Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Handa, Hiroshi; Yamakawa, Natsuko; Imadome, Ken Ichi; Yahata, Takashi; Kotaki, Ryutaro; Ogata, Jun; Kakizaki, Masatoshi; Fujita, Koji; Lü, Jun; Yokoyama, Kazuaki; Okuyama, Kazuki; Sato, Ai; Takamatsu, Masako; Kurosaki, Natsumi; Alba, Syakira Mohamad; Azhim, Azran; Horie, Ryouichi; Watanabe, Toshiki; Kitamura, Toshio; Ando, Kiyoshi; Kashiwagi, Takao; Matsui, Toshimitsu; Okamoto, Akinao; Handa, Hiroshi; Kuroda, Masahiko; Nakamura, Naoya; Kotani, Ai

doi:10.1182/blood-2017-07-794529

Cited by 80 publications

(99 citation statements)

References 55 publications

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“…BART miRNA were found lacking in 71% of DLBCL cases (49). On the other hand, DLBCL patients with high BART miRNA expression in the blood showed worse prognosis than patients with low expression (50). Although high expression of BART miRNAs is possibly important for malignant transformation of lymphoma, it may be disadvantageous for lymphoma cells survival by escaping immune surveillance.…”

Section: Depletion Of Viral Mirnas In Ebv-associated Tumorsmentioning

confidence: 95%

Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases

et al. 2020

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Epstein-Barr virus (EBV) is an oncogenic human herpes virus that was discovered in 1964. Viral non-coding RNAs, such as BamHI-A rightward fragment-derived microRNAs (BART miRNAs) or BamHI-H rightward fragment 1-derived miRNAs (BHRF1 miRNA) in EBV-infected cells have been recently reported. Host miRNAs are also upregulated upon EBV infection. Viral and host miRNAs are important in maintaining viral infection and evasion of host immunity. Although miRNAs in EBV-infected cells often promote cell proliferation by targeting apoptosis or cell cycle, this review focuses on the regulation of the recognition of the host immune system. This review firstly describes the location and organization of two clusters of viral miRNAs, then describes evasion from host immune surveillance systems by modulating viral gene expression or inhibiting innate and acquired immunity by viral miRNAs as well as host miRNAs. Another topic is the enigmatic depletion of viral miRNAs in several types of EBV-infected tumor cells. Finally, this review introduces the strong correlation of nasopharyngeal cancer cases with a newly identified single nucleotide polymorphism that enhances BART miRNA promoter activity.

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Section: Depletion Of Viral Mirnas In Ebv-associated Tumorsmentioning

confidence: 95%

Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases

et al. 2020

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“…Further, CD11b + Gr-1 − (monocyte populations) were also increased in the spleen of dasatinib-treated mice. Our group previously found that monocytes and macrophages play a supportive role in tumorigenesis of EBV + lymphoma in a humanized mouse model 37 . Hence, it is also possible that the increase in these cells is a cause of tumor progression in the dasatinib-treated mice.…”

Section: Discussionmentioning

confidence: 92%

“…In addition, the cell fraction of myelomonocytes were investigated since we reported that monocytes and macrophages support EBV-induced tumorigenesis in another humanized mouse model 37 . We observed an increase in CD11b High Gr-1 Low cells in the blood and spleen of the dasatinib-treated mice.…”

Section: Dasatinib Does Not Improve Tumorigenesis Of Lcl-xenograft Micementioning

confidence: 99%

Dasatinib exacerbates splenomegaly of mice inoculated with Epstein-Barr virus-infected lymphoblastoid cell lines

Kotaki

Kawashima

Yamamoto

et al. 2020

Sci Rep

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Latent infection of epstein-Barr virus (eBV) is associated with a poor prognosis in patients with B cellmalignancy. We examined whether dasatinib, a multi kinase inhibitor, which is broadly used for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia is effective on EBV-positive B cell malignancies, using lymphoblastoid cell lines (LCLs) in vitro and in vivo. As a result, in vitro experiments showed that dasatinib induced cell death of the eBV-LcLs which was not accompanied with a lytic reactivation of EBVs. To evaluate the effectiveness in EBV latency type III represented by immunodeficiency lymphoma, LCL-inoculated immunodeficient NOD/shi-scid/Il2rg nul (NOG) mice were treated with dasatinib. However, in vivo experiments revealed that dasatinib treatment exacerbated tumor cell infiltration into the spleen of LCL-inoculated NOG mice, whereas tumor size at the inoculated site was not affected by the treatment. These results suggest that dasatinib exacerbates the pathogenesis at least in some situations although the drug is effective in vitro. Hence, we should carefully examine a possibility of dasatinib repositioning for eBV + B cell malignancies.Epstein-Barr virus (EBV) is a human oncogenic herpesvirus which persistently infects more than 90% of the healthy adult humans 1,2 . While primary EBV infection in adolescents causes infectious mononucleosis, the infection in childhood is usually asymptomatic. After the primary infection, EBV establishes a lifelong persistent infection preferentially in resting memory B cells 3-5 . Although the persistent EBV infection is usually asymptomatic, EBV may be involved in various B cell malignancies, such as diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, classical Hodgkin lymphoma, and post-transplant lymphoproliferative disorder.Several studies have reported that EBV is associated with a poor prognosis in patients with classical Hodgkin lymphoma and DLBCL, typically in an aged population 6-9 . Malignant EBV + B cells express several genes encoded in the EBV genome, including latent membrane proteins (LMPs) and EBV nuclear antigens (EBNAs) 2 . Based on expression profiles of the EBV-derived molecules, EBV + B cell malignancies are classified into three types of latency, latency I, II, and III. A small-scaled study in our institute suggested that patients with latency III EBV + DLBCL had a very poor prognosis, namely they died within one year from diagnosis, even though they were treated with R-CHOP, a standard therapy for DLBCL 9 . Latency III EBV + cells express most EBV-derived genes among the three types. Hence, the EBV-derived factors may be involved in the poor prognosis of the patients with latency III EBV + DLBCL. One possible therapeutic target for latency III EBV + B cell malignancies is signal transduction pathways from LMPs. LMPs, including LMP1 and LMP2A, which mimic signal transduction from

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“…Interestingly, the circulating vesicles have been shown to contain nucleic acid in the form of DNA, mRNA and microRNA (miRNA), which may have important biological effects on cells that take up this material (Lefebvre & Lecuyer, ). A recent study found that Epstein–Barr virus (EBV)‐infected cells release exosomes that can influence lymphoproliferation in uninfected cells (Higuchi et al , ). Using two strains of EBV that vary based on their ability to induce lymphoproliferation, EBV‐free exosomes derived from cells infected with the more aggressive viral strain were able to induce lymphoproliferative disease in mice in the absence of EBV itself.…”

Section: Exosomesmentioning

confidence: 99%

“…Using two strains of EBV that vary based on their ability to induce lymphoproliferation, EBV‐free exosomes derived from cells infected with the more aggressive viral strain were able to induce lymphoproliferative disease in mice in the absence of EBV itself. The effect was traced to BamHI fragment A rightward transcript (BART) miRNA transferred in exosomes (Higuchi et al , ). In addition to these important biological effects, the purification and deep sequence analysis of the extracellular vesicles from tumours may provide important diagnostic and prognostic information for patients with NHL.…”

Section: Exosomesmentioning

confidence: 99%

Lymphoma diagnostics: getting more from less

Galardy

Bedekovics²,

Macintyre

et al. 2019

Br J Haematol

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In the modern era, clinicians and pathologists increasingly make challenging diagnoses in patients with suspected lymphoma using minimal amounts of diagnostic material. The increase in utilization of minimally invasive procedures, such as fine needle aspiration or needle core biopsies, lead to challenges in our ability to make accurate histopathological assessments of disease, including the integration of new diagnostic and prognostic testing, with smaller amounts of material. The trend towards minimally invasive diagnostics is also often in conflicting interest with researchers seeking to study tissue specimens to better understand the biology and genetics of these diseases to move the field forward. Thankfully, there are emerging fields which seek to extract large amounts of diagnostic and prognostic data out of material that is circulating in the blood of patients with lymphoma. Here we will review recent exciting data regarding the use of circulating tumour cells, circulating tumour DNA, and the detection and utility of circulating exosomes and how it can assist in diagnosis, prognosis and therapeutic monitoring. These advances hold the promise to enable continued safe patient care while also advancing discovery, translational and clinical research.

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Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Cited by 80 publications

References 55 publications

Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases

Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases

Dasatinib exacerbates splenomegaly of mice inoculated with Epstein-Barr virus-infected lymphoblastoid cell lines

Lymphoma diagnostics: getting more from less

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