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

Elucidation of MDS pathogenesis based on understanding the roles of newly identified SWI/SNF complex

Research Project

Project/Area Number 20H03717
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 InstitutionFoundation for Biomedical Research and Innovation at Kobe

Principal Investigator

Inoue Daichi  公益財団法人神戸医療産業都市推進機構, その他部局等, 研究員(副センター長・部長クラス) (80735746)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2022: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2020: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
KeywordsBRD9 / 造血幹細胞 / SWI/SNF複合体 / クロマチンリモデリング / CTCF / RNAスプライシング / 骨髄異形成症候群 / クロマチン / スプライシング / クロマチン制御 / 細胞分化 / 急性骨髄性白血病 / 遺伝子変異
Outline of Research at the Start

本研究では骨髄異形成症候群において高頻度に検出されるSF3B1変異の下流標的としてのBRD9ならびにncBAFの造血幹細胞における役割を解明する。申請者が作成したBrd9条件的ノックアウトマウスを用いて造血・分化・形質転換における役割を評価し、特にSF3B1変異に伴うBRD9喪失に伴うクロマチン3次元構造の変化を明らかとすることで、骨髄異形成症候群の未知の発症機構を明らかとし、メカニズムに基づいた新規治療応用へとつなげる。

Outline of Final Research Achievements

Beyond DNA mutations, post-transcriptional regulatory mechanisms at the RNA level are gaining significant attention in cancer research. Notably, tumor cell-specific RNA dysregulation is emerging as a critical area of investigation, particularly given that RNA splicing-related gene mutations have been identified in approximately half of myelodysplastic syndromes (MDS). Despite this, the understanding of such dysregulation remains limited. In this study, we investigated the phenomenon wherein BRD9, a vital component of the novel SWI/SNF complex responsible for chromatin remodeling, is frequently lost in cancer cells due to the aberrant splicing. Utilizing knockout mice as our primary model, we concentrated on elucidating the role of BRD9 in hematopoietic stem cells (HSCs). Our research uncovered how aberrant splicing of BRD9 affects the cell fate of HSCs through the chromatin regulation.

Academic Significance and Societal Importance of the Research Achievements

本研究成果はゲノム変異を認めないBRD9遺伝子が転写後RNAレベルでの制御破綻によって機能喪失をきたし、それに伴うクロマチン状態の改変が造血幹細胞の新たな運命制御を示唆する知見と言える。このように、がんにおいては、DNAレベルの異常を伴わなくとも、他の重要な遺伝子の転写を脱制御するような現象が転写制御因子のRNAレベルで起こりうることを実験的に証明した成果と言え、今後の病態理解や治療応用につながる内容と言える。

Report

(4 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (27 results)

All 2023 2022 2020 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 6 results,  Open Access: 5 results) Presentation (18 results) (of which Int'l Joint Research: 8 results,  Invited: 17 results) Remarks (2 results)

  • [Int'l Joint Research] Memorial Sloan Kettering Cancer Center(米国)

    • Related Report
      2022 Annual Research Report
  • [Journal Article] BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state2023

    • Author(s)
      Xiao Muran、、、、Yokoyama Akihiko、、、、、Inoue Daichi
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 1-22

    • DOI

      10.1038/s41467-023-44081-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis.2022

    • Author(s)
      Hayashi Y, Inoue D, et al.
    • Journal Title

      Cell Reports

      Volume: VOLUME 39, ISSUE 6 Issue: 6 Pages: 110805-110805

    • DOI

      10.1016/j.celrep.2022.110805

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Aberrant <i>EVI1</i> splicing contributes to <i>EVI1</i>-rearranged leukemia2022

    • Author(s)
      Tanaka Atsushi、Kunimoto Hiroyoshi et al.
    • Journal Title

      Blood

      Volume: 140 Issue: 8 Pages: 875-888

    • DOI

      10.1182/blood.2021015325

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dysregulated minor intron splicing in cancer.2022

    • Author(s)
      Nishimura K*, Yamazaki H*, Zang W, Inoue D.
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 9 Pages: 2934-2942

    • DOI

      10.1111/cas.15476

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation2022

    • Author(s)
      Chen Sisi, Inoue Daichi, Abdel-Wahab Omar et al.
    • Journal Title

      Cancer Discovery

      Volume: 12 Issue: 10 Pages: 2434-2453

    • DOI

      10.1158/2159-8290.cd-21-1631

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Exploring the mechanistic link between SF3B1 mutation and ring sideroblast formation in myelodysplastic syndrome2022

    • Author(s)
      Ochi Tetsuro、Fujiwara Tohru、Ono Koya、Suzuki Chie、Nikaido Maika、Inoue Daichi、Kato Hiroki、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Nakamura Yukio、Harigae Hideo
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 14562-14562

    • DOI

      10.1038/s41598-022-18921-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Altered Post-transcriptional regulation in malignant hematopoiesis2023

    • Author(s)
      Daichi Inoue
    • Organizer
      IRCMS Mini Symposium on Normal Hematopoiesis and Transformation
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dual roles of BRD9 in normal and malignant hematopoiesis2023

    • Author(s)
      Daichi Inoue
    • Organizer
      ASH/JSH 2023 Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 骨髄異形成症候群における骨髄間質細胞の病態解明2023

    • Author(s)
      井上大地
    • Organizer
      第22回日本再生医療学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] BRD9を標的とした血液がん治療2023

    • Author(s)
      井上大地
    • Organizer
      第27回日本がん分子標的治療学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Deciphering the Mechanisms of Cancer Development Driven by Aberrant Splicing Events2023

    • Author(s)
      Daichi Inoue
    • Organizer
      SECOND JCA-AACR PRECISION CANCER MEDICINE INTERNATIONAL CONFERENCE
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dual roles of BRD9 in normal and malignant hematopoiesis.2023

    • Author(s)
      Inoue Daichi
    • Organizer
      ASH/JSH 2023 Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies Symposium
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ブロモドメインタンパクの転写後制御を介した造血幹細胞運命制御機構2022

    • Author(s)
      井上大地
    • Organizer
      第45回日本分子生物学会年会(幕張)
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ブロモドメインタンパクのスプライシング異常がもたらす細胞運命制御2022

    • Author(s)
      井上大地
    • Organizer
      第95回日本生化学会大会(名古屋)
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Dysregulated Minor Intron Splicing and Cancer.2022

    • Author(s)
      Inoue Daichi
    • Organizer
      第81回日本癌学会学術総会(横浜)
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Dissecting the mechanisms for cancer development caused by aberrant splicing.2022

    • Author(s)
      Inoue Daichi
    • Organizer
      The 12th AACR-JCA Joint Conference
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Aberrant splicing events lead to altered cell fate of hematopoietic stem cells.2022

    • Author(s)
      Inoue Daichi
    • Organizer
      The 19th Stem Cell Research Symposium
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] スプライシング異常を介した新規発がん機構2020

    • Author(s)
      井上大地
    • Organizer
      第92回日本遺伝学会ワークショップ
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Clarifying the Role of Minor Introns in Cancer Predisposition2020

    • Author(s)
      井上大地
    • Organizer
      The 4th CCII Seminar
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] マイナーイントロンを介した発癌機構2020

    • Author(s)
      井上大地
    • Organizer
      鶴岡カンファレンス2020
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] RNAの視点からみた造血器腫瘍2020

    • Author(s)
      井上大地
    • Organizer
      第11回神奈川MDS研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] イントロンから発癌を読み解く2020

    • Author(s)
      井上大地
    • Organizer
      東京血液懇話会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] スプライシング異常から紐解く造血器腫瘍2020

    • Author(s)
      井上大地
    • Organizer
      第3回先端医科学研究センター「マルチオミックスによる遺伝発現制御の先端的医学共同研究拠点」セミナー
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ZRSR2 Mutation Induced Minor Intron Retention Drives MDS and Diverse Cancer Predisposition Via Aberrant Splicing of LZTR12020

    • Author(s)
      井上大地
    • Organizer
      The 62nd ASH Annual Meeting and Exposition
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 神戸医療産業都市推進機構先端医療研究センター血液・腫瘍研究部

    • URL

      https://www.fbri-kobe.org/laboratory/research5/

    • Related Report
      2022 Annual Research Report
  • [Remarks] 造血と白血病を制御する未知の機構を解明

    • Related Report
      2022 Annual Research Report

URL: 

Published: 2020-04-28   Modified: 2025-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi