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Targeting transcription and epigenetic factors through modulation of protein-protein interactions

Research Project

Project/Area Number 19H03685
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionThe University of Tokyo

Principal Investigator

Goyama Susumu  東京大学, 大学院新領域創成科学研究科, 教授 (80431849)

Co-Investigator(Kenkyū-buntansha) 長門石 曉  東京大学, 医科学研究所, 特任准教授 (30550248)
高橋 宏隆  愛媛大学, プロテオサイエンスセンター, 准教授 (70432804)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywords骨髄系腫瘍 / 転写因子 / エピゲノム制御因子 / タンパク質間相互作用 / エピゲノム因子 / RUNX1 / CBFB / EVI1 / ASXL1
Outline of Research at the Start

転写因子やエピゲノム制御因子は、様々な遺伝子の発現を制御することにより生体の恒常性を維持している。転写・エピゲノム因子の異常が様々な疾患の原因となることは以前からよく知られていたが、これまで阻害剤の開発は困難であった。しかし最近の技術革新により、タンパク質間相互作用制御に基づく創薬が可能となってきた。そこで本研究では、最新のタンパク質工学を活用して、難治性造血器腫瘍原因分子RUNX1, EVI1, ASXL1を標的とする新しい治療薬を開発する。

Outline of Final Research Achievements

The development of drugs targeting transcription and epigenomic factors has been considered difficult, but recent technological innovations have enabled drug discovery based on Protein-Protein Interaction (PPI) regulation. In this study, we utilized the latest PPI regulation technology to identify compounds that inhibit transcription factor RUNX1-CBFB binding, compounds that bind to RUNX1 and E3 ubiquitin ligase STUB1, and compounds that inhibit epigenomic regulator ASXL1-BAP1 binding. In addition, RUNX1-targeted nucleic acid drugs were developed. Based on these results, the development of novel drugs targeting hematopoietic transcription factors and epigenetic regulators will be promoted in the future.

Academic Significance and Societal Importance of the Research Achievements

転写因子やエピゲノム制御因子は、様々な遺伝子の発現を制御する役割を持ち、がんの発症・進展にも深く関与しています。しかし、転写・エピゲノム因子を標的とする薬剤の開発は難しいと考えられてきました。本研究では、タンパク質間の相互作用を制御する最新の技術を活用して、これまで有効な治療薬が存在しなかった転写因子RUNX1や、エピゲノム制御因子ASXL1の機能を阻害する薬剤を開発しました。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (30 results)

All 2022 2021 2020 2019 Other

All Journal Article (7 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (21 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] CHIP‐associated mutant ASXL1 in blood cells promotes solid tumor progression2022

    • Author(s)
      Liu Xiaoxiao、Sato Naru、Shimosato Yuko、Wang Teh‐Wei、Denda Tamami、Chang Yu‐Hsuan、Yabushita Tomohiro、Fujino Takeshi、Asada Shuhei、Tanaka Yosuke、Fukuyama Tomofusa、Enomoto Yutaka、Ota Yasunori、Sakamoto Takeharu、Kitamura Toshio、Goyama Susumu
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 4 Pages: 1182-1194

    • DOI

      10.1111/cas.15294

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors2022

    • Author(s)
      Tanaka Yosuke....Goyama Susumu、Komatsu Norio、Takaku Tomoiku、Kitamura Toshio
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 271-271

    • DOI

      10.1038/s41467-021-27928-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CRISPR/Cas9-mediated base-editing enables a chain reaction through sequential repair of sgRNA scaffold mutations2021

    • Author(s)
      Fukushima, T., Tanaka, Y., Adachi, K., Masuyama, N., Tsuchiya, A., Asada, S., Ishiguro, S., Mori, H., Seki, M., Yachie, N., Goyama, S., Kitamura, T.
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1

    • DOI

      10.1038/s41598-021-02986-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells2021

    • Author(s)
      Yamamoto Keita、Goyama Susumu、Asada Shuhei、Fujino Takeshi、Yonezawa Taishi、Sato Naru、Takeda Reina、Tsuchiya Akiho、Fukuyama Tomofusa、Tanaka Yosuke、Yokoyama Akihiko、Toya Hikaru、Kon Ayana、Nannya Yasuhito、Onoguchi-Mizutani Rena、Nakagawa Shinichi、Hirose Tetsuro、Ogawa Seishi、Akimitsu Nobuyoshi、Kitamura Toshio
    • Journal Title

      Cell Reports

      Volume: 36 Issue: 8 Pages: 109576-109576

    • DOI

      10.1016/j.celrep.2021.109576

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway2021

    • Author(s)
      Fujino Takeshi、Goyama Susumu、Sugiura Yuki、Inoue Daichi、Asada Shuhei、Yamasaki Satoshi、Matsumoto Akiko、Yamaguchi Kiyoshi、Isobe Yumiko、Tsuchiya Akiho、Shikata Shiori、Sato Naru、Morinaga Hironobu、Fukuyama Tomofusa、Tanaka Yosuke、Fukushima Tsuyoshi、Takeda Reina、Yamamoto Keita、Honda Hiroaki et al
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 1826-1826

    • DOI

      10.1038/s41467-021-22053-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Acute myeloid leukemia stem cells from genomic and immunological perspectives2020

    • Author(s)
      合山 進
    • Journal Title

      Rinsho Ketsueki

      Volume: 61 Issue: 9 Pages: 1130-1137

    • DOI

      10.11406/rinketsu.61.1130

    • NAID

      130007937125

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2020 Annual Research Report
  • [Journal Article] Acute myeloid leukemia stem cells2020

    • Author(s)
      合山 進
    • Journal Title

      Rinsho Ketsueki

      Volume: 61 Issue: 4 Pages: 336-342

    • DOI

      10.11406/rinketsu.61.336

    • NAID

      130007839377

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2020 Annual Research Report
  • [Presentation] イマチニブとIRAK1/4 阻害剤との併用は慢性骨髄性白血病幹細胞の駆逐に効果的である2021

    • Author(s)
      田中洋介、竹田玲奈、福島剛、合山進、北村俊雄
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] リピッドナノパーティクルを活用したRUNX1ノックダウンは、T細胞白血病の増殖を抑制する2021

    • Author(s)
      飯田孝平、土屋秋穂、川田滋久、菅野美津子、合山進
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A histone modifier ASXL1 interacts with NONO and is involved in paraspeckle formation in hematopoietic cells2021

    • Author(s)
      山本圭太、合山進、浅田修平、藤野赳至、米澤太志、佐藤成、竹田玲奈、福山朋房、田中洋介、横山明彦、昆彩奈、南谷泰仁、小野口玲菜、秋光信佳、小川誠司、北村俊雄
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Hyperactive NK cells in Rag2-deficient mice suppress the development of acute myeloid leukemia2021

    • Author(s)
      杉本絵美、合山進、林康貴、浅田修平、福島剛、川瀬竜也、斎藤健、吉田卓、山崎聡、海渡裕太、今井陽一、福山朋房、田中洋介、榎本豊、北村俊雄
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] p53活性化薬は、NK細胞と協調して急性骨髄性白血病の発症を抑制する2021

    • Author(s)
      合山進、杉本絵美、北村俊雄
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Hyperactive NK cells in Rag2-deficient mice suppress the development of acute myeloid leukemia2021

    • Author(s)
      杉本絵美、合山進、林康貴、浅田修平、海渡裕太、今井陽一、福山朋房、田中洋介、北村俊雄
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Somatic ASXL1 mutation in blood cells promote solid tumor progression2021

    • Author(s)
      劉瀟瀟、佐藤成、北村俊雄、合山進
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ASXL1変異を伴う血液細胞が固形腫瘍の発症、進展に及ぼす影響2021

    • Author(s)
      劉瀟瀟、北村俊雄、合山進
    • Organizer
      第25回造血器腫瘍研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Asxl1 と Stag2 の変異は協調して遺伝子発現を変化させ骨髄異形成症候群の発症を誘導する2021

    • Author(s)
      藤野赳至、越智陽太郎、昆彩奈、合山進、小川誠司、北村俊雄
    • Organizer
      第25回造血器腫瘍研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 造血幹・前駆細胞におけるASXL1変異による核内構造体形成異常の解析2021

    • Author(s)
      山本圭太、合山進、浅田修平、藤野赳至、米澤太志、佐藤成、竹田玲奈、福山朋房、田中洋介、横山明彦、昆彩奈、南谷泰仁、小川誠司、北村俊雄
    • Organizer
      第25回造血器腫瘍研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] タンパク質工学を活用した転写因子標的療法の開発2021

    • Author(s)
      合山進
    • Organizer
      先端医療シーズ開発フォーラム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Epigenetic Regulator ASXL1 Promotes Paraspeckle Formation through C-terminal Intrinsically Disordered Region in Hematopoietic Cells2020

    • Author(s)
      山本圭太、合山進、北村俊雄
    • Organizer
      ISEH 2020 Virtual Scientific Meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mutant ASXL1 induces expansion of hematopoietic stem cells through activation of Akt/mTOR pathway2020

    • Author(s)
      藤野赳至、合山進、Yuki Sugiura、井上大地、浅田修平、Satoshi Yamasaki、Akiko Matsumoto、Kiyoshi Yamaguchi、土屋秋穂、四方紫織、佐藤成、Hironobu Morinaga、福山朋房、田中洋介、福島剛、竹田玲奈、山本圭太、本田浩章、Emi K. Nishimura、古川洋一、Tatsuhiro Shibata、Omar Abdel-Wahab、末松誠、北村俊雄
    • Organizer
      ISEH 2020 Virtual Scientific Meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clonal Hematopoiesis Associated with Mutant ASXL1 Accelerates Atherosclerosis in Mice2020

    • Author(s)
      佐藤成、合山進、浅田修平、藤野赳至、劉瀟瀟、竹田玲奈、山本圭太、米澤大志、北村俊雄
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] DTX2はRUNX1のユビキチン化および脱アセチル化を促進し、白血病細胞の増殖を抑制する2020

    • Author(s)
      米澤大志、北村俊雄、合山進
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] AML幹細胞 -ゲノム学および免疫学との融合-2020

    • Author(s)
      合山進
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Combination of ASXL1 mutation and Stag2 loss lead to development of myelodysplastic syndromes2020

    • Author(s)
      藤野赳至、越智陽太郎、昆彩奈、合山進、小川誠司、北村俊雄
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Development of RUNX1 inhibitor2019

    • Author(s)
      米澤大志、高橋弘隆、澤崎達也、北村俊雄、合山進
    • Organizer
      第三回 乳癌転移若手研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Development of RUNX1-CBFB interaction inhibitor for RUNX1-dependent leukemias2019

    • Author(s)
      米澤大志、高橋弘隆、澤崎達也、北村俊雄、合山進
    • Organizer
      プロテインアイランド松山
    • Related Report
      2019 Annual Research Report
  • [Presentation] Development of RUNX1-CBFB interaction inhibitor for RUNX1-dependent leukemias2019

    • Author(s)
      米澤大志、高橋弘隆、澤崎達也、北村俊雄、合山進
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The ubiquitin ligase DTX2 promotes nuclear export of RUNX1 and inhibits RUNX1-dependent leukemogenesis2019

    • Author(s)
      米澤大志、高橋弘隆、澤崎達也、北村俊雄、合山進
    • Organizer
      The 61st American Society of Hematology annual meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Remarks]

    • URL

      https://webpark2162.sakura.ne.jp/

    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 「物質送達キャリア及び組成物」2021

    • Inventor(s)
      合山進、菅野美津子、川田滋久
    • Industrial Property Rights Holder
      合山進、菅野美津子、川田滋久
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-146112
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
    • Overseas

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Published: 2019-04-18   Modified: 2024-01-30  

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