Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells

// Shotaro Ando 1 , Jun-ichi Kawada 1 , Takahiro Watanabe 2 , Michio Suzuki 1 , Yoshitaka Sato 2 , Yuka Torii 1 , Masato Asai 3 , Fumi Goshima 2 , Takayuki Murata 2 , Norio Shimizu 4 , Yoshinori Ito 1 , Hiroshi Kimura 2 1 Departments of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 2 Departments of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 3 Departments of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan 4 Center of Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan Correspondence to: Jun-ichi Kawada, email: kawadaj@med.nagoya-u.ac.jp Keywords: tofacitinib, EBV, lymphoma, cell-cycle arrest Received: June 13, 2016      Accepted: October 03, 2016      Published: October 08, 2016 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.