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.
Highlights
The Epstein-Barr virus (EBV) is a ubiquitous virus that has infected up to 95% of the adult population worldwide
The JAK3/STAT5 pathway is activated in EBVpositive T and natural killer (NK) cell lines and tofacitinib inhibits its activation
To determine the presence and activation status of the JAK3/STAT5 pathway in EBV negative or positive B, T and NK cell lines, we examined the expression of JAK3, and the expression and phosphorylation status of STAT5, in an EBV-negative B cell line (BJAB), an EBV-transformed lymphoblastoid cell line (LCL), EBVnegative T cell lines (Jurkat and MOLT4), EBV-positive T cell lines (SNT13,15 and 16), an EBV-negative NK cell line (KHYG1), and EBV-positive NK cell lines (KAI3 and SNK6)
Summary
The Epstein-Barr virus (EBV) is a ubiquitous virus that has infected up to 95% of the adult population worldwide. EBV predominantly infects B cells, it infects T or NK cells, especially in association with lymphoid malignancies including NK/T-cell lymphoma, hydroa vacciniforme-like lymphoma, and chronic active EBV disease (CAEBV) [1,2,3,4]. As some types of EBVassociated lymphoma are often refractory and resistant to conventional chemotherapies, various novel treatments have been attempted. Some progress has been achieved with treatments such as rituximab (a humanized monoclonal antibody against CD20) and EBV-specific cytotoxic T lymphocyte infusion, the effects of those new therapies are still restricted. Novel approaches involving targeted molecular therapies are desirable, especially for T or NK cell malignancies [5,6,7,8,9]
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