 2 (SH2) domain, which has previously been reported to be mutated in T- or NK-cell neoplasms. No mutation was detected in the STAT3 SH2 domain in patients with CAEBV. Next, we investigated the effects of ruxolitinib, an inhibitor of both JAK1 and JAK2, which phosphorylates and activates STAT3. Ruxolitinib suppressed the phosphorylation of STAT3 in EBV-positive T- or NK-cell lines. Ruxolitinib also decreased the viable cell number of EBV-positive T- or NK-cell lines and PBMCs from patients with CAEBV. Furthermore, ruxolitinib suppressed the production of inflammatory cytokines in the cell lines and CAEBV patient-derived cells. In conclusion, constitutively activated STAT3, which promotes survival and cytokine production, could be a therapeutic target for CAEBV.