Identification of differences between hematopoietic stem cell and leukemia stem cell will lead to the creation of new therapeutic concepts

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16741
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Osaka University
• Principal Investigator: JIA WEIZHEN 大阪大学, 微生物病研究所, 助教 (40791281)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: Galectin-3 / 造血幹細胞 / 白血病 / 細胞周期

Outline of Final Research Achievements

During our extensive exploration into the mechanism of hematopoietic stem cell (HSC) quiescence maintenance, we found that Galectin-3 (Gal-3) is highly expressed in quiescent HSCs. The percentage of long-term HSCs (LT-HSC) in the G0 phase decreased in bone marrow (BM) from Gal-3 knockout (KO) relative to wild-type mice and that lost reconstruction ability of LT-HSCs in Gal-3 KO mice. These results illustrate that Gal-3 regulates the cell-cycle of HSCs and plays a critical role in maintaining the quiescent state.
Our research on the mechanism of how Gal-3 maintains HSC quiescence found that angiopoietin-1 or thrombopoietin, secreted from BM niche cells, binds to the receptor Tie2 or Mpl on the surface of cells. Nuclear translocation of NF-κB mediated by activated PI3K/AKT pathway following stimulation by Tie2 or Mpl expressed in HSCs promotes the production of Gal-3, which then binds to Sp1 and induces p21 transcription which in turn results in the inhibition of cell-cycle progression.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞は単なる幹細胞としての生物学的な興味のみならず，白血病などがん幹細胞との関連性も強く示唆されており、造血幹細胞の分子機構を理解することはきわめて重要な課題である。本研究では造血幹細胞におけるGal-3がp21転写制御により細胞周期のG0期維持に寄与していることが認められ、造血幹細胞の休眠状態維持にとって重要であることを明らかにした。一方、Gal-3の発現制御が白血病幹細胞の増殖を抑制することを見出した。本研究成果を通して、有効な幹細胞の培養、移植、正常な幹細胞を守る抗がん剤治療，さらにはがん幹細胞への適用などへの応用に寄与できると推測される。