• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

骨髄異形成症候群におけるポリコーム群タンパク質の役割の検討

Research Project

Project/Area Number 13J09414
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field 腫瘍生物学
Research InstitutionThe University of Tokyo

Principal Investigator

川畑 公人  東京大学, 医科学研究所, 特別研究員(PD)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥4,320,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥720,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywords骨髄異形成症候群 / EZH2 / エピジェネティクス / ABCトランスポーター / レトロウィルスベクター / 造血器腫瘍 / 腫瘍幹細胞 / ヒストン修飾 / 造血機腫 / マイクロアレイ
Outline of Annual Research Achievements

難治性血液腫瘍である骨髄異形成症候群におけるポリコーム群タンパクEZH2の役割を研究した。同腫瘍においてはEZH2の機能欠失型変異が認められる。
レトロウィルスベクターを用いた遺伝子導入技術により疾患モデルマウスを作成した。その結果骨髄異形成症候群の発症進行において重要な腫瘍幹細胞の特定をすることができたと考えている。
それらのマウスにおいて骨髄異形成症候群を発症させることたできた。発症マウスの骨髄腫瘍細胞は次のマウスに継代することが可能で、この系において骨髄異形成症候群の腫瘍幹細胞性が維持されていると考える。発症マウスの骨髄細胞を用いて遺伝子発現マイクロアレイ解析を行った。正常造血幹細胞の遺伝子であるATP結合カセットトランスポーター(以下ABCトランスポーター)がEZH2に直接制御されている事を発見した。この分子は他にも抗がん剤の薬剤耐性や、脂質代謝や尿酸の代謝、固形がんにおけるがん幹細胞の遺伝子であることが知られる。骨髄異形成症候群においてABCトランスポータがポリコームの制御を受けているとするのは世界に先駆けた発表となる。
更に我々は臨床検体を解析し、その中でABCトランスポーター(特にABCG2)の発現が予後不良の骨髄異形成症候群で高いことを観察した。悪性腫瘍の公共データであるTCGAにおいてもABCG2は骨髄異形成症候群に特異的な高発現を示すことが分かった。またEZH2の変異がない症例でも、EZH2を標的とする変異を有する例においてABCG2が高くなることを発見し現在追加実験中である。
この様な欠失型EZH2変異を用いてヒトの疾患に近い病態を再現できた。また最近ではこの続きのプロジェクトとして骨髄の間質が腫瘍のマウスにおいては改変されている所見を得ており今後のこの分野における発展を期待している。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (25 results)

All 2016 2015 2014 2013

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Acknowledgement Compliant: 5 results,  Open Access: 5 results) Presentation (16 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD).2016

    • Author(s)
      Kitamura T, Watanabe-Okochi N, Enomoto Y, Nakahara F, Oki T, Komeno Y, Kato N, Doki N, Uchida T, Kagiyama Y, Togami K, Kawabata KC, Nishimura K, Hayashi Y, Nagase R, Saika M, Fukushima T, Asada S, Fujino T, Izawa Y, Horikawa S, Fukuyama T, Tanaka Y, Ono R, Goyama S, Nosaka T, Kitaura J, Inoue D
    • Journal Title

      Journal of Biochemistry

      Volume: 159 Issue: 1 Pages: 17-25

    • DOI

      10.1093/jb/mvv114

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Role played by Prx1-dependent extracellular matrix properties in vascular smooth muscle development in embryonic lungs.2015

    • Author(s)
      Ihida-Stansbury K, Ames J, Chokshi M, Aiad N, Sanyal S, Kawabata KC, Levental I, Sundararaghavan HG, Burdick JA, Janmey P, Miyazono K, Wells RG, Jones PL.
    • Journal Title

      Pulm Circ.

      Volume: 5 Issue: 2 Pages: 382-397

    • DOI

      10.1086/681272

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] A C-terminal mutant of CCAAT-enhancer-binding protein α (C/EBPα-C(m)) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-C(m).2015

    • Author(s)
      Togami K, Kitaura J, Uchida T, Inoue D, Nishimura K, Kawabata KC, Nagase R, Horikawa S, Izawa K, Fukuyama T, Nakahara F, Oki T, Harada Y, Harada H, Aburatani H, Kitamura T.
    • Journal Title

      Exp Hematol.

      Volume: 43(4) Issue: 4 Pages: 300-308

    • DOI

      10.1016/j.exphem.2014.11.011

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.2015

    • Author(s)
      Inoue D, Kitaura J, Matsui H, Hou HA, Chou WC, Nagamachi A, Kawabata KC, Togami K, Nagase R, Horikawa S, Saika M, Micol JB, Hayashi Y, Harada Y, Harada H, Inaba T, Tien HF, Abdel-Wahab O, Kitamura T.
    • Journal Title

      Leukemia

      Volume: 29(4) Issue: 4 Pages: 847-57

    • DOI

      10.1038/leu.2014.301

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The molecular basis of myeloid malignancies.2014

    • Author(s)
      Kitamura T, Inoue D, Okochi-Watanabe N, Kato N, Komeno Y, Lu Y, Enomoto Y, Doki N, Uchida T, Kagiyama Y, Togami K, Kawabata KC, Nagase R, Horikawa S, Hayashi Y, Saika M, Fukuyama T, Izawa K, Oki T, Nakahara F, Kitaura J.
    • Journal Title

      Proc Jpn Acad Ser B Phys Biol Sci.

      Volume: 90(10) Pages: 389-404

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells.2014

    • Author(s)
      Nakahara F, Kitaura J, Uchida T, Nishida C, Togami K, Inoue D, Matsukawa T, Kagiyama Y, Enomoto Y, Kawabata KC, Chen-Yi L, Komeno Y, Izawa K, Oki T, Nagae G, Harada Y, Harada H, Otsu M, Aburatani H, Heissig B, Hattori K, Kitamura T.
    • Journal Title

      Blood

      Volume: 123(25) Issue: 25 Pages: 3932-42

    • DOI

      10.1182/blood-2013-01-476747

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Hes1 up-regulation contributes to the development of FIP1L1-PDGFRA-positive leukemia in blast crisis.2014

    • Author(s)
      Uchida T, Kawabata KC, Kitamura T., et al.
    • Journal Title

      Exp Hematol.

      Volume: S0301-472X(14) Issue: 5 Pages: 56-3

    • DOI

      10.1016/j.exphem.2014.01.009

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TGF-β-inducedapoptosis of B-cell lymphoma Ramos cells through reduction of MS4A1/CD20.2013

    • Author(s)
      Kawabata KC, Ehata S, Komuro A, Takeuchi K, Miyazono K.
    • Journal Title

      Oncogene

      Volume: 32(16) Issue: 16 Pages: 2096-106

    • DOI

      10.1038/onc.2012.219

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Myelodysplastic syndromes are induced by histone methylation-altering ASXL1 mutations.2013

    • Author(s)
      Inoue D, Kitaura J, Kawabata KC, Kitamura T., et al.
    • Journal Title

      J Clin Invest.

      Volume: 123(11) Pages: 4627-40

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] ATP-binding Cassette Transporter G2 (Abcg2) Plays Oncogenic Roles in Myelodysplastic Syndrome in Mouse BMT Model and Characterizes Advanced MDS in Clinical Specimens2016

    • Author(s)
      Kimihito Cojin Kawabata
    • Organizer
      89th Stem Cell Biology and Regenerative Medicine Forum
    • Place of Presentation
      東大医科研病院8階会議室(東京都港区)
    • Year and Date
      2016-03-23
    • Related Report
      2015 Annual Research Report
  • [Presentation] ABCG2 Shows High Expression in MDS and Promotes MDS-like Diseases in BMT-model Mice with Modification of Stroma,2016

    • Author(s)
      Kimihito C Kawabata, Yasutaka Hayashi, Daichi Inoue, Hiroko Sakurai, Yuka Harada, Susumu Goyama, Hironori Harada, Jiro Kitaura, Hiroyuki Aburatani, Toshio Kitamura,
    • Organizer
      20th Annual Meeting of Hematological Malignancy Study Group
    • Place of Presentation
      上総アーク(千葉県木更津市)
    • Year and Date
      2016-02-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] Higher Expression of ATP-binding Cassette Transporter G2 (ABCG2) Is Specific to Advanced Myelodysplastic Syndrome and Promotes Inefficient Hematopiesis via Conversions of Tumor Microenvironment2016

    • Author(s)
      Kimihito C Kawabata, Yasutaka Hayashi, Daichi Inoue, Hiroko Sakurai, Yuka Harada, Susumu Goyama, Hironori Harada, Jiro Kitaura, Hiroyuki Aburatani, Toshio Kitamura,
    • Organizer
      JSPS-NUS Symposium
    • Place of Presentation
      シンガポール、シンガポール
    • Year and Date
      2016-01-14
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A Patient-derived EZH2 mutant induces MDS-like diseases with derepressed ABCG2 expression in mice.,2015

    • Author(s)
      Kimihito C Kawabata, Yasutaka Hayashi, Daichi Inoue, Hiroko Sakurai, Yuka Harada, Susumu Goyama, Hironori Harada, Jiro Kitaura, Hiroyuki Aburatani, Toshio Kitamura,
    • Organizer
      53rd Annual Meeting of American Society of Hematology
    • Place of Presentation
      フロリダ州オーランド、米国
    • Year and Date
      2015-12-05
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Truncated Form EZH2 Mutation Promotes Myeloid Tumorigenesis in Mouse BMT Model via Upregulation of Tumor Stem Cell Genes,2015

    • Author(s)
      Kimihito C Kawabata, Daichi Inoue, Jiro Kitaura, Susumu Goyama, Hironori Harada, Toshio Kitamura,
    • Organizer
      77th Annual Meeting of Japanese Society of Hematology
    • Place of Presentation
      石川県立音楽堂(石川県金沢市)
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
  • [Presentation] Truncated Form EZH2 Mutation Promotes Myeloid Tumorigenesis in Mouse BMT Model via Upregulation of Tumor Stem Cell Genes2015

    • Author(s)
      Kimihito C Kawabata, Daichi Inoue, Jiro Kitaura, Susumu Goyama, Hironori Harada, Toshio Kitamura,
    • Organizer
      74th Annual Meeting of Japanese Cancer Association
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] Patient-Derived EZH2 Mutation Induces MDS-like Diseases with Derepressed ABCG2 Expression in Mice2015

    • Author(s)
      Kimihito C Kawabata, Daichi Inoue, Jiro Kitaura, Yuka Harada, Susumu Goyama, Hironori Harada, Hiroyuki Aburatani, Toshio Kitamura,
    • Organizer
      44th Annual Meeting of International Society for Experimental Hematology
    • Place of Presentation
      京都国際会議場(京都府京都市)
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Truncated Form EZH2 Mutation Promotes Myeloid Tumorigenesis in Mouse BMT Model via Upregulation of Tumor Stem Cell Markers2015

    • Author(s)
      Kimihito C Kawabata, Daichi Inoue, Jiro Kitaura, Hironori Harada, Toshio Kitamura
    • Organizer
      13th Stem Cell Research Symposium
    • Place of Presentation
      伊藤国際会館(東京都文京区)
    • Year and Date
      2015-05-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] Dominant Negative EZH2 Promotes Myeloid Tumorigenesis in Mouse BMT Model via Promotion of Tumor Initiating Capacity2015

    • Author(s)
      川畑 公人
    • Organizer
      がん支援活動公開シンポジウム
    • Place of Presentation
      東京 一橋講堂
    • Year and Date
      2015-01-28
    • Related Report
      2014 Annual Research Report
  • [Presentation] EZH2 Truncated Form Mutant Promotes Myeloid Tumorigenesis in Mouse BMT Model via Promotion of Tumor Initiating Capacity2015

    • Author(s)
      川畑 公人
    • Organizer
      第19回造血器腫瘍研究会
    • Place of Presentation
      佐賀 グランデはがくれ
    • Year and Date
      2015-01-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] Dominant negative EZH2 promotes myeloid tumorigenesis in mouse BMT model2014

    • Author(s)
      Kimihito C. Kawabata
    • Organizer
      第76回日本血液学会学術集会(Science Exchange Training Programとしてアメリカ血液学会幹部の前で発表)
    • Place of Presentation
      大阪 大阪国際会議場
    • Year and Date
      2014-11-02
    • Related Report
      2014 Annual Research Report
  • [Presentation] SETドメイン欠失EZH2はマウス骨髄移植において骨髄性腫瘍を促進する2014

    • Author(s)
      川畑 公人
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪 大阪国際会議場
    • Year and Date
      2014-10-31
    • Related Report
      2014 Annual Research Report
  • [Presentation] Dominant-negative EZH2 in mouse BMT model promotes myeloid malignancy via regulation of tumor-initiating capacity in myeloid cells.2014

    • Author(s)
      Kimihito C. Kawabata
    • Organizer
      第72回幹細胞治療研究フォーラム
    • Place of Presentation
      東京 東京大学医科学研究所病院8階ホール
    • Year and Date
      2014-07-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] Dominant Negative EZH2 Promotes Myeloid Tumorigenesis in Mouse BMT Model2014

    • Author(s)
      Kimihito C. Kawabata
    • Organizer
      第12回幹細胞シンポジウム
    • Place of Presentation
      福岡 九州大学医学部百年記念講
    • Year and Date
      2014-05-31
    • Related Report
      2014 Annual Research Report
  • [Presentation] Dominant Negative EZH2 in Mouse BMT Model2014

    • Author(s)
      川畑 公人
    • Organizer
      新学術領域細胞運命制御若手の会
    • Place of Presentation
      静岡 浜名湖グランドホテル
    • Year and Date
      2014-04-18
    • Related Report
      2014 Annual Research Report
  • [Presentation] Dominant negative EZH2を用いたマウス骨髄移植モデルの検討2014

    • Author(s)
      川畑公人
    • Organizer
      第18回造血器腫瘍研究会
    • Place of Presentation
      東京 がん研究会がん研究所
    • Year and Date
      2014-02-07
    • Related Report
      2013 Annual Research Report

URL: 

Published: 2014-01-29   Modified: 2024-03-26  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi