Functional analysis of STAP family proteins in CML

• Project/Area Number: 19K17829
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Osaka University
• Principal Investigator: Jun Toda 大阪大学, 医学部附属病院, 医員 (90770834)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 慢性骨髄性白血病 / 白血病幹細胞 / STAP-1 / アダプター蛋白 / CML / CML幹細胞 / STAP蛋白 / BCR-ABL / STAP

Outline of Research at the Start

本研究では、STAP-1またはSTAP-2 KOマウスにて作製したCMLモデルにおいて、STAP蛋白ファミリーがCMLの病勢進行と幹細胞へ与える影響を検討し、その機構について明らかにする。Gene expression profilingを行うことで、特にCML幹細胞におけるBcr-Abl依存性・非依存性経路でのSTAP蛋白の作用メカニズムを詳細に解析する予定である。

Outline of Final Research Achievements

First, I found that STAP-1 expression was up-regulated in human CML stem cells compared to normal stem cells.
Next, we conducted experiments in mice. Analysis of STAP-1 deficient CML mice revealed a significant decrease in the number of CML stem cells, and annexin staining revealed enhanced apoptosis in STAP-1 deficient CML stem cells, suggesting that STAP-1 contributes to survival by inhibiting apoptosis in CML stem cells.
We also performed RNA sequencing using CML stem cells and found that STAP-1 is involved in the phosphorylation of STAT5, which in turn regulates the expression of anti-apoptotic factors such as Bcl-2 and Bcl-xl. These data indicate that STAP-1 is an important molecule for the maintenance of CML stem cells. In this study, STAP-1-mediated signaling was newly identified as one of the therapeutic targets for stem cell targeting.

Academic Significance and Societal Importance of the Research Achievements

今回のSTAP-1を介したシグナル伝達の解明はCML幹細胞をターゲットとした治療の開発において、大きな意義があると考えられた。また、STAP-1そのものも、正常造血への影響が少ないと考えられるため、副作用の少ない、新たな治療標的として用いられることが期待される。

Research Products

• [Journal Article] Signal-transducing adapter protein-1 is required for maintenance of leukemic stem cells in CML. (2020)
  • Author(s): Toda J, Ichii M, Oritani K, Shibayama H, Tanimura A, Saito H, Yokota T, Motooka D, Okuzaki D, Kitai Y, Muromoto R, Kashiwakura JI, Matsuda T, Hosen N, Kanakura Y.
  • Journal Title: Oncogene Volume: 39 Issue: 34 Pages: 5601-5615
  • DOI: 10.1038/s41388-020-01387-9
  • Peer Reviewed / Open Access
• [Journal Article] Signal-transducing adaptor protein-2 delays recovery of B lineage lymphocytes during hematopoietic stress (2020)
  • Author(s): Ichii Michiko、Oritani Kenji、Toda Jun、Saito Hideaki、Shi Henyun、Shibayama Hirohiko、Motooka Daisuke、Kitai Yuichi、Muromoto Ryuta、Kashiwakura Jun-ichi、Saitoh Kodai、Okuzaki Daisuke、Matsuda Tadashi、Kanakura Yuzuru
  • Journal Title: Haematologica Volume: in press Issue: 2 Pages: 225573-225573
  • DOI: 10.3324/haematol.2019.225573
  • Peer Reviewed / Open Access
• [Presentation] STAP-1 is Required for Maintenance of Leukemic Stem Cells in Chronic Myeloid Leukemia. (2019)
  • Author(s): Jun Toda, Michiko Ichii, Kenji Oritani, Hideaki Saito, Yuichi Kitai, Ryuta Muromoto, Jun-ichi Kashiwakura, Kodai Saitoh, Tadashi Matsuda, Yuzuru Kanakura
  • Organizer: JSH international symposium 2019
  • Int'l Joint Research
• [Presentation] Therapeutic potential of the signal-transducing adaptor protein-1 (STAP-1) inhibition for CML treatment (2019)
  • Author(s): Jun Toda, Michiko Ich, Hirohiko Shibayama, Hideaki Saito, Tadashi Matsuda, Kenji Oritani, and Yuzuru Kanakura
  • Organizer: 日本血液学会 2019