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

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.

Chronic active Epstein–Barr virus infection: a bi-faceted disease with inflammatory and neoplastic elements

“…STAT3 also mediates the intracellular signaling downstream of the cytokine receptors and regulates inflammation [28]. We observed constitutive activation of STAT3 in EBV-positive T or NK-cell lines established from EBV-T/NK-lymphoid neoplasms as well as in neoplastic EBV-positive T or NK cells obtained from CAEBV patients [29]. Of note, we observed no mutation in the SH2 domain of the STAT3 gene, which is an essential site for activation of molecules that are hot spots of activating mutation in other T or NK-cell tumors; therefore, it seems likely that the upstream molecules may contribute to the activation.…”

“…Several studies have suggested that STAT3 is activated downstream of LMP1 through the activation of NF-jB [30,31]. Interestingly, Onozawa et al [29] found that inhibition of the tyrosine kinase JAK1/2, which phosphorylates STAT3, by its inhibitor ruxolitinib, inhibited STAT3 activation in EBV-positive T or NK-cell lines. Ruxolitinib was shown to suppress proliferation and to induce apoptosis of these cells.…”

STAT3 Dysregulation in Mature T and NK Cell Lymphomas

“…A multi-center phase II study evaluating the efficacy of ruxolitinib in relapsed/refractory PTCL and CTCL observed overall response rates (ORR) of up to 40% with a trend towards higher ORR and more durable responses among patients with JAK/STAT alterations [64]. Ruxolitinib suppresses STAT3 and decreases the viability of Epstein-Barr virus (EBV)-positive T or NK cell lines and PBMCs from patients with chronic active Epstein-Barr virus infection (CAEBV) [71]. Interestingly, JAK1/2 inhibitor treatment was associated with an increased risk of progression to aggressive lymphomas in patients with myelofibrosis who have a preexisting B cell clone in their bone marrow [89].…”

JAK inhibitors for refractory lymphoma

“…In this issue of Oncotarget , Onozawa et al . report that signal transducers and activators of transcription (STAT) 3 is constitutively active in both EBV+ T/NK cell lines and peripheral blood mononuclear cells from CAEBV patients [ 7 ]. They also show that ruxolitinib, an inhibitor of Janus kinase (JAK)1/2, suppresses not only the viability of EBV-infected T/NK cells but also their production of inflammatory cytokines.…”