Epstein-Barr Virus Utilizes Ikaros in Regulating Its Latent-Lytic Switch in B Cells

Iempridee, Tawin; Reusch, Jessica A.; Riching, Andrew S.; Johannsen, Eric; Dovat, Sinisa; Kenney, Shannon C.; Mertz, Janet E.

doi:10.1128/jvi.03706-13

Cited by 25 publications

(23 citation statements)

References 95 publications

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“…In contrast, concomitant addition of a clinically relevant concentration of idelalisib completely suppressed stimulation of BMRF1, pGSK3α/β Ser21/9 , and pAKT Ser427 (Figure 3C). LTP may also regulate EBV reactivation through PI3K-mediated suppression of the transcription factor Forkhead-box-O1 (FoxO1), which if suppressed leads to loss of Ikaros (30), an EBV latency regulator (15). Treatment of DAUDI cells with LEN slightly decreased FoxO1 and depleted Ikaros, leading to the enhancement of BZLF1 and BMRF1 and the induction of pAKT Ser473 (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

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Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

Jones

Iempridee

Wang

et al. 2016

Clinical Cancer Research

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Purpose Lenalidomide, thalidomide, and pomalidomide (LTP) are immunomodulatory agents approved for use in multiple myeloma, but in some settings, especially with alkylating agents, an increase in Hodgkin’s lymphoma (HL) and other secondary primary malignancies (SPM) has been noted. Some of these malignancies have been linked to Epstein-Barr virus (EBV), raising the possibility that immunomodulatory drugs disrupt latent EBV infection. Experimental Design We studied the ability of LTP to reactivate latently infected EBV-positive cell lines in vitro and in vivo, and evaluated the EBV viral load in archived serum samples from patients who received a lenalidomide, thalidomide and dexamethasone (LTD) combination. Results Treatment of EBV-infected B-cell lines with LTP at physiologically relevant concentrations induced the immediate early gene BZLF1, the early gene BMRF1, and the late proteins VCA and BCFR1. This occurred in the potency order pomalidomide>lenalidomide>thalidomide, and the nucleoside analogue ganciclovir enhanced the cytotoxic effects of lenalidomide and pomalidomide in Burkitt’s lymphoma cells in vitro and in vivo. EBV reactivation was related to phosphatidylinositol-3 kinase (PI3K) stimulation and Ikaros suppression, and blocked by the PI3K-δ inhibitor idelalisib. Combinations of lenalidomide with dexamethasone or rituximab increased EBV reactivation compared to lenalidomide alone and, importantly, lenalidomide with melphalan produced even greater reactivation Conclusions We conclude LTP may reactivate EBV-positive resting memory B-cells thereby enhancing EBV lytic cycle and host immune suppression.

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Section: Resultsmentioning

confidence: 99%

“…MUTU-I cells were infected with a Lentivirus encoding Ikaros or a control virus as previously described (15). …”

Section: Methodsmentioning

confidence: 99%

Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

Jones

Iempridee

Wang

et al. 2016

Clinical Cancer Research

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“…Thus, EBV reactivation likely occurs, in part, by enhancement of Z transcriptional activity as a direct consequence of loss of Oct-2 and PAX5. We recently discovered that in the absence of R expression, Ikaros (another cellular transcription factor abundantly present in B cells), contributes to maintenance of EBV latency, in part, by increasing Oct-2 expression [59]; interestingly, once R is expressed, Ikaros promotes lytic gene expression and directly associates with R [59]. The transcriptional activity of Z is also suppressed, in part, by SUMOylation at Z lysine 12 [60].…”

Section: Factors Contributing To Maintenance Of Ebv Latencymentioning

confidence: 99%

Regulation of the latent-lytic switch in Epstein–Barr virus

Kenney

Mertz

2014

Seminars in Cancer Biology

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233

235

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Epstein–Barr virus (EBV) infection contributes to the development of several different types of human malignancy, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. As a herpesvirus, EBV can establish latent or lytic infection in cells. EBV-positive tumors are composed almost exclusively of cells with latent EBV infection. Strategies for inducing the lytic form of EBV infection in tumor cells are being investigated as a potential therapy for EBV-positive tumors. In this article, we review how cellular and viral proteins regulate the latent-lytic EBV switch in infected B cells and epithelial cells, and discuss how harnessing lytic viral reactivation might be used therapeutically.

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“…31 Tet-On-inducible TRIPZ lentiviral vectors expressing NT shRNA or shRNAs targeting H19 (H19 shRNA1 and H19 shRNA2) were used to produce lentiviruses. In brief, 293 T cells from 10 cm dishes were co-transfected with 4 mg lentiviral vector(s), 1.4 mg psPAX2, and 0.6 mg VSVG.…”

Section: Infection Of Cell Lines With Lentivirusmentioning

confidence: 99%

Long non-coding RNA H19 enhances cell proliferation and anchorage-independent growth of cervical cancer cell lines

Iempridee

2016

Exp Biol Med (Maywood)

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Long non-coding RNA H19 is aberrantly expressed in multiple malignancies and its expression levels correlate with recurrence, metastasis, and patient survival. Despite numerous reports documenting the role of H19 in carcinogenesis, its contribution to cervical cancer development is still largely unknown. In this study, I observed that H19 expression was elevated in cervical cancer cell lines and could be detected in extracellular vesicles in the culture medium. In addition, I demonstrated, by overexpression and knockdown experiments, that H19 promoted cell proliferation and multicellular tumor spheroid formation without significantly affecting apoptosis and cell migration. Finally, treatment with transforming growth factor beta and hypoxia-mimetic CoCl 2 could modulate H19 levels in a cell line-specific manner. These findings indicate that H19 promotes both anchorage-specific andindependent growth of cervical cancer cell lines and may serve as a potential target for cancer diagnosis and therapy.

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Epstein-Barr Virus Utilizes Ikaros in Regulating Its Latent-Lytic Switch in B Cells

Cited by 25 publications

References 95 publications

Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

Regulation of the latent-lytic switch in Epstein–Barr virus

Long non-coding RNA H19 enhances cell proliferation and anchorage-independent growth of cervical cancer cell lines

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