研究者詳細 - 木村　宏

論文 - 木村　宏

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Oncogenesis of CAEBV revealed: Intragenic deletions in the viral genome and leaky expression of lytic genes 査読有り

Murata Takayuki, Okuno Yusuke, Sato Yoshitaka, Watanabe Takahiro, Kimura Hiroshi

REVIEWS IN MEDICAL VIROLOGY 30 巻 ( 2 ) 頁： e2095 2020年3月

Antitumor activity of CDK inhibitor alsterpaullone in Epstein-Barr virus-associated lymphoproliferative disorders. 査読有り国際共著

Watanabe T, Sato Y, Masud HMAA, Takayama M, Matsuda H, Hara Y, Yanagi Y, Yoshida M, Goshima F, Murata T, Kimura H

Cancer science 2020年1月

Epstein-Barr Virus BBRF2 Is Required for Maximum Infectivity Open Access

Al Masud, HMA; Yanagi, Y; Watanabe, T; Sato, Y; Kimura, H; Murata, T

MICROORGANISMS 7 巻 ( 12 ) 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Microorganisms

Epstein-Barr virus (EBV) is a member of the gammaherpesvirinae, which causes infectious mononucleosis and several types of cancer. BBRF2 is an uncharacterized gene of EBV and is expressed during the lytic phase. To evaluate its function, BBRF2-knockout EBV was prepared using bacterial artificial chromosome (BAC) technology and the CRISPR/Cas9 system. Although viral gene expression, DNA synthesis, and progeny secretion were not affected, the infectivity of progeny viruses was significantly reduced by the disruption of BBRF2. When expressed alone, BBRF2 protein localized to the nucleus and cytoplasm, while the coexpression of an interacting partner, BSRF1, resulted in its relocalization to the cytoplasm. Interestingly, the coexpression of BBRF2 protected BSRF1 from proteasome/ubiquitin-dependent degradation. Therefore, BBRF2, together with BSRF1, augments viral infectivity.

DOI： 10.3390/microorganisms7120705

NK-cell post-transplant lymphoproliferative disease with chronic active Epstein-Barr virus infection-like clinical findings.

Iemura T, Kondo T, Hishizawa M, Yamashita K, Kimura H, Takaori-Kondo A

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2019年8月

Editorial: Epstein-Barr Virus-Associated T/NK-Cell Lymphoproliferative Diseases

Fujiwara Shigeyoshi, Kimura Hiroshi

FRONTIERS IN PEDIATRICS 7 巻 ( JULY ) 頁： 285 2019年7月

Viral DNA loads in various blood components of patients with Epstein-Barr virus-positive T/NK cell lymphoproliferative diseases.

Kawada JI, Kamiya Y, Sawada A, Iwatsuki K, Izutsu K, Torii Y, Kimura H, Ito Y

The Journal of infectious diseases 2019年6月

The BOLF1 gene is necessary for effective Epstein-Barr viral infectivity

Al Masud H. M. Abdullah, Watanabe Takahiro, Sato Yoshitaka, Goshima Fumi, Kimura Hiroshi, Murata Takayuki

VIROLOGY 531 巻頁： 114-125 2019年5月

S-Like-Phase Cyclin-Dependent Kinases Stabilize the Epstein-Barr Virus BDLF4 Protein To Temporally Control Late Gene Transcription Open Access

Sato, Y; Watanabe, T; Suzuki, C; Abe, Y; Al Masud, HMA; Inagaki, T; Yoshida, M; Suzuki, T; Goshima, F; Adachi, J; Tomonaga, T; Murata, T; Kimura, H

JOURNAL OF VIROLOGY 93 巻 ( 8 ) 2019年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Virology

Temporally controlled gene expression is necessary for the propagation of herpesviruses. To achieve this, herpesviruses encode several transcriptional regulators. In Epstein-Barr virus, BcRF1 associates with five viral proteins (BDLF4, BGLF3, BFRF2, BVLF1, and BDLF3.5) to form the viral late (L) gene regulatory complex, which is called the viral preinitiation complex (vPIC), on TATT-containing promoters. However, regulation of the vPIC has been largely unexplored. In this study, we performed two screens using a kinase inhibitor library and identified a series of cyclin-dependent kinase (CDK) inhibitors that downregulated the expression of L genes without any impact on viral DNA replication through destabilization of the BDLF4 protein. Knockdown of CDK2 by short hairpin RNA (shRNA) and proteasome inhibitor treatment showed that phosphorylation of the BDLF4 protein prevented ubiquitin-mediated degradation. Moreover, we demonstrated that cyclin A- and E-associated CDK2 complexes phosphorylated BDLF4 in vitro, and we identified several serine/threonine phosphorylation sites in BDLF4. Phosphoinactive and phosphomimic mutants revealed that phosphorylation at threonine 91 plays a role in stabilizing BDLF4. Therefore, our findings indicate that S-like-phase CDKs mediate the regulation of L gene expression through stabilization of the BDLF4 protein, which makes the temporal L gene expression system more robust. IMPORTANCE Late (L) genes represent more than one-third of the herpesvirus genome, suggesting that many of these genes are indispensable for the life cycle of the virus. With the exception of BCRF1, BDLF2, and BDLF3, Epstein-Barr virus L genes are transcribed by viral regulators, which are known as the viral preinitiation complex (vPIC) and the host RNA polymerase II complex. Because the vPIC is conserved in beta- and gammaherpesviruses, studying the control of viral L gene expression by the vPIC contributes to the development of drugs that specifically inhibit these processes in beta- and gammaherpesvirus infections/diseases. In this study, we demonstrated that CDK inhibitors induced destabilization of the vPIC component BDLF4, leading to a reduction in L gene expression and subsequent progeny production. Our findings suggest that CDK inhibitors may be a therapeutic option against beta- and gammaherpesviruses in combination with existing inhibitors of herpesvirus lytic replication, such as ganciclovir.

DOI： 10.1128/JVI.01707-18

Web of Science

Scopus

PubMed

Initial Characterization of the Epstein-Barr Virus BSRF1 Gene Product

Yanagi Yusuke, Al Masud H. M. Abdullah, Watanabe Takahiro, Sato Yoshitaka, Goshima Fumi, Kimura Hiroshi, Murata Takayuki

VIRUSES-BASEL 11 巻 ( 3 ) 2019年3月

Defective Epstein-Barr virus in chronic active infection and haematological malignancy (vol 4, pg 404, 2019) 国際共著 Open Access

Okuno, Y; Murata, T; Sato, Y; Muramatsu, H; Ito, Y; Watanabe, T; Okuno, T; Murakami, N; Yoshida, K; Sawada, A; Inoue, M; Kawa, K; Seto, M; Ohshima, K; Shiraishi, Y; Chiba, K; Tanaka, H; Miyano, S; Narita, Y; Yoshida, M; Goshima, F; Kawada, JI; Nishida, T; Kiyoi, H; Kato, S; Nakamura, S; Morishima, S; Yoshikawa, T; Fujiwara, S; Shimizu, N; Isobe, Y; Noguchi, M; Kikuta, A; Iwatsuki, K; Takahashi, Y; Kojima, S; Ogawa, S; Kimura, H

NATURE MICROBIOLOGY 4 巻 ( 3 ) 頁： 544 - 544 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Microbiology

In the version of this Letter originally published, in the sentence beginning “The major driver role of DDX3X mutations..”, the citation “Fig. 2a–f” should have been “Fig. 2”. In addition, in the sentence beginning “Another finding of interest was the presence of identical driver mutations..”, the citation “Fig. 3a,b and Fig. 4” should have been “Fig. 3”. This has now been amended in all versions of the Letter.

DOI： 10.1038/s41564-019-0387-8

Web of Science

Scopus

PubMed

EBV Viral Loads in Diagnosis, Monitoring, and Response Assessment Open Access

Kimura, H; Kwong, YL

FRONTIERS IN ONCOLOGY 9 巻 ( FEB ) 頁： 62 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Oncology

The quantification of circulating Epstein Barr virus (EBV) DNA loads has played an important role in the diagnosis and management of EBV-associated lymphoid malignancies. Viral load measurement is particularly useful for monitoring EBV-DNA in hematopoietic stem cell transplant patients, and for assessing the prognosis or response to therapy of EBV-associated intractable lymphomas like extranodal NK/T-cell lymphoma, nasal type. Cell-free EBV-DNA in plasma can be used as a biomarker for estimating the severity or prognosis of these lymphomas. In addition to plasma, whole blood has been used for the management of transplant patients. Although measuring EBV-DNA has been useful, there is a lack of standardization and the optimal specimens for measuring viral loads are unknown. This can be attributed to the different forms of EBV-DNA that exist in peripheral blood and the different pathologies that result from diverse EBV disease states. As a result, guidelines for EBV diagnosis or the initiation of treatment are unclear. However, the newly established World Health Organization standard for EBV quantification will encourage collaborative studies across institutions and countries to establish proper guidelines for EBV diagnosis and the initiation of treatment.

DOI： 10.3389/fonc.2019.00062

Overview of EBV-Associated T/NK-Cell Lymphoproliferative Diseases

Kimura Hiroshi, Fujiwara Shigeyoshi

FRONTIERS IN PEDIATRICS 6 巻 2019年1月

[Clinical features of adult-onset chronic active Epstein-Barr virus infection].

Kawamoto K, Miyoshi H, Seto M, Kimura H, Ohshima K

[Rinsho ketsueki] The Japanese journal of clinical hematology 60 巻 ( 8 ) 頁： 944 - 952 2019年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本血液学会

<p>慢性活動性EBウイルス感染症（chronic active Epstein-Barr virus infection, CAEBV）は，Epstein-Barr virus（EBV）の再活性化（感染細胞の再増殖）による慢性持続性もしくは再発性の発熱やリンパ節腫脹，肝脾腫，皮疹などの伝染性単核球症様症状などを呈する疾患である。CAEBVの診断までに明確な免疫異常や既往歴などはなくその発症機序については現在も不明である。CAEBVはEBVに感染したT細胞もしくはNK細胞のclonal expansionによって血球貪食症候群や悪性リンパ腫などの致命的な疾患をきたす予後不良の疾患である。造血幹細胞移植がおこなわれなければ，CAEBVは予後不良の経過をたどる。このentitiyはほとんどが小児発症であるため改定2016WHO分類にはEBV-positive T-cell and NK-cell lymphoproliferative disease of childhoodのうちのchronic active EBV infection of T- and NK-cell type, systemic formとして収載されている。しかし同様の病態が成人にも発症することが知られるようになり，今回我々は成人発症CAEBV（adult-onset CAEBV）の臨床的特徴について多数例において検討した。その検討結果を報告するとともに，近年報告されているCAEBVを含むEBV-NK/T/LPDsにおける遺伝子異常などの結果を踏まえて成人発症のCAEBVの病態について概説する。</p>

DOI： 10.11406/rinketsu.60.944

PubMed

CiNii Research

[EBV and Lymphomagenesis].

Kimura H, Okuno Y

Uirusu 69 巻 ( 1 ) 頁： 13 - 22 2019年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本ウイルス学会

Epstein-Barr virus (EBV)はヘルペスウイルス科に属する二本鎖DNAウイルスである．腫瘍ウイルスであるEBVは様々なリンパ系腫瘍と関連しており，そのリンパ腫原性については，MYCの転座・活性化など，Burkittリンパ腫を中心に広範な研究がなされてきた．しかしながら，Burkittリンパ腫以外のリンパ系腫瘍については，レセプターや宿主遺伝子の役割を含め，腫瘍化メカニズムについて不明な点が多く，その全貌は明らかとなっていない．近年，我々はEBV関連リンパ腫で，高率に欠損ウイルスが認められること，ウイルス複製に関わる遺伝子を欠損した場合にリンパ腫形成能が増すことをマウスモデルで示し，報告した．これまでも他の腫瘍ウイルスの遺伝子変異について多くの報告があるが，EBVのように70以上の遺伝子を有する大型ウイルスでの遺伝子欠失の成り立ちと意義については，未だ不明な点が多い．本稿では，欠失EBVを含めた最近の知見を中心に，EBVのリンパ腫原性について概説する．

DOI： 10.2222/jsv.69.13

PubMed

CiNii Research

JAK inhibitors for refractory lymphoma. Open Access

Kimura H

Oncotarget 9 巻 ( 68 ) 頁： 32883 - 32884 2018年8月

Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells 査読有り

Kawada Jun-ichi, Ando Shotaro, Torii Yuka, Watanabe Takahiro, Sato Yoshitaka, Ito Yoshinori, Kimura Hiroshi

CANCER MEDICINE 7 巻 ( 4 ) 頁： 1275-1284 2018年4月

Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells

Ichikawa Takaya, Okuno Yusuke, Sato Yoshitaka, Goshima Fumi, Yoshiyama Hironori, Kanda Teru, Kimura Hiroshi, Murata Takayuki

MSPHERE 3 巻 ( 6 ) 2018年

BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon De Novo Infection 査読有り

Konishi Natsuno, Narita Yohei, Hijioka Fumiya, Al Masud H. M. Abdullah, Sato Yoshitaka, Kimura Hiroshi, Murata Takayuki

MSPHERE 3 巻 ( 2 ) 2018年

EBV in T-/NK-Cell Tumorigenesis.

Kimura H

Advances in experimental medicine and biology 1045 巻頁： 459-475 2018年

Human Herpesviruses Preface

Kimura, H

HUMAN HERPESVIRUSES 1045 巻頁： V - V 2018年

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