Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection

Yoshimori, Mayumi; Shibayama, Haruna; Imadome, Ken‐Ichi; Kawano, Fuminori; Ohashi, Ayaka; Nishio, Miwako; Shimizu, Norio; Kurata, Morito; Fujiwara, Shigeyoshi; Arai, Ayako

doi:10.1182/bloodadvances.2020002417

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…CMV and EBV are the most closely related clinical viruses with a clear therapeutic association (Einsele et al, 2020;Yoshimori et al, 2021). There seems to be a bidirectional relationship between the two viruses, and a high incidence/low clearance rate of CMV infection and a high incidence and delayed immune reconstitution of EBV-PTLD are key to all of these findings (Green et al, 2013;Chiereghin et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Association Between Cytomegalovirus and Epstein-Barr Virus Co-Reactivation and Hematopoietic Stem Cell Transplantation

Zhang

Jia

et al. 2022

Front. Cell. Infect. Microbiol.

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The co-reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in patients undergoing hematopoietic stem cell transplantation (HSCT) has been found. Research has shown that the reactivation of CMV or EBV is closely related to poor HSCT outcomes. In this study, we describe the clinical characteristics of HSCT patients with co-reactivation of CMV and EBV. We retrospectively reviewed the medical records of 327 patients who underwent HSCT at the Peking University People’s Hospital Institute of Hematology. Co-reactivation of CMV and EBV was observed in a total of 75 patients (22.9%) who also had a higher incidence of hemorrhagic cystitis (P=0.000). HSCT patients with CMV and co-reactivation of CMV and EBV had a significantly lower 1-year overall survival (OS; P=0.050). Further, COX regression analysis showed that viral infection was a risk factor for 1-year OS (HR, 12.625 for co-reactivation vs. no reactivation, p=0.021, and HR 13.580 for CMV reactivation vs. no reactivation, P=0.013). In conclusion, the patients with CMV reactivation had poorer outcome after HSCT regardless of EBV reactivation.

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Section: Introductionmentioning

confidence: 99%

Association Between Cytomegalovirus and Epstein-Barr Virus Co-Reactivation and Hematopoietic Stem Cell Transplantation

Zhang

Jia

et al. 2022

Front. Cell. Infect. Microbiol.

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“…According to our previous report, ruxolitinib, a JAK1/2 inhibitor suppressed STAT3 activation and IFN-γ production of EBV-positive NK cells in patients' cells [22]. Recently, we also observed that a proteasome inhibitor bortezomib suppressed IFN-γ production not only in EBV-positive T-or NK-cells but also in xenograft model of CAEBV [32]. Additionally, emapalumab, a neutralizing anti-IFN-γ monoclonal antibody has been reported for its efficacy to treat primary HLH [33].…”

Section: Discussionmentioning

confidence: 69%

Interferon-γ Produced by EBV-Positive Neoplastic NK-Cells Induces Differentiation into Macrophages and Procoagulant Activity of Monocytes, Which Leads to HLH

Yoshimori

Nishio

Ohashi

et al. 2021

Cancers

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Epstein–Barr virus (EBV)-positive T- or NK-cell neoplasms show progressive systemic inflammation and abnormal blood coagulation causing hemophagocytic lymphohistiocytosis (HLH). It was reported that inflammatory cytokines were produced and secreted by EBV-positive neoplastic T- or NK-cells. These cytokines can induce the differentiation of monocytes into macrophages leading to HLH. To clarify which products of EBV-positive neoplastic T- or NK-cells have effects on monocytes, we performed a co-culture assay of monocytes with the supernatants of EBV-positive T- or NK-cell lines. The expression of differentiation markers, the phagocytosis ability, and the mRNA expression of the inflammatory cytokines of THP-1, a monocytic cell line, clearly increased after culturing with the supernatants from EBV-NK-cell lines. Co-culturing with the supernatants promoted the expression of CD80 and CD206 as well as M1 and M2 macrophage markers in human monocytes. Co-culturing with the supernatants of EBV-NK-cell lines significantly enhanced the procoagulant activity and the tissue factor expression of monocytes. Interferon (IFN)-γ was elevated extremely not only in the supernatant of EBV-NK-cell lines but also in the plasma of EBV-positive NK-cell neoplasms patients accompanying HLH. Finally, we confirmed that IFN-γ directly enhanced the differentiation into M1-like macrophages and the procoagulant activity of monocytes. Our findings suggest that IFN-γ may potentially serve as a therapeutic target to regulate HLH in EBV-positive NK-cell neoplasms.

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“…Our results showed that simvastatin induced growth inhibition and apoptosis in sCAEBV cells, and, moreover, reduced the viral load of EBV-DNA in PB of the xenograft models. We recently reported the effects bortezomib, a proteasome inhibitor, on sCAEBV xenograft models 13) . The mice with significantly decreased EBV-DNA load in PB clearly showed reduced infiltration of EBV-positive cells in the liver.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Induces Anti-Tumor Effects on Systemic CAEBV <i>In Vitro</i> and <i>In Vivo</i>

Oshima

Yoshimori

Ohashi

et al. 2022

J St. Marianna Univ

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Background: Systemic chronic active Epstein-Barr virus infection (sCAEBV) is a rare and fatal lymphoid neoplasm characterized by sustained systemic inflammation and clonal proliferation of EBV-infected T or NK cells. Because the mechanisms responsible for the development of the disorder have not been elucidated to date, its optimal chemotherapy has not been established, and the prognosis of sCAEBV has remained very poor. We previously found and reported that simvastatin, an inhibitor of HMG-CoA reductase, inhibits prenylation of intracellular signal-mediating molecules in adult T-cell lymphoma/leukemia cells. On the basis of these findings, we hypothesized that simvastatin could also induce apoptosis in EBV-positive T or NK cells from sCAEBV. Methods: We examined two clinical samples of EBV-positive T-cell lines derived from sCAEBV, SNT8 and SNT15. The samples were obtained from six patients with sCAEBV. The in vitro effects of simvastatin on the cells were examined by XTT and Annexin V assay, and the in vivo effects of simvastatin on sCAEBV were examined in xenograft models of sCAEBV generated from NOD/Shi-scid/IL-2Rγ null mice. Results: Simvastatin suppressed proliferation and induced apoptosis in the cell lines in a dose-dependent manner. Simvastatin also suppressed proliferation and induced apoptosis of peripheral blood mononuclear cells derived from patients with sCAEBV with infected cell types of CD4 in 3 patients, CD8 in 2 patients, and CD56 in 1 patient. The presence of farnesyl pyrophosphate, one of the intermediates in the mevalonate pathway, restored the number of viable SNT8 and SNT15 cells treated with simvastatin. Furthermore, oral administration of simvastatin reduced EBV-DNA in the peripheral blood of sCAEBV xenograft models. Conclusions: Simvastatin may be an attractive reagent for sCAEBV.

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Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection

Cited by 6 publications

References 46 publications

Association Between Cytomegalovirus and Epstein-Barr Virus Co-Reactivation and Hematopoietic Stem Cell Transplantation

Association Between Cytomegalovirus and Epstein-Barr Virus Co-Reactivation and Hematopoietic Stem Cell Transplantation

Interferon-γ Produced by EBV-Positive Neoplastic NK-Cells Induces Differentiation into Macrophages and Procoagulant Activity of Monocytes, Which Leads to HLH

Simvastatin Induces Anti-Tumor Effects on Systemic CAEBV <i>In Vitro</i> and <i>In Vivo</i>

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