Functional elucidation of shelterin factor TIN2 in leukemic stem cells and its application to the development of novel therapeutic strategies

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22638
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Kyushu University
• Principal Investigator: Arai Fumio 九州大学, 医学研究院, 教授 (90365403)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: 造血幹細胞 / 白血病幹細胞 / TIN2 / ミトコンドリア / 活性酸素種

Outline of Final Research Achievements

Shelterin complex (consisting of POT1, TPP1, TIN2, TRF1, TRF2, and RAP1) play essential roles in maintaining HSC function. We found that TIN2 localized in the mitochondria of HSCs increased reactive oxygen species (ROS) production and decreased self-renewal capacity. POT1 and TPP1 contributed to inhibiting the mitochondrial transfer of TIN2. On the other hand, TIN2 expression was upregulated in leukemic GMP (L-GMP), which possibly contributes to the energy metabolism in mitochondria in L-GMP. However, overexpression of TIN2 in L-GMP inhibited proliferation. Therefore, we need further investigation to clarify the function of mitochondrial TIN2 in leukemic stem cells.

Free Research Field

幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、シェルタリン因子TIN2がミトコンドリアに移行した場合、正常造血幹細胞では自己複製を抑制するが、白血病幹細胞では増殖に働くということを見出している。ミトコンドリアTIN2が正常幹細胞とがん幹細胞で異なる作用をもつという点は、新規性の高い成果であると考えられる。
今後、TPP1とPOT1aのタンパク導入によるミトコンドリアTIN2の機能抑制は、正常造血幹細胞の体外増幅と白血病幹細胞の抑制の両方に応用が可能であり、再生医療とがん治療の発展に同時に貢献出来ると考えられる。