Research for regulatory mechanisms of normal hematopoietic stem cell and leukemia stem cell pool via mTOR Complex 1

• Project/Area Number: 22790906
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: HOSHII Takayuki 金沢大学, がん進展制御研究所, 助教 (20464042)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 幹細胞 / シグナル伝達 / mTOR複合体

Research Abstract

Although dysregulation of mTOR complex 1(mTORC1) promotes leukemogenesis, how mTORC1 affects established leukemia is unclear. We investigated the role of mTORC1 in mouse model of acute myeloid leukemia. Raptor deficiency significantly suppressed leukemia progression by causing apoptosis of differentiated, but not undifferentiated, leukemia cells. Strikingly, a subset of AML cells with undifferentiated phenotypes survived long-term in the absence of mTORC1 activity. Thus, AML cells lacking mTORC1 activity can self-renew as AML stem cells.

Research Products

• [Journal Article] mTORC1is essential for leukemia propagation but not stem cell self-renewal. (2012)
  • Author(s): Hoshii. T
  • Journal Title: J Clin Invest. Volume: 122 Issue: 6 Pages: 2114-2129
  • DOI: 10.1172/jci62279
  • Peer Reviewed
• [Journal Article] mTORC1 in Intestinal CD11c+CD11b+Dendritic Cells Regulates Intestinal Homeostasis by Promoting IL-10 Production (2012)
  • Author(s): Ohtani M, Hoshii T, Fujii H, Koyasu S, Hirao A, Matsuda S.
  • Journal Title: J Immunol Volume: 188 Issue: 10 Pages: 4736-40
  • DOI: 10.4049/jimmunol.1200069
  • Peer Reviewed
• [Journal Article] PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi-1 expression and nuclear translocation of RORγ (2012)
  • Author(s): Kurebayashi Y. Nagai S. Ikejiri A. Ohtani M. Ichiyama K. Baba Y. Yamada T. Egami S. Hoshii T. Hirao A. Matsuda S. Koyasu S.
  • Journal Title: Cell Reports Volume: 1 Issue: 4 Pages: 360-373
  • DOI: 10.1016/j.celrep.2012.02.007
  • Peer Reviewed
• [Journal Article] PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi-1 expression and nuclear translocation of ROR<gamma (2012)
  • Author(s): Kurebayashi Y
  • Journal Title: >Cell Reports Volume: (in press)
  • Peer Reviewed
• [Journal Article] mTORC1 is essential for leukemia-propagation but not stem cell self-renewal (2012)
  • Author(s): Hoshii T
  • Journal Title: The Journal of Clinical Investigation Volume: (in press)
  • Peer Reviewed
• [Journal Article] NKX2. 2 suppresses self-renewal of glioma-initiating cells (2011)
  • Author(s): Muraguchi T, Tanaka S, Yamada D, Tamase A, Nakada M, Nakamura H, Hoshii H, Ooshio T, Tadokoro Y, Naka K, Ino Y, Todo T, Kuratsu J, Saya H, Hamada J
  • Journal Title: Cancer Res Volume: 71 Issue: 3 Pages: 1135-45
  • DOI: 10.1158/0008-5472.can-10-2304
  • Peer Reviewed
• [Journal Article] Molecular pathology of tumor-initiating cells : lessons from Philadelphia chromosome-positive leukemia (2011)
  • Author(s): Naka K, Hoshii T, Tadokoro Y, Hirao A.
  • Journal Title: Pathol Int Volume: 61 Issue: 9 Pages: 501-8
  • DOI: 10.1111/j.1440-1827.2011.02688.x
  • NAID: 10031185122
  • Peer Reviewed
• [Journal Article] NKX2.2 suppresses self-renewal of glioma-initiating cells. (2011)
  • Author(s): Muraguchi T, Hoshii T.Hirao A
  • Journal Title: Cancer Res Volume: 71 Pages: 1135-1145
  • Peer Reviewed
• [Journal Article] Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells. (2011)
  • Author(s): Naka K, Hoshii T, Hirao A.
  • Journal Title: Cancer Sci Volume: 101 Pages: 1577-1581
  • NAID: 10026594276
  • Peer Reviewed
• [Journal Article] Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells (2010)
  • Author(s): Naka K, Hoshii T, Hirao A.
  • Journal Title: Cancer Sci Volume: 101 Issue: 7 Pages: 1577-81
  • DOI: 10.1111/j.1349-7006.2010.01584.x
  • NAID: 10026594276
  • Peer Reviewed
• [Presentation] 急性骨髄性白血病細胞の増殖と幹細胞維持におけるmTORC1の機能解析 (2012)
  • Author(s): 星居孝之
  • Organizer: 第16回造血器腫瘍研究会
  • Place of Presentation: 国立がん研究センター(東京都)
• [Presentation] 急性骨髄性白血病細胞の増殖と幹細胞維持におけるmTOR複合体1(mTORC1)の機能解析 (2012)
  • Author(s): 星居孝之
  • Organizer: 新学術領域「細胞運命制御」若手の会
  • Place of Presentation: 軽井沢プリンスホテル(長野県)
• [Presentation] Rapamycin inhibits initiation of T-ALL induced by activation of oncogenic K-ras (2011)
  • Author(s): 星居孝之
  • Organizer: 第11回日本分子生物学会春季シンポジウム
  • Place of Presentation: 石川県立音楽堂(石川県)
  • Year and Date: 2011-05-26
• [Presentation] Roles of mTORC1 signaling innormal hematopoiesis andleukemogenesis (2011)
  • Author(s): 星居孝之
  • Organizer: 日米血液腫瘍セミナー
  • Place of Presentation: 湘南国際村センター(神奈川県)
• [Presentation] Rapamycin inhibits initiation of T-ALL induced by activation of oncogenic K-ras (2010)
  • Author(s): 星居孝之
  • Organizer: 第69回 日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2010-09-22
• [Presentation] TSC-mTOR signaling controlsthe hematopoietic stem cell pool (2010)
  • Author(s): 星居孝之
  • Organizer: 日本分子生物学会第10回春季シンポジウム
  • Place of Presentation: ホテル松島大観荘(宮城県)
  • Year and Date: 2010-06-07
• [Presentation] Strict regulation of mTOR signaling is essential for hematopoietic stem cell maintenancein vivo (2010)
  • Author(s): 星居孝之
  • Organizer: 第8回幹細胞シンポジウム
  • Place of Presentation: 淡路夢舞台(兵庫県)
  • Year and Date: 2010-05-15
• [Presentation] Strict regulation mTOR signaling is essential for hematopoietic stem cell maintenance in vivo (2010)
  • Author(s): 星居孝之
  • Organizer: 第8回 幹細胞シンポジウム
  • Place of Presentation: 淡路国際夢舞台(兵庫)
  • Year and Date: 2010-05-15