Pathological analysis and evaluation of a novel therapeutic target using a humanized mouse model in EBV-associated lymphoproliferative disorder

• Project/Area Number: 18K15165
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Nagoya University
• Principal Investigator: Watanabe Takahiro 名古屋大学, 医学系研究科, 助教 (10624398)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: EBV / LPD / CDK / マウスモデル / がん / vPIC / ウイルス / 遺伝子 / ウイルス学

Outline of Final Research Achievements

Epstein-Barr virus (EBV) is implicated in immunodeficiency-associated lymphoproliferative disorders. We have previously shown that cyclin-dependent kinase (CDK) inhibitors are able to specifically suppress the expression of viral late genes, particularly those encoding structural proteins. In this study, we examined whether CDK inhibitors confer a therapeutic effect against LPDs in vivo. Treatment with an inhibitor of the CDK2 complex resulted in a survival benefit and suppressed tumor invasion in a mouse model of LPDs. Inhibition of CDK efficiently induced G1 cell cycle arrest and apoptosis in EBV-positive B cells. These results suggest that CDK inhibitors suppress cell cycle progression, resulting in the antitumor effect.

Academic Significance and Societal Importance of the Research Achievements

CD20モノクローナル抗体製剤であるリツキシマブはEBV関連LPDに対して有効であることが証明されているが、ときにCD20陰性の腫瘍細胞の選択的増殖による耐性化が問題である。またDNA複製機構をターゲットとした既存の抗ヘルペスウイルス薬はEBV感染症に対する有効性が示されていない。このような既存の抗ヘルペスウイルス薬は骨髄抑制を誘発するため、免疫不全の患者においては投与が困難である。CDK阻害剤が後期遺伝子発現を阻害すると共に、アポトーシスを効率よく誘導することから、LPDの重症化克服をするべく新しい治療戦略の提供に繋がると考えられた。

Research Products

• [Journal Article] Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection (2021)
  • Author(s): Inagaki T, Sato Y, Ito J, Takaki M, Okuno Y, Yaguchi M, Masud MHAA, Watanabe T, Sato K, Iwami S, MurataT, Kimura H
  • Journal Title: Frontiers in Microbiology Volume: 11 Pages: 575255-575255
  • DOI: 10.3389/fmicb.2020.575255
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RNAseq analysis identifies involvement of EBNA2 in PD-L1 induction during Epstein-Barr virus infection of primary B cells (2021)
  • Author(s): Yanagi Yusuke、Okuno Yusuke、Narita Yohei、Masud H.M. Abdullah Al、Watanabe Takahiro、Sato Yoshitaka、Kanda Teru、Kimura Hiroshi、Murata Takayuki
  • Journal Title: Virology Volume: 557 Pages: 44-54
  • DOI: 10.1016/j.virol.2021.02.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antitumor activity of cyclin‐dependent kinase inhibitor alsterpaullone in Epstein‐Barr virus‐associated lymphoproliferative disorders (2019)
  • Author(s): Watanabe Takahiro、Sato Yoshitaka、Masud H. M. Abdullah Al、Takayama Masahiro、Matsuda Hiroki、Hara Yuya、Yanagi Yusuke、Yoshida Masahiro、Goshima Fumi、Murata Takayuki、Kimura Hiroshi
  • Journal Title: Cancer Science Volume: 111 Issue: 1 Pages: 279-287
  • DOI: 10.1111/cas.14241
  • Peer Reviewed / Open Access
• [Journal Article] S-Like-Phase Cyclin-Dependent Kinases Stabilize the Epstein-Barr Virus BDLF4 Protein To Temporally Control Late Gene Transcription (2019)
  • Author(s): Sato Yoshitaka、Watanabe Takahiro、Suzuki Chihiro、Abe Yuichi、Masud H. M. Abdullah Al、Inagaki Tomoki、Yoshida Masahiro、Suzuki Takeshi、Goshima Fumi、Adachi Jun、Tomonaga Takeshi、Murata Takayuki、Kimura Hiroshi
  • Journal Title: Journal of Virology Volume: 93 Issue: 8
  • DOI: 10.1128/jvi.01707-18
  • Peer Reviewed / Open Access
• [Journal Article] Initial Characterization of the Epstein-Barr Virus BSRF1 Gene Product. (2019)
  • Author(s): Yusuke Yanagi、H. M. bdullah Al Masud、Takahiro Watanabe、Yoshitaka Sato、Fumi Goshima、Hiroshi Kimura、Takayuki Murata
  • Journal Title: Viruses Volume: 21 Issue: 3 Pages: 01707-18
  • DOI: 10.3390/v11030285
  • Peer Reviewed / Open Access
• [Journal Article] The BOLF1 gene is necessary for effective Epstein?Barr viral infectivity (2019)
  • Author(s): Masud H. M. Abdullah Al、Watanabe Takahiro、Sato Yoshitaka、Goshima Fumi、Kimura Hiroshi、Murata Takayuki
  • Journal Title: Virology Volume: 531 Pages: 114-125
  • DOI: 10.1016/j.virol.2019.02.015
  • Peer Reviewed
• [Journal Article] Defective Epstein-Barr virus in chronic active infection and haematological malignancy. (2019)
  • Author(s): Okuno Y, Murata T, Sato Y,Yoshida K, Sawada A, Inoue M, Kawa K, Seto M, Ohshima K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, 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.
  • Journal Title: Nat Microbiol. Volume: 4 Issue: 3 Pages: 404-413
  • DOI: 10.1038/s41564-018-0334-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ヒト化マウスモデルを用いたEBV関連リンパ増殖症に対する新たな標的治療の評価 (2019)
  • Author(s): 渡辺 崇広, 木村 宏
  • Organizer: 第48回 東海乳酸菌研究会
• [Presentation] ヒト化マウスモデルを用いたEBV関連リンパ増殖症に対する新たな標的治療の評価 (2019)
  • Author(s): 木村宏、渡辺崇広
  • Organizer: 第48回東海乳酸菌研究会
• [Presentation] 慢性活動性EBV感染症およびEBV 関連リンパ腫における変異株の存在意義 (2019)
  • Author(s): 渡辺崇広、 村田貴之、佐藤好隆、成田洋平、MASUD H. M. Abdullah Al、五島 典、奥野友介、木村 宏
  • Organizer: 第28回EBウイルス感染症研究会
• [Presentation] S-phase CDKs stabilize the Epstein-Barr virus BDLF4 protein to temporally control late gene transcription (2018)
  • Author(s): Takahiro Watanabe, Yoshitaka Sato, Chihiro Suzuki, Yuichi Abe, Fumi Goshima, Takayuki Murata, Hiroshi Kimura
  • Organizer: International Conference on EBV & KSHV 2018
  • Int'l Joint Research
• [Presentation] The presence of defective Epstein-Barr virus in patients with chronic active EBV infection and EBV-associated hematological malignancy (2018)
  • Author(s): Takahiro Watanabe, Yusuke Okuno, Takayuki Murata, Yoshitaka Sato, Yoshinori Ito, H. M. Abdullah Al Masud, Fumi Goshima, Jun-ichi Kawada, Seiji Kojima, Seishi Ogawa, Hiroshi Kimura
  • Organizer: 第66回日本ウイルス学会学術集会