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2013 Fiscal Year Final Research Report

Oncogene addiction of ATL cells and abnormal Polycomb-miRNA-signal transduction

Research Project

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Project/Area Number 23390250
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionThe University of Tokyo

Principal Investigator

WATANABE Toshiki  東京大学, 新領域創成科学研究科, 教授 (30182934)

Co-Investigator(Kenkyū-buntansha) UCHIMARU Kaoru  東京大学, 医科学研究所, 准教授 (60251203)
NAKANO Kazumi  東京大学, 大学院・新領域創成科学研究科, 助教 (60549591)
Project Period (FY) 2011-04-01 – 2014-03-31
Keywords血液腫瘍学 / HTLV-1 / NP-κB / エピジェネティクス / シグナル伝達
Research Abstract

Based on our comprehensive dataset from ATL patient samples, we addressed the exact molecular mechanism of ATL, which should be targeted in clinical regimens. Using a microarray technique, we identified leukemic cell-specific gene expression pattern. In addition, we revealed activation of p38 and Hedgehog signaling pathways, which supported pro-survival capability.
We performed global histone methylation profiling of patient-derived primary ATL cells. We successfully detected the numerous gene promoters with aberrant repressive H3K27me3 mark in ATL cells. Interestingly, Tax-triggered immortalizing cells partially mimicked the methylation pattern observed in ATL cells. In parallel, we identified an intimate relationship between NF-kB signaling and EZH2. Despite the absence of EZH2 active mutation observed in DLBCL, EZH2 inhibitors significantly killed patient ATL cells. Our findings indicate that ATL is characterized by EZH2-dependent robust and global epigenetic rearrangement.

  • Research Products

    (34 results)

All 2014 2013 2012 2011

All Journal Article (14 results) (of which Peer Reviewed: 6 results) Presentation (17 results) (of which Invited: 5 results) Book (3 results)

  • [Journal Article] CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-1-infected cells in adult T-cell leukemia/lymphoma2014

    • Author(s)
      Kobayashi S, Nakano K, Watanabe E, Ishigaki T, Ohno N, Yuji K, Oyaizu N, Asanuma S, Yamagishi M, Yamochi T, Watanabe N, Tojo A, Watanabe T, Uchimaru K
    • Journal Title

      Clin Cancer Res

      Volume: (in press)

    • Peer Reviewed
  • [Journal Article] 特集 : ATL/HTLV-1研究の最近の進展「miRNAを用いた成人T細胞白血病(ATL)がん幹細胞を標的とした新規治療法開発研究の現状」2014

    • Author(s)
      渡邉俊樹
    • Journal Title

      血液内科

      Volume: 68(1) Pages: 65-70

  • [Journal Article] Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promotes T-cell growth2013

    • Author(s)
      Asanuma S, Yamagishi M, Kawanami K, Nakano K, Sato-Otsubo A, Muto S, Sanada M, Yamochi T, Kobayashi S, Utsunomiya A, Iwanaga M, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
    • Journal Title

      Cancer Sci

      Volume: 104(8) Pages: 1097-1106

    • DOI

      10.1111/cas.12181

    • Peer Reviewed
  • [Journal Article] 特集 : リンパ系腫瘍-最新の病態解析と治療-「成人T細胞白血病/リンパ腫の分子病態解析と治療の進歩」2013

    • Author(s)
      渡邉俊樹
    • Journal Title

      最新医学

      Volume: 68(10) Pages: 40-47

  • [Journal Article] 特集 : 血液疾患におけるエピゲノム異常と治療「ATL発症におけるエピゲノム解析の進歩(The State of the Art in Epigenomics of Adult T Cell Leukemia)」2013

    • Author(s)
      山岸誠, 渡邉俊樹
    • Journal Title

      血液内科

      Volume: 66(3) Pages: 308-315

  • [Journal Article] The microRNA regulatory network in normal- and HTLV-1-transformed T cells2012

    • Author(s)
      D' Agostino DM, Zanovello P, Watanabe T, Ciminale V
    • Journal Title

      Adv Cancer Res

      Volume: 113 Pages: 45-83

    • DOI

      10.1016/B978-0-12-394280-7.00002-6

    • Peer Reviewed
  • [Journal Article] New Paradigm of T cell Signaling : Learning from Malignancies (Review Article)2012

    • Author(s)
      Yamagishi M, Watanabe T
    • Journal Title

      J Clin Cell Immunol

      Volume: S12: 007 Pages: 15

    • DOI

      10.4172/2155-9899.S12-007

    • Peer Reviewed
  • [Journal Article] Molecular Hallmarks of Adult T Cell Leukemia. (Review Article)2012

    • Author(s)
      Yamagishi M, Watanabe T
    • Journal Title

      Front. Microbiol

      Volume: 3 Pages: 334

    • DOI

      10.3389/fmicb.2012.00334

    • Peer Reviewed
  • [Journal Article] Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kB pathway in adult T-cell leukemia and other cancers2012

    • Author(s)
      Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A, Matsuda Y, Sato-Otsubo A, Muto S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
    • Journal Title

      Cancer Cell

      Volume: 21(1) Pages: 121-135

    • DOI

      10.1016/j.ccr.2011.12.015

    • Peer Reviewed
  • [Journal Article] 特集 : microRNAの発現制御の異常と疾患「成人T細胞白血病(ATL)におけるmicroRNAの発現異常」2012

    • Author(s)
      山岸誠, 渡邉俊樹
    • Journal Title

      細胞

      Volume: 44(10) Pages: 15-22

  • [Journal Article] 特集 : ATLの基礎と臨床「総論ATL研究の進展」2012

    • Author(s)
      渡邉俊樹
    • Journal Title

      細胞

      Volume: 44(8) Pages: 2-5

  • [Journal Article] 特集 : ATLの基礎と臨床「ATL細胞のゲノムエピゲノム異常と発現異常」2012

    • Author(s)
      山岸誠, 渡邉俊樹
    • Journal Title

      細胞

      Volume: 44(8) Pages: 18-22

  • [Journal Article] 総説「2. HTLV-1感染症とmiRNA」2012

    • Author(s)
      山岸誠, 渡邉俊樹
    • Journal Title

      ウイルス

      Volume: 62(1) Pages: 9-18

  • [Journal Article] 特集(1) : HTLV-1感染の検査と臨床「成人T細胞白血病(ATL)とHTLV-1研究の現状」2011

    • Author(s)
      渡邉俊樹
    • Journal Title

      医療と検査機器・試薬/別冊機器・試薬

      Volume: 34(4) Pages: 437-446

  • [Presentation] Diverse ways of modulating Polycomb group function and host epigenome in adult T cell leukemia2013

    • Author(s)
      Yamagishi M, Fujikawa D, Kurokawa N, Soejima A, Nakagawa S, Nakano K, Utsunomiya A, Yamaguchi K, Uchimaru K, Watanabe T
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      ロイトン札幌, 札幌
    • Year and Date
      20131011-13
  • [Presentation] The CD7 vs CADM1 plot in FACS is useful for selecion of advanced HTLV-1 carriers2013

    • Author(s)
      Kobayashi S, Watanabe E, Ishigaki T, Ohno N, Yuji K, Nakano K, Yamochi T, Watanabe T, Watanabe N, Tojo A, Uchimaru K
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      ロイトン札幌, 札幌
    • Year and Date
      20131011-13
  • [Presentation] Hematological neoplasms and viral Infections2013

    • Author(s)
      Watanabe T
    • Organizer
      XXVI Symposium IACRLRD
    • Place of Presentation
      Lingotto Conference Center, Torino, Italy
    • Year and Date
      20130911-14
    • Invited
  • [Presentation] Molecular hallmarks of adult T cell leukemia : miRNA, pigenetics, and emerging signaling abnormalities2013

    • Author(s)
      Yamagishi M, Fujikawa D, Kurokawa N, Soejima A, Takahashi R, Sakai N, Nakagawa S, Nakano K, Kobayashi S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
    • Organizer
      16th International Conference on Human Retrovirology HTLV and Related Viruses
    • Place of Presentation
      Montreal, Canada
    • Year and Date
      20130626-30
  • [Presentation] EPIGENETIC DEREGULATION OF MIRNA IN MALIGNANT LYMPHOMAS2013

    • Author(s)
      Yamagishi M, Watanabe T
    • Organizer
      18th Congress of EHA
    • Place of Presentation
      Stockholm, Sweden
    • Year and Date
      20130612-16
  • [Presentation] 「ATLの分子病態を基盤とした新規治療法の可能性」, 腫瘍別シンポジウム2013

    • Author(s)
      渡邉俊樹
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜, 横浜
    • Year and Date
      2013-10-03
  • [Presentation] ATL多段階発癌の分子機構解明へのアプローチ2013

    • Author(s)
      渡邉俊樹
    • Organizer
      第1回ATL疾患検討会
    • Place of Presentation
      東京コンファレンスセンター・有明, 東京
    • Year and Date
      2013-07-13
    • Invited
  • [Presentation] HTLV-1タンパク質TaxはPolycombタンパク質EZH2との相互作用を介してエピジェネティクスの脱制御を誘導する2012

    • Author(s)
      藤川大, 山岸誠, 黒川直也, 副島あい, 石田尚臣, 中野和民, 渡邉俊樹
    • Organizer
      第60回日本ウイルス学会学術集会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      20121113-15
  • [Presentation] Molecular hallmarks of adult T cell leukemia : miRNA epigenetics and emerging signaling abnormalities2012

    • Author(s)
      Yamagishi M, Takahashi R, Nakano K, Asanuma S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
    • Organizer
      第74回日本血液学会学術集会
    • Place of Presentation
      京都国際会議場
    • Year and Date
      20121019-21
  • [Presentation] 多機能性分子miR-31の発現低下とがん関連シグナル伝達2012

    • Author(s)
      山岸誠, 渡邉俊樹
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      ロイトン札幌, 札幌
    • Year and Date
      2012-09-20
  • [Presentation] 成人T細胞白血病(ATL)におけるmicroRNA発現異常とその意義2012

    • Author(s)
      渡邉俊樹
    • Organizer
      平成24年度遺伝子病制御研究所研究集会
    • Place of Presentation
      北海道大学医学部学友会館フラテ, 札幌
    • Year and Date
      2012-09-18
    • Invited
  • [Presentation] HTLV-1によるATL発症機構の解明を目指して-新規治療法開発への可能性2012

    • Author(s)
      渡邉俊樹
    • Organizer
      平成24年度熊本大学名医に学ぶセミナー
    • Place of Presentation
      熊本大学医学部, 熊本
    • Year and Date
      2012-05-30
    • Invited
  • [Presentation] ATL細胞の増殖の仕組みと新たな治療法の開発2012

    • Author(s)
      渡邉俊樹
    • Organizer
      ATLシンポジウムin沖縄
    • Place of Presentation
      沖縄
    • Year and Date
      2012-03-10
    • Invited
  • [Presentation] Polycomb -microRNAsignal transduction linkage in adult T-cell leukemia (ATL)2011

    • Author(s)
      Watanabe T
    • Organizer
      Todai Forum 2011"Forum on Systems Biology and Genomic Medicine"-Hormone Receptor and Intracellular Signaling : From Chromatin to Clinic
    • Place of Presentation
      Lyon, France
    • Year and Date
      20111020-21
  • [Presentation] Genetic and Epigenetic Loss of miR-31 Activates NIK-dependent NF-κ B Pathway in Adult T-cell Leukemia2011

    • Author(s)
      Yamagisi M, Nakano K, Yamochi T, Miyake A, Kagami Y, Tsutsumi A, Otsubo A, Ogawa S, Utsunomiya A, Yamaguchi K, Uchimaru K, Watanabe T
    • Organizer
      The 15th International Conference on Human Retrovirology : HTLV and Related Viruses
    • Place of Presentation
      Lueven, Belgium
    • Year and Date
      20110605-08
  • [Presentation] Polycomb-Mediated Epigenetic Silencing of miR-31 Activates NF-κ B Signalingin Adult T-cell Leukemia2011

    • Author(s)
      Yamagishi M, Nakano K, Yamochi T, Utsunomiya A, Yamaguchi K, Uchimaru K, Watanabe T
    • Organizer
      第73回日本血液学会学術集会
    • Place of Presentation
      名古屋
    • Year and Date
      2011-10-14
  • [Presentation] Polycomb依存的なエピジェネティック異常によるmiR-31の発現低下とNF-kB活性化機構2011

    • Author(s)
      山岸誠, 中野和民, 矢持忠徳, 宇都宮與, 山口一成, 内丸薫, 渡邉俊樹
    • Organizer
      第70回日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2011-10-03
  • [Book] 「IV.リンパ球系3. 成人T細胞白血病/リンパ腫におけるNF-kB経路の活性化」, Annual Review2014血液2014

    • Author(s)
      渡邉俊樹
    • Total Pages
      240(147-152)
    • Publisher
      中外医学社
  • [Book] Adult T-cell leukemia-lymphoma. Chapter 108, Abeloff' s Clinical Oncology 5th Edition. Edited by Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE2013

    • Author(s)
      Tsukasaki K, Watanabe T, Tobinai K
    • Total Pages
      2072-2092
    • Publisher
      Elsevier
  • [Book] 「第1章3腫瘍ウイルス(HTLV, HPV, EBVなど)」, がん生物学イラストレイテッド2011

    • Author(s)
      渡邉俊樹
    • Total Pages
      411(43-49)
    • Publisher
      羊土社

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Published: 2015-06-25   Modified: 2023-03-16  

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