Analysis for the role of mTORC1 in the self-renew of leukemia stem cell

• Project/Area Number: 24790967
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• 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): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: mTOR / 自己複製 / 白血病幹細胞

Research Abstract

Mammalian target of rapamycin (mTOR) is identified as a target protein of immunosuppressive agent rapamycin, and this protein kinase is known to form two different complexes, named mTORC1 and mTORC2. In past years, we reported that mTORC1 inactivation, by Raptor deficiency, apparently suppressed the acute myeloid leukemia (AML) cell propagation and differentiation, but some AML cells with stem cell properties survived and proliferated in vivo. To identify the molecular mechanisms to maintain the stem cell like population after mTORC1 inactivation, we performed a quantitative phosphoproteomics study and cell surface proteomics study. We identified mTORC1 downstream candidate genes from phosphoproteomics study, and AML-stem cell associated cell surface molecules from cell surface protemics study. The findings will provide the new therapeutic targets for drug-resistant leukemia therapy.

Research Products

• [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
• [Journal Article] Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells. (2013)
  • Author(s): Hoshii T, Kasada A, Hatakeyama T, Ohtani M, Tadokoro Y, Naka K, Ikenoue T, Ikawa T, Kawamoto H, Fehling HJ, Araki K, Yamamura K, Matsuda S, Hirao A
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Issue: 10 Pages: 3805-3810
  • DOI: 10.1073/pnas.1320265111
  • Peer Reviewed
• [Journal Article] Metabolic regulation of osteoclast differentiation and function (2013)
  • Author(s): Indo Y, Takeshita S, Ishii K, Hoshii T, Aburatani H, Hirao A, Ikeda K
  • Journal Title: J Bone Miner Res Volume: 28 Issue: 11 Pages: 2392-2399
  • DOI: 10.1002/jbmr.1976
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. (2013)
  • Author(s): Ichimura, Y., Waguri, S., Sou, Y., Kageyama, S., Hasegawa, J., Ishimura, R., Saito, T., Yang, Y., Kouno, T., Fukutomi, T., Hoshii, T., Atsushi, H., Takagi, K., Mizushima, T., Motohashi, H., Lee, M-S., Yoshimori, T., Tanaka, K., Yamamoto, M., and Komatsu, K.
  • Journal Title: Mol Cell Volume: 51 Issue: 5 Pages: 618-631
  • DOI: 10.1016/j.molcel.2013.08.003
  • Peer Reviewed / Open Access
• [Journal Article] Abundant nucleostemin expression supports the undifferentiated properties of germ cell tumors (2013)
  • Author(s): Uema, N., Ooshio, T., Harada, K., Naito, M., Naka, K., Hoshii, T., Tadokoro, Y., Ohta, K., Ali, M.A., Katano, M., Soga, T., Nakanuma, Y., Okuda, A., Hirao, A.
  • Journal Title: Am. J. Pathol. Volume: 183 Issue: 2 Pages: 592-603
  • DOI: 10.1016/j.ajpath.2013.04.018
  • Peer Reviewed
• [Journal Article] Mechanistic/mammalian target protein of rapamycin signaling in hematopoietic stem cells and leukemia. (2013)
  • Author(s): Hirao A, Hoshii T.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 8 Pages: 977-82
  • DOI: 10.1111/cas.12189
  • NAID: 120005830607
  • Peer Reviewed
• [Journal Article] Nucleostemin in injury-induced liver regeneration. (2012)
  • Author(s): Shugo. H
  • Journal Title: Stem cells Dev. Volume: 21 Issue: 16 Pages: 3044-3054
  • DOI: 10.1089/scd.2011.0725
  • Peer Reviewed
• [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
• [Presentation] mTORC1 inactivation prevents and eradicates acute lymphoblastic T-cell leukemia (2013)
  • Author(s): Takayuki Hoshii, Atuo Kasada, Tomoki Hatakeyama, Masashi Ohtani, Yuko Tadokoro, Kazuhito Naka, Tsuneo Ikenoue, Tomokatsu Ikawa, Hiroshi Kawamoto, Asushi Iwama, Kimi Araki, Ken-ichi Yamamura, Satoshi Matsuda, Atsushi Hirao
  • Organizer: 2013 ASH annual meeting and exposition, New Orleans
  • Place of Presentation: LA (USA)
• [Presentation] mTORC1 is essential for T lineage-committed cell in normal lymphopoiesis and leukemogenesis (2013)
  • Author(s): 星居孝之, 笠田篤郎, 大谷真志, 池上恒雄, 伊川友活, 河本宏, 荒木喜美, 山村研一, 松田達志, 平尾敦
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: さっぽろ芸文館・ロイトン札幌・札幌市教育分化会館(北海道)
• [Presentation] T 細胞発生と急性T リンパ性白血病におけるmTORC1 の機能解析 (2013)
  • Author(s): 星居孝之
  • Organizer: 平成25年度がん若手研究者ワークショップ
  • Place of Presentation: 蓼科グランドホテル滝の湯(長野県)
• [Presentation] 白血病クラスI変異による細胞分化異常におけるmTORC1 活性の機能解析 (2013)
  • Author(s): 星居孝之
  • Organizer: 新学術領域研究「細胞運命制御」
  • Place of Presentation: グランドエクシブ鳴門(徳島県)
• [Presentation] mTORC1 is essential for propagation of earliest T lineage-committed cell in normal lymphopoiesis and leukemogenesis (2013)
  • Author(s): 星居孝之, 笠田篤郎, 平尾敦
  • Organizer: 第11回幹細胞シンポジウム
  • Place of Presentation: 東京大学伊藤国際学術センター(東京都)
• [Presentation] 活性型K-Ras 変異による白血病発症におけるmTOR 複合体1 の役割 (2013)
  • Author(s): 星居孝之
  • Organizer: 第17回造血器腫瘍研究会
  • Place of Presentation: シーガイア・コンベンションセンター(宮崎県)
• [Presentation] mTORC1 is essential for propagation of earliest T lineage-committed cell in normal lymphopoiesis and leukemogenesis (2013)
  • Author(s): 星居孝之、笠田篤郎、平尾敦
  • Organizer: 第11回幹細胞シンポジウム
  • Place of Presentation: 東京大学伊藤国際学術センター（東京都）
• [Presentation] T細胞発生と急性Tリンパ性白血病におけるmTORC1の機能解析 (2013)
  • Author(s): 星居孝之
  • Organizer: 平成25年度がん若手研究者ワークショップ
  • Place of Presentation: 蓼科グランドホテル滝の湯（長野県）
• [Presentation] mTORC1 is essential for T lineage-committed cell in normal lymphopoiesis and leukemogenesis (2013)
  • Author(s): 星居孝之、笠田篤郎、大谷真志、池上恒雄、伊川友活、河本宏、荒木喜美、山村研一、松田達志、平尾敦
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: さっぽろ芸文館・ロイトン札幌・札幌市教育分化会館（北海道）
• [Presentation] mTORC1 inactivation prevents and eradicates acute lymphoblastic T-cell leukemia (2013)
  • Author(s): Takayuki Hoshii, Atuo Kasada, Tomoki Hatakeyama, Masashi Ohtani, Yuko Tadokoro, Kazuhito Naka, Tsuneo Ikenoue, Tomokatsu Ikawa, Hiroshi Kawamoto, Asushi Iwama, Kimi Araki, Ken-ichi Yamamura, Satoshi Matsuda, Atsushi Hirao
  • Organizer: 2013 ASH annual meeting and exposition
  • Place of Presentation: New Orleans, LA (USA)
• [Presentation] Analysis of survival signals in mTORC1-deficient acute myeloid leukemia stem cells (2012)
  • Author(s): Hoshii T, Hirao A
  • Organizer: International symposium on genetic and epigenetic control of cell fate
  • Place of Presentation: グランドプリンスホテル京都(京都府)
• [Presentation] AML stem cells lacking mTORC1 self-renew but have defective leukemia-initiating capacity in mice (2012)
  • Author(s): 星居孝之, 田所優子, 仲一仁, 大塩貴子, 村口輝之, 杉山直幸, 曽我朋義, 荒木喜美, 山村研一, 平尾敦
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館(京都府)
• [Presentation] Acute myeloid leukemia stem cells lacking mTORC1 self-renew but have defective leukemia-initiating capacity in mice (2012)
  • Author(s): 星居孝之, 仲一仁, 村口輝行, 曽我朋義, 荒木喜美, 山村研一, 平尾敦
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館・札幌市教育分化会館(北海道)
• [Presentation] Acute myeloid leukemia stem cells lacking Raptor self-renew but have defective leukemia initiating capacity in mice (2012)
  • Author(s): 星居孝之, 田所優子, 仲一仁, 大塩貴子, 村口輝之, 杉山直幸, 曽我朋義, 荒木喜美, 山村研一, 平尾敦
  • Organizer: International Society for Stem Cell Research (ISSCR) 10th Annual Meeting
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] mTORC1 シグナルによる造血細胞の増殖・分化制御 (2012)
  • Author(s): 星居孝之
  • Organizer: 新学術領域研究「細胞運命制御」
  • Place of Presentation: グランドプリンスホテル広島(広島県)
• [Presentation] mTORC1シグナルによる造血細胞の増殖・分化制御 (2012)
  • Author(s): 星居孝之
  • Organizer: 新学術領域研究「細胞運命制御」
  • Place of Presentation: グランドプリンスホテル（広島県）
• [Presentation] Acute myeloid leukemia stem cells lacking Raptor self-renew but have defective leukemia initiating capacity in mice (2012)
  • Author(s): 星居孝之
  • Organizer: International Society for Stem Cell Research (ISSCR) 10th Annual Meeting
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] Acute myeloid leukemia stem cells lacking mTORC1 self-renew but have defective leukemia-initiating capacity in mice (2012)
  • Author(s): 星居孝之
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館・札幌市教育分化会館（北海道）
• [Presentation] AML stem cells lacking mTORC1 self-renew but have defective leukemia-initiating capacity in mice (2012)
  • Author(s): 星居孝之
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府）
• [Presentation] Analysis of survival signals in mTORC1-deficient acute myeloid leukemia stem cells (2012)
  • Author(s): 星居孝之
  • Organizer: International symposium on genetic and epigenetic control of cell fate
  • Place of Presentation: グランドプリンスホテル京都（京都府）
• [Remarks] 金沢大学がん進展制御研究所遺伝子・染色体構築研究分野ホームページ
  • URL: http://www.kanazawa-u.ac.jp/~ganken/hirao-hp/index.html
• [Remarks] 金沢大学がん進展制御研究所ホームページ
  • URL: http://www.kanazawa-u.ac.jp/%7Eganken/
• [Remarks] 金沢大学がん進展制御研究所遺伝子・染色体構築研究分野ホームページ
  • URL: http://www.kanazawa-u.ac.jp/~ganken/hirao-hp/index.html
• [Remarks] 金沢大学がん進展制御研究所ホームページ
  • URL: http://www.kanazawa-u.ac.jp/%7Eganken/