EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells

Abstract

Epstein–Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

Epstein‐Barr virus LMP2A utilizes Syk and PI3K to activate NF‐κB in B‐cell lymphomas to increase MIP‐1α production

“…Previous studies demonstrate that LMP2A activates NF‐κB in a murine transgenic mouse model and more recent studies demonstrate that LMP2A activates a NF‐κB dependent luciferase reporter in human T cells . However, the ability of LMP2A to activate NF‐κB has not been demonstrated in human B cells.…”

“…Numerous studies indicate that PI3K activates AKT to specifically increase the nuclear translocation of NF‐κB by phosphorylating IκB kinase, which positively regulates NF‐κB activity and p65 nuclear translocation . More recently, data demonstrate that LMP2A activates an NF‐κB‐dependent luciferase reporter in human T cell lines, further suggesting that LMP2A activates NF‐κB in human cells. We did not see a statistically significant increase in the p50 subunit of NF‐κB, which heterodimerizes with p65 to increase transcription .…”

“…activates an NF-κB-dependent luciferase reporter in human T cell lines, 47 further suggesting that LMP2A activates NF-κB in human cells. We did not see a statistically significant increase in the p50 subunit of NF-κB, which heterodimerizes with p65 to increase transcription.…”

“…Previous studies demonstrate that LMP2A activates NF-κB in a murine transgenic mouse model 34 and more recent studies demonstrate that LMP2A activates a NF-κB dependent luciferase reporter in human T cells. 47 The p65 subunit of NF-κB heterodimerizes with p50 to activate transcription. 48 As shown in Figure 4B, there is a trend that LMP2A increases p50 nuclear localization that did not reach suggesting that there are substantial amounts of p50 available to heterodimerize with p65 to increase MIP-1α levels.…”

Evaluation of the prognostic importance of c-myc and bcl-2 expressions and the presence of epstein-barr virus in classical hodgkin lymphoma

“…It has been shown that the presence of Bcl-2, c-Myc, and Bcl-6 expressions in diffuse large B-cell lymphomas are related with poor prognosis (19,20) and the presence of p-53 mutation in mantle cell lymphomas is a predictor of aggressive behaviour (21,22). It has also been determined that presence of EBV in T-cell NHLs is related with poor prognosis (23,24). minutes of protease 3, and the INFORM EBER steps were applied; then 6 minutes of red counterstain was performed on the background and dark-blue nuclear staining was considered to be positive in HRS cells.…”