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Study for oncovirus-mediated epigenetic abnormality in the early phase of tumorigenesis

Research Project

Project/Area Number 18K08317
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionThe University of Tokyo

Principal Investigator

Yamagishi Makoto  東京大学, 大学院新領域創成科学研究科, 特任講師 (90625261)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsHTLV-1 / EBV / エピジェネティクス / シングルセル解析 / ウイルス / エピゲノム / トランスクリプトーム / EBウイルス / 悪性リンパ腫 / EZH2
Outline of Final Research Achievements

We performed integrative molecular analyses of over time samples from patients with ATL and asymptomatic HTLV-1 carriers (AC) to provide direct evidence of molecular time and disease progression and to identify the common epigenetic abnormalities. We found that the HTLV-1 infected cells from all infected individuals including patients with ATL and also AC with low proviral loads showed abnormal transcriptome with largely common pattern. ATAC-seq and ChIP-seq revealed that epigenetic dysregulation of infected cells is a background characteristic of the abnormal transcriptome. Importantly, disease-specific chromatin structure and histone modification pattern are involved in the progression of infected cells. The results provide the possible mechanism of virus-associated epigenetic abnormality that is a molecular basis of ATL development. Furthermore, we successfully identified some important functional genes involved in the pathogenesis of ATL.

Academic Significance and Societal Importance of the Research Achievements

前癌状態の解明は、癌の予防、早期治療介入を達成する上で不可欠である。HTLV-1及びEBV感染は最初のhitであることは自明であるが、発症リスク評価は確立されておらず、臨床的に有効な介入法もない。関連疾患発症後の予後は極めて不良である。本研究の成果は、将来の早期治療介入の実現において重要な基礎的データであり、今後のさらなる研究によってエピゲノム異常を標的としたより安全で効果の高い治療法の開発が促進されると期待される。また、エピゲノム異常による素地の形成が、がんの進化過程において不可欠であることを示す重要な成果である。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (37 results)

All 2020 2019 2018

All Journal Article (16 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 11 results,  Open Access: 10 results) Presentation (21 results) (of which Int'l Joint Research: 3 results,  Invited: 7 results)

  • [Journal Article] A high-throughput detection method for the clonality of Human T-cell leukemia virus type-1-infected cells in vivo2020

    • Author(s)
      Saito M, Hasegawa H, Yamauchi S, Nakagawa S, Sasaki D, Nao N, Tanio M, Wada Y, Matsudaira T, Momose H, Kuramitsu M, Yamagishi M, Nakashima M, Nakahata S, Iha H, Ogata M, Imaizumi Y, Uchimaru K, Morishita K, Watanabe T, Miyazaki Y, Yanagihara K.
    • Journal Title

      Int J Hematol.

      Volume: 112 Issue: 3 Pages: 300-306

    • DOI

      10.1007/s12185-020-02935-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mortality and risk of progression to adult T-cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.2020

    • Author(s)
      Nagasaka M, Yamagishi M, Yagishita N, Araya N, Kobayashi S, Makiyama J, Kubokawa M, Yamauchi J, Hasegawa D, Coler-Reilly ALG, Tsutsumi S, Uemura Y, Arai A, Takata A, Inoue E, Hasegawa Y, Watanabe T, Suzuki Y, Uchimaru K, Sato T, Yamano Y.
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 117(21) Issue: 21 Pages: 11685-11691

    • DOI

      10.1073/pnas.1920346117

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Successful clinical sequencing by molecular tumor board in an elderly patient with refractory Sezary syndrome2020

    • Author(s)
      Hijikata K, Yokoyama K (co-1st and co-corresponding author), Yokoyama N, Matsubara Y, Shimizu E, Nakashima M, Yamagishi M, Ota Y, Lim L, Yamaguchi R, Ito M, Tanaka Y, Denda T, Tani K, Yotsuyanagi H, Imoto S, Miyano S, Uchimaru K, Tojo A.
    • Journal Title

      JCO Precis Oncol

      Volume: 4 Issue: 4 Pages: 534-560

    • DOI

      10.1200/po.19.00254

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mortality and risk of progression to adult T-cell leukemia/lymphoma in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.2020

    • Author(s)
      Nagasaka M, Yamagishi M, Yagishita N, Araya N, Kobayashi S, Makiyama J, Kubokawa M, Yamauchi J, Hasegawa D, Coler-Reilly A, Tsutsumi S, Uemura Y, Arai A, Takata A, Inoue E, Hasegawa Y, Watanabe T, Suzuki Y, Uchimaru K, Sato T, Yamano Y.
    • Journal Title

      Proc. Natl. Acad. Sci. U S A

      Volume: in press

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells.2020

    • Author(s)
      Ikebe E, Matsuoka S, Tezuka K, Kuramitsu M, Okuma K, Nakashima M, Kobayashi S, Makiyama J, Yamagishi M, Oyadomari S, Uchimaru K, Hamaguchi I.
    • Journal Title

      Blood Adv

      Volume: in press

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas2019

    • Author(s)
      Yamagishi M., Hori M., Fujikawa D., Ohsugi T., Honma D., Adachi N., Katano H., Hishima T., Kobayashi S., Nakano K., Nakashima M., Iwanaga M., Utsunomiya A., Tanaka Y., Okada S., Tsukasaki K., Tobinai K., Araki K., Watanabe T., Uchimaru K.
    • Journal Title

      Cell Reports

      Volume: 29 Issue: 8 Pages: 2321-2337

    • DOI

      10.1016/j.celrep.2019.10.083

    • NAID

      120006901051

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD4+ CADM1+ cell percentage predicts disease progression in HTLV-1 carriers and indolent adult T-cell leukemia/lymphoma.2019

    • Author(s)
      Makiyama J, Kobayashi S, Watanabe E, Ishigaki T, Kawamata T, Nakashima M, Yamagishi M, Nakano K, Tojo A, Watanabe T, Uchimaru K.
    • Journal Title

      Cancer Sci.

      Volume: 110(12) Issue: 12 Pages: 3746-3753

    • DOI

      10.1111/cas.14219

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach2019

    • Author(s)
      Katsuya H, Islam S, Tan, Ito J, Miyazato P, Matsuo, Inada Y, Iwase, Uchiyama Yoshikazu、Hata Hiroyuki、Sato T, Yagishita N, Araya N, Ueno T, Nosaka K, Tokunaga M, Yamagishi M, Watanabe T, Uchimaru K, Fujisawa J-i, Utsunomiya A, Yamano Y, Satou Y
    • Journal Title

      Cell Reports

      Volume: 29 Issue: 3 Pages: 724-735

    • DOI

      10.1016/j.celrep.2019.09.016

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 成人T細胞白血病研究におけるシングルセル解析の有用性2019

    • Author(s)
      山岸誠、鈴木穣、渡邉俊樹、内丸薫
    • Journal Title

      実験医学

      Volume: 37(20) Pages: 3448-3453

    • Related Report
      2019 Research-status Report
  • [Journal Article] HTLV-1感染細胞の腫瘍化メカニズム2019

    • Author(s)
      山岸誠、内丸薫
    • Journal Title

      細胞

      Volume: 51(10) Pages: 8-11

    • Related Report
      2019 Research-status Report
  • [Journal Article] Correlation of two distinct metastasis-associated proteins, MTA1 and S100A4, in angiogenesis for promoting tumor growth.2019

    • Author(s)
      Ishikawa M, Osaki M, Yamagishi M, Onuma K, Ito H, Okada F, Endo H.
    • Journal Title

      Oncogene

      Volume: in press Issue: 24 Pages: 4715-4728

    • DOI

      10.1038/s41388-019-0748-z

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] HTLV-1-Mediated Epigenetic Pathway to Adult T-Cell Leukemia-Lymphoma.2018

    • Author(s)
      Yamagishi M, Fujikawa D, Watanabe T, Uchimaru K.
    • Journal Title

      Front Microbiol.

      Volume: 9 Pages: 1686-1686

    • DOI

      10.3389/fmicb.2018.01686

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] HIV LTR-driven antisense RNA by itself has regulatory function and may curtail virus reactivation from latency2018

    • Author(s)
      Kobayashi-Ishihara M, Terahara K, Martinez JP, Yamagishi M, Iwabuchi R, Brander C, Ato M, Watanabe T, Meyerhans A, Tsunetsugu-Yokota Y
    • Journal Title

      Front. Microbiol.

      Volume: 9 Pages: 1066-1066

    • DOI

      10.3389/fmicb.2018.01066

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 成人T細胞白血病・リンパ腫のエピゲノム異常と新規EZH1/2阻害剤の開発2018

    • Author(s)
      山岸誠
    • Journal Title

      臨床血液

      Volume: 59 Pages: 432-438

    • NAID

      130006733376

    • Related Report
      2018 Research-status Report
  • [Journal Article] HTLV-1感染細胞におけるゲノム・エピゲノム異常2018

    • Author(s)
      山岸誠
    • Journal Title

      医学のあゆみ

      Volume: 267 Pages: 771-775

    • Related Report
      2018 Research-status Report
  • [Journal Article] 悪性リンパ腫におけるEZH1/EZH2依存性エピゲノム異常と創薬2018

    • Author(s)
      山岸誠
    • Journal Title

      血液内科

      Volume: 78 Pages: 87-92

    • NAID

      40021792435

    • Related Report
      2018 Research-status Report
  • [Presentation] 異所性に発現する異常型電位依存性 Ca2+チャネル Cav3.2 による 細胞内 Ca2+シグナルへの影響2020

    • Author(s)
      廣内 大成、山岸 誠、中島 誠、小林 誠一郎、牧山 純也、宇都宮 與、渡邉 俊樹、鈴木 穣、内丸 薫
    • Organizer
      第79回日本癌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] VAV1 / PLCG1 の協調的変異による TCR シグナル伝達経路の異常な活性化2020

    • Author(s)
      横溝 明香里、山岸 誠、廣内 大成、久世 裕太、窪川 美雪、宇都宮 與、福田 隆浩、渡邉 俊樹、鈴木 穣、内丸 薫
    • Organizer
      第79回日本癌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 多層シングルセルプラットフォームによるクローン構造解析とTCR 経路変異の生物学的意義の検討2020

    • Author(s)
      山岸 誠、鈴木 穣、窪川 美雪、久世 裕太、横溝 明香里、鈴木 絢子、小林 誠一郎、中島 誠、宇都宮 與、森島 聡子、福田 隆浩、渡邉 俊樹、内丸 薫
    • Organizer
      第79回日本癌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] HTLV-1 感染前がんモデルにおけるエピジェネティックなMAPK/ERK 経路の活性化2020

    • Author(s)
      水池 潤、山岸 誠、大高 時文、中嶋 伸介、小林 誠一郎、中島 誠、新谷 奈津美、牧山 純也、宇都宮 與、田中 勇悦、渡邉 俊樹、山野 嘉久、鈴木 穣、藤澤 順一、内丸 薫
    • Organizer
      第79回日本癌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Genetic profiling of aggressive ATL from a nationwide prospective study (2015-2018)2020

    • Author(s)
      Yamagishi Y, et al.
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] HTLV-1関連疾患の病原性メカニズムと新規治療法の開発2019

    • Author(s)
      山岸誠
    • Organizer
      SRC2019 (Summer Retrovirus Conference)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 悪性リンパ腫におけるエピゲノム異常の重要性2019

    • Author(s)
      山岸誠
    • Organizer
      第20回基礎血液懇話会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Development and molecular analysis of synthetic lethality by targeting EZH1 and EZH2 in malignant lymphomas2019

    • Author(s)
      山岸誠
    • Organizer
      第13回日本エピジェネティクス研究会年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] がんや感染症のエピゲノム破綻を標的とした新規EZH1/2阻害薬の開発2019

    • Author(s)
      山岸誠
    • Organizer
      第1回日本医学会連合Rising Starリトリート
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Transcriptomic and epigenomic characteristics of HTLV-1-infected cells in asymptomatic carriers, HAM/TSP, and ATL2019

    • Author(s)
      Makoto Yamagishi, Seiichiro Kobayashi, Junya Makiyama, Natsumi Araya, Makoto Nakashima, Masako Iwanaga, Atae Utsunomiya, Yuetu Tanaka, Toshiki Watanabe, Yoshihisa Yamano, Kaoru Uchimaru
    • Organizer
      19th International Conference on Human Retrovirology HTLV and Related Viruses
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 末梢血CD4+CADM1+細胞集団の割合とぶどう膜炎の重症度に関する検討2019

    • Author(s)
      牧山純也、鴨居功樹、小林誠一郎、渡辺恵理、石垣知寛、中島誠、山岸誠、中野和民、東條有伸、渡邉俊樹、大野京子、内丸薫
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] ATL細胞におけるヒストンメチル化酵素複合体の解析2019

    • Author(s)
      桑原彩夏、山岸誠、宇都宮與、渡邉俊樹、内丸薫
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] HTLV-1感染細胞におけるIFN-JAK1-STAT1経路の機能的意義2019

    • Author(s)
      滝澤絵梨菜、山岸誠、石崎伊純、志賀遥菜、中島誠、新谷奈津美、宇都宮與、中村龍文、田中勇悦、山野嘉久、渡邉俊樹、内丸薫
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] HTLV-1感染初期においてTaxが宿主に与える影響の解析2019

    • Author(s)
      水池潤、山岸誠、小林誠一郎、中島誠、新谷奈津美、牧山純也、宇都宮與、田中勇悦、渡邉俊樹、山野嘉久、内丸薫
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] ATLにおけるIKZF familyの発現及び機能的意義の検討2019

    • Author(s)
      李小寓、山岸誠、中島誠、小林誠一郎、牧山純也、宇都宮與、渡邉俊樹、内丸薫
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] ウイルスと宿主を標的としたクリニカルシーケンス技術の開発2018

    • Author(s)
      山岸誠
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 悪性リンパ腫における EZH1/EZH2依存的なエピゲノム異常と創薬2018

    • Author(s)
      山岸誠
    • Organizer
      第22回日本がん分子標的治療学会学術集会、Anti-Cancer Trestment Japan 合同シンポジウム
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Development of an epigenetic drug against ATL2018

    • Author(s)
      Makoto Yamagishi
    • Organizer
      IRVA Tokyo Conference 2018 & International Symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Functional importance of JAK-STAT pathways in HTLV-1 infected cells2018

    • Author(s)
      Izumi Ishizaki, Makoto Yamagishi, Haruna Shiga, Atae Utsunomiya, Yuetsu Tanaka, Toshiki Watanabe, Kaoru Uchimaru
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] ATL及びHAM発症に至る遺伝子発現異常の推移と運命制御メカニズム2018

    • Author(s)
      山岸誠、新谷奈津美、石崎伊純、小林誠一郎、牧山純也、佐藤知雄、八木下尚子、宇都宮與、中村龍文、田中勇悦、渡邉俊樹、山野嘉久、内丸薫
    • Organizer
      第5回日本HTLV-1学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] HTLV-1関連疾患の発症メカニズムにおけるJAK-STAT経路の機能的意義の検討2018

    • Author(s)
      石崎伊純、山岸誠、志賀遥菜、新谷奈津美、宇都宮與、中村龍文、田中勇悦、山野嘉久、渡邉俊樹、内丸薫
    • Organizer
      第5回日本HTLV-1学会学術集会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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