title: Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.
abstract: Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.
authors.affiliation: Departments of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Ando
authors.affiliation: Departments of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kawada
authors.affiliation: Departments of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Departments of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Departments of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Departments of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Torii
authors.affiliation: Departments of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Asai
authors.affiliation: Departments of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Goshima
authors.affiliation: Departments of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Murata
authors.affiliation: Center of Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Departments of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Departments of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000821:virology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D053616:Janus Kinase 3 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D016399:Lymphoma, T-Cell / Q000209:etiology* / Q000473:pathology*; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D050799:STAT5 Transcription Factor; C479163:tofacitinib; D053616:Janus Kinase 3
keywords: EBV; cell-cycle arrest; lymphoma; tofacitinib