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2013 年度 実績報告書

EZH2を基点とした難治性白血病の克服

研究課題

研究課題/領域番号 24890045
研究機関東京大学

研究代表者

植田 航希  東京大学, 医学部附属病院, 助教 (80632190)

研究期間 (年度) 2012-08-31 – 2014-03-31
キーワードpolycomb / EZH2 / MLL
研究概要

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.

現在までの達成度 (区分)
理由

25年度が最終年度であるため、記入しない。

今後の研究の推進方策

25年度が最終年度であるため、記入しない。

  • 研究成果

    (1件)

すべて 2014

すべて 雑誌論文 (1件) (うち査読あり 1件)

  • [雑誌論文] Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p162014

    • 著者名/発表者名
      Koki Ueda, Akihide Yoshimi, Yuki Kagoya, Satoshi Nishikawa, Victor E. Marquez, Masahiro Nakagawa and Mineo Kurokawa
    • 雑誌名

      Cancer Science

      巻: 00 ページ: 0000

    • DOI

      10.1111/cas.12386

    • 査読あり

URL: 

公開日: 2015-05-28  

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