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Overcoming therapy-resistant leukemia using EZH2 inhibitor

Research Project

Project/Area Number 24890045
Research Category

Grant-in-Aid for Research Activity Start-up

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

Principal Investigator

UEDA Koki  東京大学, 医学部附属病院, 助教 (80632190)

Project Period (FY) 2012-08-31 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsEZH2 / MLL / polycomb / leukemia
Research Abstract

EZH2 inhibitor DZNep and shRNA for EZH2 strongly suppressed the proliferation of MLL-related leukemia cell lines and immortalized cells harboring MLL fusion genes with high specificity. In vivo administration of DZNep and transduction of shRNA targeting EZH2 decreased the leukemic granulocyte macrophage progenitors (LGMPs) and prolonged survival of MLL/AF9 and MLL/ENL-induced leukemic mice. Limiting dilution transplantation assay revealed that frequency of leukemia stem cells (LSCs) was reduced by DZNep administration. Expression analysis suggested that p16 up-regulation was responsible for LSC reduction. In fact, knockdown of p16 completely canceled the survival advantage of mice which received DZNep. Chromatin immunoprecipitation assays suggested that both H3K4 and H3K27 methylation marks were highly enriched around the TSS of p16, together with EZH2 and Bmi1. Therefore removal of EZH2 is supposed to convert the promoter of p16 to an active state.

Report

(3 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Annual Research Report
  • Research Products

    (8 results)

All 2014 2012 Other

All Journal Article (2 results) (of which Peer Reviewed: 1 results) Presentation (6 results)

  • [Journal Article] Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16.2014

    • Author(s)
      Ueda K, Yoshimi A, Kagoya Y, Nishikawa S, Marquez VE, Nakagawa M, Kurokawa M.
    • Journal Title

      Cancer Science

      Volume: (in press) Issue: 5 Pages: 0-0

    • DOI

      10.1111/cas.12386

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16

    • Author(s)
      Koki Ueda, Akihide Yoshimi, Yuki Kagoya, Satoshi Nishikawa, Victor E. Marquez, Masahiro Nakagawa and Mineo Kurokawa
    • Journal Title

      Cancer Science

      Volume: (Epub)

    • Related Report
      2013 Final Research Report
  • [Presentation] Inhibition of EZH2 Depletes MLL Fusion Leukemia Stem Cells Through Restoration of p162012

    • Author(s)
      Koki Ueda, Akihide Yoshimi, Masahiro Nakagawa, Satoshi Nishikawa, Victor E Marquez, Keiki Kumano and Mineo Kurokawa
    • Organizer
      (53rd) Annual Meeting of the American Society of Hematology
    • Place of Presentation
      Atlanta, GA(Poster Board no.: III-602)
    • Related Report
      2013 Final Research Report
  • [Presentation] The histone methyltransferase EZH2 Plays a crucial role in MLL-related leukemia2012

    • Author(s)
      Koki Ueda, Akihide Yoshimi, Masahiro Nakagawa, Satoshi Nishikawa, Keiki Kumano and Mineo Kurokawa
    • Organizer
      第74回日本血液学会総会
    • Place of Presentation
      京都
    • Related Report
      2013 Final Research Report
  • [Presentation] The histone methytransferase EZH2 plays a crucial role in MLL-related leukemia (ヒストンメチル化酵素EZH2はMLL関連白血病の維持に重要な役割を果たしている)2012

    • Author(s)
      Koki Ueda, Akihide Yoshimi, Masahiro Nakagawa, Satoshi Nishikawa, Keiki Kumano and Mineo Kurokawa
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌
    • Related Report
      2013 Final Research Report
  • [Presentation] The histone methytransferase EZH2 plays a crucial role in MLL-related leukemia

    • Author(s)
      植田航希
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌
    • Related Report
      2012 Annual Research Report
  • [Presentation] The histone methyltransferase EZH2 Plays a crucial role in MLL-related leukemia

    • Author(s)
      植田航希
    • Organizer
      第74回日本血液学会総会
    • Place of Presentation
      京都
    • Related Report
      2012 Annual Research Report
  • [Presentation] Inhibition of EZH2 Depletes MLL Fusion Leukemia Stem Cells Through Restoration of p16 Expression

    • Author(s)
      植田航希
    • Organizer
      Annual Meeting of the American Society of Hematology in Atlanta
    • Place of Presentation
      アトランタ,USA
    • Related Report
      2012 Annual Research Report

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Published: 2012-11-27   Modified: 2019-07-29  

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