Elucidation of the regulatory mechanisms of integrin expression by super-enhancer analysis

• Project/Area Number: 18KK0440
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Research Field: Tumor diagnostics
• Research Institution: Kumamoto University
• Principal Investigator: NAMBU AKIKO 熊本大学, 大学院生命科学研究部(医), 特別研究員 (40572087)
• Project Period (FY): 2019 – 2022
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: 白血病 / インテグリン / エンハンサー / 脳腫瘍幹細胞 / がん幹細胞 / 脳腫瘍 / プロテオミクス / スーパーエンハンサー

Outline of Final Research Achievements

The aim of this study is to elucidate the regulatory mechanism of integrin expression in leukemia, and to apply and develop this idea and methodology to the regulatory mechanism of integrin expression in glioblastoma stem cells. Our results showed that ITGA9 is highly expressed in AML stem cells (LSCs), and that ITGA9 expression is involved in AML proliferation by increasing MYC expression and promoting AML ribosome biogenesis through activation of the AKT/PI3K pathway. These basic findings suggest that the expression of TGA9 may be regulated by MYC itself or by a cluster of super-enhancer genes formed on the MYC locus.

Academic Significance and Societal Importance of the Research Achievements

本研究は, スーパーエンハンサーを解析することにより, がん関連遺伝子インテグリンの発現制御機構を明らかにする新しい試みであり, 本研究によって得られた知識や技術は脳腫瘍のみならず, 他の腫瘍においても応用可能であると考えられる. また本研究によって得られた結果を発展させることで, 今後白血病や脳腫瘍において新たな治療標的を探索することができる可能性があることから, 本研究成果は腫瘍生物学にとって重要な基礎的知見を提供できたと考えられる.

Research Products

• [Int'l Joint Research] Cancer Science Institute(シンガポール) (2019)
  • Year and Date: 2019-04-01
• [Journal Article] Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells (2023)
  • Author(s): Koh CP., Bahirvani AG., Wang CQ., Yokomizo T., Ng CEL., Du L., Tergaonkar V., Voon DC., Kitamura H., Hosoi H., Sonoki T., Michelle MMH., Tan LJ., Niibori-Nambu A., Zhang Y., Perkins AS., Hossain Z., Tenen DG., Ito Y., Venkatesh B., Osato M.
  • Journal Title: Gene Volume: 851 Pages: 147049-147049
  • DOI: 10.1016/j.gene.2022.147049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bone marrow-targetable Green Tea Catechin-Based Micellar Nanocomplex for synergistic therapy of Acute myeloid leukemia. (2022)
  • Author(s): Bae KH, Lai F, Mong J, Niibori-Nambu A, Chan KH, Her Z, Osato M, Tan MH, Chen Q, Kurisawa M.
  • Journal Title: J Nanobiotechnology Volume: 20 Issue: 1 Pages: 481-481
  • DOI: 10.1186/s12951-022-01683-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Super-silencers regulated by chromatin interactions control apoptotic genens. (2022)
  • Author(s): Ying Zhang, Kaijing Chen, Yichao Cai, Akiko Nambu, Yi Z See, Chaoyu Fu, Anandhkumar Raju, Manikandan Lakshmanan, Motomi Osato, Vinay Tergaonkar, Melissa J Fullwood.
  • Journal Title: BioRixv Volume: 1 Pages: 476559-476559
  • DOI: 10.1101/2022.01.17.476559
  • Open Access / Int'l Joint Research
• [Journal Article] Trib1 promotes the development of acute myeloid leukemia in a Ts1Cje mouse model of Down syndrome (2021)
  • Author(s): Yoshino Seiko、Tanaka Miwa、Sunami Yoshitaka、Takahara Tomoko、Yamazaki Yukari、Homme Mizuki、Niibori-Nambu Akiko、Osato Motomi、Minami Takashi、Ishihara Keiichi、Nakamura Takuro
  • Journal Title: Leukemia Volume: 36 Issue: 2 Pages: 558-561
  • DOI: 10.1038/s41375-021-01384-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RUNX1-ETO (RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner (2021)
  • Author(s): Abdallah Mohamed Gaber、Niibori-Nambu Akiko、Morii Mariko、Yokomizo Takako、Yokomizo Tomomasa, at al.
  • Journal Title: Leukemia Volume: 35 Issue: 10 Pages: 2983-2988
  • DOI: 10.1038/s41375-021-01268-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines (2021)
  • Author(s): Hosoi Hiroki、Niibori-Nambu Akiko、Nah Giselle Sek Suan、Bahirvani Avinash Govind、Mok Michelle Meng Huang、Sanda Takaomi、Kumar Alan Prem、Tenen Daniel G.、Ito Yoshiaki、Sonoki Takashi、Osato Motomi
  • Journal Title: Gene Volume: 774 Pages: 145421-145421
  • DOI: 10.1016/j.gene.2021.145421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A two-pronged anti-leukemic agent based on a hyaluronic acid?green tea catechin conjugate for inducing targeted cell death and terminal differentiation (2020)
  • Author(s): Liang Kun、Bae Ki Hyun、Nambu Akiko、Dutta Bibek、Chung Joo Eun、Osato Motomi、Kurisawa Motoichi
  • Journal Title: Biomaterials Science Volume: 8 Issue: 1 Pages: 497-505
  • DOI: 10.1039/c9bm01146c
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Molecular mimicry of niche-interacting status by ITGA9 overexpression underlies the extramedullary maintenance of leukemia stem cells in AML. (2022)
  • Author(s): Bibek Dutta
  • Organizer: NCIS Annual Research Meeting 2022
  • Int'l Joint Research
• [Presentation] Molecular mimicry of niche-interacting status by ITGA9 overexpression underlines the extramedullary maintenance of leukemia stem cells in AML (2021)
  • Author(s): Akiko Niibori-Nambu
  • Organizer: SICS 2021
  • Int'l Joint Research
• [Presentation] Targeting Integrin a9 by a Blocking Monoclonal Antibody in Acute Myeloid Leukemia (2020)
  • Author(s): Akiko Niibori-Nambu
  • Organizer: Frontiers in Cancer Scneince
• [Presentation] Targeting Integrin a9 by a Blocking Monoclonal Antibody in Acute Myeloid Leukemia (2019)
  • Author(s): Akiko Niibori-Nambu
  • Organizer: Frontiers in Cancer Science
• [Presentation] argeting Integrin a9 by a Blocking Monoclonal Antibody in Acute Myeloid Leukemia (2019)
  • Author(s): Akiko Niibori-Nambu
  • Organizer: RUNX meeting
  • Int'l Joint Research