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Epigenetic pathogenesis of multiple myeloma related to drug resistance

Research Project

Project/Area Number 16K09839
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionChiba University

Principal Investigator

Naoya Mimura  千葉大学, 医学部附属病院, 助教 (00422220)

Research Collaborator Iwama Atsuhi  東京大学, 医科学研究所, 教授 (70244126)
Nakaseko Chiaki  千葉大学, 大学院医学研究院, 特任教授 (30323398)
Iseki Tohru  千葉大学, 医学部附属病院, 講師 (10232365)
Oshima Motohiko  東京大学, 医科学研究所, 助教 (70506287)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords多発性骨髄腫 / ヒストンメチル化異常 / EZH2/EZH1共阻害剤 / プロテアソーム阻害剤 / 骨髄腫モデルマウス / EZH2/EZH1阻害剤 / UTX / BRAF / EZH2/1共阻害剤 / 血液内科学 / エピジェネティクス
Outline of Final Research Achievements

In this study, we have shown that a dual EZH2/EZH1 inhibitor UNC1999 is effective alone and in combination with proteasome inhibitors in our preclinical multiple myeloma (MM) models. We have also shown that EZH2 overexpression is related to drug resistance in MM. Moreover, we have created a conditional mouse model of post-germinal center malignancies with a concurrent Utx loss and Braf V600E mutation. A significant number of compound mice developed plasma cell neoplasms with extramedullary disease. Our mouse model could be a useful tool for understanding the role of epigenetic dysfunction in MM and studying novel therapeutic agents.

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫はいまだ治癒できない難治性悪性腫瘍であり、新たなアプローチを介した治療法の開発が待たれている。本研究により、EZH2/EZH1共阻害剤が新たな治療選択肢となるための分子基盤が示された。またプロテアソーム阻害剤は現在骨髄腫の第一選択薬として広く用いられているが、不応例や、長期投与による耐性化や有害事象が問題となっている。EZH2/EZH1共阻害剤との併用により、骨髄腫患者の予後向上に寄与できると期待される。更に、ヒト多発性骨髄腫の病態を模倣した骨髄腫モデルマウスの開発により、骨髄腫の分子病態メカニズムの解明や新規治療薬の創出に大いに貢献できるものと期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (20 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (3 results) Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results) Presentation (12 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results) Book (4 results)

  • [Int'l Joint Research] マウントサイナイ医科大学(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] マウントサイナイ医科大学(米国)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] マウントサイナイ医科大学(米国)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition.2017

    • Author(s)
      Ola Rizq, Naoya Mimura, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Yuko Kato, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Changshan Wang, Tetsuhiro Chiba, Anqi Ma, Jian Jin, Tohru Iseki, Chiaki Nakaseko, and Atsushi Iwama
    • Journal Title

      Clinical Cancer Research

      Volume: 23(16) Issue: 16 Pages: 4817-4830

    • DOI

      10.1158/1078-0432.ccr-16-2735

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Utx Insufficiency Cooperates with Braf V600E in the Induction of Myeloma in Mice2018

    • Author(s)
      Ola Rizq, Naoya Mimura, Motohiko Oshima, Shuji Momose, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Atsunori Saraya, Tohru Iseki, Emiko Sakaida, Chiaki Nakaseko, Yutaka Okuno, Hiroaki Honda, Jun-ichi Tamaru, and Atsushi Iwama
    • Organizer
      The 60th ASH annual meeting (SanDiego, USA)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Loss of Utx Cooperates with Braf V600E Mutation to Induce Post-Germinal Center B-cell Disorders in Mice2018

    • Author(s)
      Ola Rizq, Naoya Mimura, Motohiko Oshima, Syuji Momose, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Atsunori Saraya, Tohru Iseki, Emiko Sakaida, Chiaki Nakaseko, Yutaka Okuno, Hiroaki Honda, Jun-ichi Tamaru, and Atsushi Iwama
    • Organizer
      The 9th JSH international symposium (Kyoto, Japan)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規骨髄腫マウスモデルの作成2018

    • Author(s)
      リズクオラ, 三村尚也, 井関徹, 堺田惠美子, 中世古知昭, 岩間厚志
    • Organizer
      第43回日本骨髄腫学会学術集会 (千葉市)
    • Related Report
      2018 Annual Research Report
  • [Presentation] Loss of Utx with Braf V600E induces mature B-cell tumorigenesis in a conditional mouse model2018

    • Author(s)
      Ola Rizq, Naoya Mimura, Motohiko Oshima, Shuji Momose, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Atsunori Saraya, Tohru Iseki, Emiko Sakaida, Chiaki Nakaseko, Yutaka Okuno, Hiroaki Honda, Jun-ichi Tamaru, and Atsushi Iwama
    • Organizer
      第80回日本血液学会総会(大阪市)
    • Related Report
      2018 Annual Research Report
  • [Presentation] 骨髄腫治療におけるプロテアソーム阻害剤とEZH2/1共阻害剤の相乗効果の分子メカニズム2017

    • Author(s)
      三村尚也
    • Organizer
      第42回日本骨髄腫学会学術集会
    • Place of Presentation
      日本赤十字看護大学(東京都渋谷区)
    • Year and Date
      2017-05-27
    • Related Report
      2016 Research-status Report
  • [Presentation] 骨髄腫治療におけるプロテアソーム阻害剤とEZH2/1阻害剤の相乗効果の分子メカニズム2017

    • Author(s)
      三村尚也
    • Organizer
      第42回日本骨髄腫学会学術集会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 骨髄腫における治療標的としてのエピゲノム異常2017

    • Author(s)
      三村尚也
    • Organizer
      第58回日本リンパ網内系学会総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Molecular mechanism behind the synergistic activity of proteasome inhibition and PRC2 inhibition in the treatment of multiple myeloma.2016

    • Author(s)
      14.Ola Rizq, Naoya Mimura, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Yuko Kato, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Changshan Wang, Anqi Ma, Jian Jin, Tohru Iseki, Chiaki Nakaseko, and Atsushi Iwama.
    • Organizer
      The 58th Annual Meeting of the American Society of Hematology
    • Place of Presentation
      San Diego Convention Center, California, USA
    • Year and Date
      2016-12-03
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Combined inhibition of PRC2 and proteasome as a potential therapy for multiple myeloma2016

    • Author(s)
      Ola Rizq, 三村尚也, 大島基彦, 更屋敦則, 小出周平, 加藤裕子, 青山和正, 井関徹, 中世古知昭, 岩間厚志
    • Organizer
      第78回日本血液学会総会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] PRC2 Inhibition Sensitizes Myeloma Cells to Proteasome Inhibitor.2016

    • Author(s)
      Ola Rizq, Naoya Mimura, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Yuko Kato, Kazumasa Aoyama, Changshan Wang, Tetsuhiro Chiba, Tohru Iseki, Chiaki Nakaseko, and Atsushi Iwama.
    • Organizer
      The 5th Japanese Cancer Association (JCA) - American Association for Cancer Research (AACR) Special Joint Conference
    • Place of Presentation
      Tokyo Bay Maihama Hotel Club Resort(千葉県浦安市)
    • Year and Date
      2016-07-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] EZH2・EZH1阻害剤は骨髄腫細胞のボルテゾミブ感受性を増強する2016

    • Author(s)
      Ola Rizq, 三村尚也, 井関徹, 中世古知昭, 岩間厚志
    • Organizer
      第41回日本骨髄腫学会学術集会
    • Place of Presentation
      あわぎんホール(徳島県徳島市)
    • Year and Date
      2016-05-28
    • Related Report
      2016 Research-status Report
  • [Presentation] 多発性骨髄腫に対する新規エピジェネティック治療2016

    • Author(s)
      三村尚也
    • Organizer
      第41回日本骨髄腫学会学術集会
    • Place of Presentation
      あわぎんホール(徳島県徳島市)
    • Year and Date
      2016-05-28
    • Related Report
      2016 Research-status Report
  • [Book] 血液内科2019年1月特集「多発性骨髄腫の分子病態解明の進歩と新たな治療展開」2019

    • Author(s)
      三村尚也(分担)
    • Publisher
      科学評論社
    • Related Report
      2018 Annual Research Report
  • [Book] 日本臨牀2018年7月特集「多発性骨髄腫-基礎・臨床研究の最新動向」2018

    • Author(s)
      三村尚也(分担)
    • Publisher
      日本臨牀社
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Book] 多発性骨髄腫学ー最新の診療と基礎研究ー2016

    • Author(s)
      三村尚也 岩間厚志(分担著者)
    • Publisher
      日本臨牀社
    • Related Report
      2016 Research-status Report
  • [Book] 多発性骨髄腫Updating第10巻2016

    • Author(s)
      三村尚也(分担著者)
    • Publisher
      医薬ジャーナル社
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2023-03-16  

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