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2013 Fiscal Year Annual Research Report

EZH2を基点とした難治性白血病の克服

Research Project

Project/Area Number 24890045
Research InstitutionThe University of Tokyo

Principal Investigator

植田 航希  東京大学, 医学部附属病院, 助教 (80632190)

Project Period (FY) 2012-08-31 – 2014-03-31
Keywordspolycomb / EZH2 / MLL
Research Abstract

Although aberrant histone methylation has been revealed to be important in MLL fusion leukemia, the role of H3K27 trimethylase EZH2 has not been fully clarified. Therefore, we investigated the role of EZH2 in MLL-related leukemia.
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.

Current Status of Research Progress
Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

  • Research Products

    (1 results)

All 2014

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

  • [Journal Article] Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p162014

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

      Cancer Science

      Volume: 00 Pages: 0000

    • DOI

      10.1111/cas.12386

    • Peer Reviewed

URL: 

Published: 2015-05-28  

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