Oncotarget

Research Papers:

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

Erika Onozawa, Haruna Shibayama, Honami Takada, Ken-Ichi Imadome, Sho Aoki, Mayumi Yoshimori, Norio Shimizu, Shigeyoshi Fujiwara, Takatoshi Koyama, Osamu Miura and Ayako Arai _

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Oncotarget. 2018; 9:31077-31089. https://doi.org/10.18632/oncotarget.25780

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Abstract

Erika Onozawa1,2, Haruna Shibayama1,2, Honami Takada1,2, Ken-Ichi Imadome3, Sho Aoki2, Mayumi Yoshimori1,2, Norio Shimizu4, Shigeyoshi Fujiwara5,6, Takatoshi Koyama2, Osamu Miura1 and Ayako Arai1,2

1Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan

2Department of Laboratory Molecular Genetics of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan

3Department of Advanced Medicine for Infections, National Center for Child Health and Development (NCCHD), Setagaya-ku, Tokyo, Japan

4Center of Stem cell and Regenerative Medicine, Institute of Research, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan

5Department of Allergy and Clinical Immunology, National Center for Child Health and Development (NCCHD), Setagaya-ku, Tokyo, Japan

6Division 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.


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