Understanding of the molecular mechanisms of hematopoietic stem cell heterogeneity by quiescence regulatory factors

• Project/Area Number: 26460361
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kanazawa University
• Principal Investigator: Ueno Masaya 金沢大学, がん進展制御研究所, 助教 (20334766)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 幹細胞 / 白血病 / 不均一性 / 治療抵抗性 / 白血病幹細胞の分子基盤解析 / 造血幹細胞の分子基盤解析

Outline of Final Research Achievements

Recent studies have revealed that hematopoietic stem cells (HSCs) form heterogeneous population with extremely diverse biological properties. By maintaining the heterogeneity, HSCs maintain the hematopoietic system for whole life, and it seems that it contributes to respond to various stresses. In this study, we focused on mTOR complex and forkhead transcription factor, FOXO, which are essential for survival and cell cycle regulation, and we identified molecules that are regulated by these pathways. Furthermore, by performing CRISPR/Cas9 screening system, we identified multiple functional molecules that contribute to regulate heterogeneity of HSCs and leukemic stem cells.

Research Products

• [Journal Article] Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance. (2016)
  • Author(s): Hegazy AM, Yamada D, Kobayashi M, Kohno S, Ueno M, Ali MA, Ohta K, Tadokoro Y, Ino Y, Todo T, Soga T, Takahashi C, Hirao A.
  • Journal Title: J Biol Chem. Volume: 291 Issue: 41 Pages: 21496-21509
  • DOI: 10.1074/jbc.m116.734756
  • Peer Reviewed / Open Access
• [Journal Article] Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients. (2014)
  • Author(s): Ali MA, Naka K, Yoshida A, Fuse K, Kasada A, Hoshii T, Tadokoro Y, Ueno M, Ohta K, Kobayashi M, Takahashi C, Hirao A.
  • Journal Title: Biochem Biophys Res Commun. Volume: 450 Issue: 1 Pages: 837-843
  • DOI: 10.1016/j.bbrc.2014.06.066
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals. (2014)
  • Author(s): Yamada D, Hoshii T, Tanaka S, Hegazy AM, Kobayashi M, Tadokoro Y, Ohta K, Ueno M, Ali MAE, Hirao A.
  • Journal Title: J Biochem. Volume: 155 Issue: 4 Pages: 227-33
  • DOI: 10.1093/jb/mvt112
  • Peer Reviewed