Roles of longevity/senescence-relating molecules in the development, maintenance and differentiation of leukemia stem cells

• Project/Area Number: 21390290
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: HIRAO Atsushi 金沢大学, がん進展制御研究所, 教授 (90343350)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2011: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2010: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 白血病 / 寿命 / 老化 / 造血幹細胞 / 白血病幹細胞 / Ras

Research Abstract

In this study, we investigated roles of senescence/longevity related molecules in the development, maintenance and differentiation of leukemia stem cells. We found that FOXO, which is a critical regulator of longevity of C. elegans, is essential for maintenance of leukemia stem cells. In addition, it was suggested that constitutive Ras, which is known to induce cellular senescence, causes leukemogenesis, collaborating with factors controlling cellular differentiation.

Research Products

• [Journal Article] mTORC1 is essential for leukemia-propagation but not stem cell self-renewal (2012)
  • Author(s): Hoshii T. TadokoroY. Naka K. Ooshio T. Muraguchi T. Sugiyama N. Soga T. Araki K. Yamamura K. Hirao A.
  • Journal Title: J. Clin. Invest. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Nucleostemin in injury-induced liver regeneration (2012)
  • Author(s): ShugoH, Ooshio T. Naito M, Naka K, Hoshii T. Tadokoro Y. Muraguchi T. Tamas A. Uema N. Yamashita T. Nakamoto Y. Suda T. Kaneko S. Hirao A.
  • Journal Title: Stem Cells and Develop. Volume: (in press)
  • 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] mTORC1 is essential for leukemia-propagation but not stem cell self-renewal (2012)
  • Author(s): Hoshii T., et.al.
  • Journal Title: J.Clin.Invest. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Inactivation of chk2 and mus81 leads to impaired lymphocytes development, reduced genomic instability, and suppression of cancer (2011)
  • Author(s): El Ghamrasni S, Pamidi A, Halaby MJ, Bohgaki M, Cardoso R, Li L, Venkatesan S, Sethu S, Hirao A, Mak TW, Hande MP, Hakem A, Hakem R.
  • Journal Title: PLoS Genet Volume: 7 Issue: 5 Pages: e1001385-e1001385
  • DOI: 10.1371/journal.pgen.1001385
  • Peer Reviewed
• [Journal Article] Invasion precedestumor mass formation in a malignant braintumor model of genetically modified neural stem cells (2011)
  • Author(s): Sampetrean O, Saga I, Nakanishi M, Sugihara E, Fukaya R, Onishi N, Osuka S, Akahata M, Kai K, Sugimoto H, Hirao A, Saya H
  • Journal Title: Neoplasia Volume: 13(9) Issue: 9 Pages: 784-91
  • DOI: 10.1593/neo.11624
  • Peer Reviewed
• [Journal Article] Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells (2011)
  • Author(s): Motohara T, Masuko S, Ishimoto T, Yae T, Onishi N, Muraguchi T, Hirao A, Matsuzaki Y, Tashiro H, Katabuchi H, Saya H, Nagano O.
  • Journal Title: Carcinogenesis Volume: 32 Issue: 11 Pages: 1597-606
  • DOI: 10.1093/carcin/bgr183
  • Peer Reviewed
• [Journal Article] Maintenance of genomic integrity in hematopoietic stem cells (2011)
  • Author(s): Naka K, Hirao A.
  • Journal Title: Int J Hematol Volume: 93 Issue: 4 Pages: 434-9
  • DOI: 10.1007/s12185-011-0793-z
  • NAID: 10029534293
  • 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, 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] 14-3-3 sigma regulates B-cell homeostasis through stabilization of FOXO1 (2011)
  • Author(s): Su YW, Hao Z, Hirao A, Yamamoto K, Lin WJ, Young A, Duncan GS, Yoshida H, Wakeham A, Lang PA, Murakami K, Hermeking H, Vogelstein B, Ohashi P, Mak TW.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Issue: 4 Pages: 1555-60
  • DOI: 10.1073/pnas.1017729108
  • Peer Reviewed
• [Journal Article] NKX2.2 suppresses self-renewal of glioma-initiating cells. (2011)
  • Author(s): Muraguchi T, et.al(著者16名中16番)
  • Journal Title: Cancer Res. Volume: 71 Pages: 35-45
  • Peer Reviewed
• [Journal Article] 14-3-3sigma regulates B-cell homeostasis through stabilization of FOXOI (2011)
  • Author(s): Su YW, et.al(著者13名中3番)
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Pages: 1555-1560
  • Peer Reviewed
• [Journal Article] TGFβ-FOXO signalling maintains leukaemia-initiating cells in chronic myeoid leukaemia (2010)
  • Author(s): Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, Nakao S, Motoyama N, Hirao A
  • Journal Title: Nature Volume: 463 Issue: 7281 Pages: 676-80
  • DOI: 10.1038/nature08734
  • Peer Reviewed
• [Journal Article] Regulation of the HIF-1alpha level is essential for hematopoietic stem cells (2010)
  • Author(s): Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T.
  • Journal Title: Cell Stem Cell Volume: 7 Issue: 3 Pages: 391-402
  • DOI: 10.1016/j.stem.2010.06.020
  • Peer Reviewed
• [Journal Article] Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression In vivo (2010)
  • Author(s): Takeuchi S, Takahashi A, Motoi N, Yoshimoto S, Tajima T, Yamakoshi K, Hirao A, Yanagi S, Fukami K, Ishikawa Y, Sone S, Hara E, Ohtani N.
  • Journal Title: Cancer Res Volume: 70 Issue: 22 Pages: 7381-90
  • DOI: 10.1158/0008-5472.can-10-0801
  • 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
• [Journal Article] Regulation of the HIF-lalpha level is essential for hematopoietic stem cells. (2010)
  • Author(s): Takubo K, et al.(著者l1名中9番)
  • Journal Title: Cell Stern Cell. Volume: 7 Pages: 391-402
  • Peer Reviewed
• [Journal Article] Intrinsic Cooperation between pl6INK4a and p21Wafl/Cipl in the Onset of Cellular Senescence and Tumor Suppression In vivo. (2010)
  • Author(s): Takeuchi S, et al.(著者13名中7番)
  • Journal Title: Cancer Res. Volume: 70 Pages: 9381-9390
  • Peer Reviewed
• [Journal Article] TGFβ-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. (2010)
  • Author(s): Naka K, et al(著者9名中9番)
  • Journal Title: Nature 463 Pages: 676-80
  • Peer Reviewed
• [Journal Article] Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin (2009)
  • Author(s): Tamase A, Muraguchi T, Naka K, Tanaka S, Kinoshita M, Hoshii T, Ohmura M, Shugo H, Ooshio T, Nakada M, Sawamoto K, Onodera M, Matsumoto K, Oshima M, Asano M, Saya H, Okano H, Suda T, Hamada JI, Hirao A.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 106 Issue: 40 Pages: 17163-8
  • DOI: 10.1073/pnas.0905016106
  • Peer Reviewed
• [Journal Article] Real-time in vivo imaging of p16Ink4a reveals cross talk with p53 (2009)
  • Author(s): Yamakoshi K, Takahashi A, Hirota F, Nakayama R, Ishimaru N, Kubo Y, Mann DJ, Ohmura M, Hirao A, Saya H, Arase S, Hayashi Y, Nakao K, Matsumoto M, Ohtani N, Hara E.
  • Journal Title: J Cell Biol Volume: 186 Issue: 3 Pages: 393-407
  • DOI: 10.1083/jcb.200904105
  • Peer Reviewed
• [Journal Article] Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin. (2009)
  • Author(s): Tamase A,(著者20名中20番)
  • Journal Title: Proc Natl Acad Sci USA. 106 Pages: 17163-8
  • Peer Reviewed
• [Journal Article] Real-time in vivo imaging of p16Ink4a reveals cross talk with p53 (2009)
  • Author(s): Yamakoshi K., et al.(著者16名中9番)
  • Journal Title: J Cell Biol. 186 Pages: 393-407
  • Peer Reviewed
• [Presentation] Roles of PI3K-AKT signaling in the maintenance of stem cell properties in normal hematopoiesis and leukemia (2011)
  • Author(s): Hirao A
  • Organizer: G0 symposium
  • Place of Presentation: OIST(沖縄)
  • Year and Date: 2011-10-24
• [Presentation] Roles of PI3K-AKT signaling in the maintenance of stem cell properties in normal hematopoiesis and leukemia (2011)
  • Author(s): Hirao A
  • Organizer: G0 symposium
  • Place of Presentation: 沖縄科学技術大学院大学(Okinawa)(招待講演)
  • Year and Date: 2011-10-24
• [Presentation] Molecular mechanisms regulating maintenance of leukemia stem cells by PI3K-AKT pathway (2011)
  • Author(s): Hirao A
  • Organizer: 第70回日本癌学会
  • Place of Presentation: 名古屋国際会議場(名古屋)
  • Year and Date: 2011-10-03
• [Presentation] Molecular mechanisms regulating maintenance of leukemia stem cells by PI3K-AKT pathway (2011)
  • Author(s): Hirao A
  • Organizer: 第70回日本癌学会
  • Place of Presentation: 名古屋国際会議場(愛知県)(招待講演)
  • Year and Date: 2011-10-03
• [Presentation] Role of PI3K-AKT signals in the maintenance of stem cells in normal hematopoiesis and leukemia (2011)
  • Author(s): Hirao A
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2011-09-24
• [Presentation] Role of PI3K-AKT signals in the maintenance of stem cells in normal hematopoiesis and leukemia (2011)
  • Author(s): Hirao A
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 国立京都国際会館(京都府)(招待講演)
  • Year and Date: 2011-09-24
• [Presentation] PI3K-AKTシグナルによるがん幹細胞制御機構の解明と治療戦略 (2011)
  • Author(s): 平尾敦
  • Organizer: 日本がん分子標的治療学会
  • Place of Presentation: ホテル日航東京(東京)
  • Year and Date: 2011-06-24
• [Presentation] Regulation of stem cell homeostasis and tumorigenesis (2010)
  • Author(s): Hirao A
  • Organizer: BMB2010
  • Place of Presentation: 神戸国際会議場(兵庫)
  • Year and Date: 2010-12-08
• [Presentation] Role of PI3K-AKT signals in the maintenance of normal and leukemia stem cells (2010)
  • Author(s): Hirao A
  • Organizer: Tokyo iPS/Stem cell symposium
  • Place of Presentation: 東京大学安田講堂(東京)
  • Year and Date: 2010-11-24
• [Presentation] Role of PI3K-AKT signals in the maintenance of normal and leukemia stem cells (2010)
  • Author(s): Hirao A
  • Organizer: Tokyo iPS/Stem cell symposium
  • Place of Presentation: 東京大学安田講堂(東京都) 招待講演
  • Year and Date: 2010-11-24
• [Presentation] 造血幹細胞および白血病幹細胞維持制御メカニズム (2010)
  • Author(s): 平尾敦
  • Organizer: 日本顕微鏡学会
  • Place of Presentation: 金沢市ホール(石川)
  • Year and Date: 2010-11-12
• [Presentation] 腫瘍悪性進展制御と細胞分化 (2010)
  • Author(s): 平尾敦
  • Organizer: 第48回日本癌治療学会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2010-10-27
• [Presentation] 栄養代謝制御シグナルと造血幹細胞 (2010)
  • Author(s): 平尾敦
  • Organizer: 第31回日本炎症・再生医学会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2010-08-06
• [Presentation] Roles of TGFβ/FoxO in the maintenance of leukemia stem cells (2010)
  • Author(s): Hirao A
  • Organizer: The 59th Fujihara Seminar, Molecularmechanisms of TGF-βsignaling anddisease
  • Place of Presentation: グランドホテルニュー王子(北海道)
  • Year and Date: 2010-07-14
• [Presentation] 白血病幹細胞制御機構の解明と治療戦略 (2010)
  • Author(s): 平尾敦
  • Organizer: 第14回日本がん分子標的治療学会学術集会
  • Place of Presentation: タワーホール船堀(東京)
  • Year and Date: 2010-07-08
• [Presentation] 幹細胞研究に基づいた脳腫瘍の発生・病態制御機構解明へのアプローチ (2010)
  • Author(s): 平尾敦
  • Organizer: 第19回日本がん転移学会学術集会
  • Place of Presentation: 金沢市ホール(石川)
  • Year and Date: 2010-06-16
• [Presentation] 寿命制御シグナルと造血幹細胞 (2010)
  • Author(s): 平尾敦
  • Organizer: 第10回日本抗加齢医学会総会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2010-06-11
• [Presentation] フォークヘッド転写因子FoxOによる造血幹細胞および白血病幹細胞制御 (2010)
  • Author(s): 平尾敦
  • Organizer: 第9回日本再生医療学会
  • Place of Presentation: 広島国際会議場(広島)
  • Year and Date: 2010-03-19
• [Presentation] Regulation of hematopoietic stem cell homeostasis and leukemia (2010)
  • Author(s): Hirao A
  • Organizer: AACR
  • Place of Presentation: Hilton Waikoloa Village(USA)
  • Year and Date: 2010-02-07
• [Presentation] Molecular mechanisms regulating maintenance of leukemia stem cells (2010)
  • Author(s): Hirao A
  • Organizer: The 15th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy(JFCR-ISCC)
  • Place of Presentation: ホテル日航東京(東京)
• [Presentation] Roles of PI3-K signals in the maintenance of normal and leukemia stem cells, ESH-ICMLF Twelfth International Conference (2010)
  • Author(s): Hirao A
  • Organizer: CHRONIC MYELOID LEUKAEMIA-Biological Basis of Therapy
  • Place of Presentation: Washignton DC, USA
• [Presentation] Molecular mechanisms regulating self-renewal of glioma-initiating cells (2010)
  • Author(s): Hirao A
  • Organizer: 第69回日本癌学会
  • Place of Presentation: 大阪国際会議場(大阪)
• [Presentation] Molecular mechanisms regulating maintenance of leukemia st em cells. (2010)
  • Author(s): Hirao A
  • Organizer: The 15th Japanese Foundation for Cancer ncer Chemotherapv(UFCR-ISCC)
  • Place of Presentation: ホテル日航東京(東京都) 招待講演
• [Presentation] Roles of PI3-K signals in the maintenance of normal and leukemia stem cells (2010)
  • Author(s): Hirao A
  • Organizer: ESH-ICMLF Twelfth International Conference, CHRONIC MYELOID LEUKAEMIA
  • Place of Presentation: Grand Hyatt Washingt on DC (USA) 招待講演
• [Presentation] Roles of TGFIβ/FoxO in the maintenance of leukemia stem cel is (2010)
  • Author(s): Hirao A
  • Organizer: The 59th Fuiihara Seminar, Molecular mechanisms of TGF-β signaling and disease
  • Place of Presentation: グランドホテルニュー王子(北海道) 招待講演
• [Presentation] Roles of FoxO3a in normal hematopoiesis and leukemia. The 4th International workshop on Cell Regulations in Division and Arrest (2009)
  • Author(s): Hirao A
  • Organizer: Okinawa
  • Place of Presentation: OISI(沖縄)
  • Year and Date: 2009-11-30
• [Presentation] フォークヘッド転写因子FoxOによる造血幹細胞および白血病幹細胞制御 (2009)
  • Author(s): 平尾敦
  • Organizer: 第82回日本生化学大会
  • Place of Presentation: 神戸国際会議場(兵庫)
  • Year and Date: 2009-10-21
• [Presentation] フォークヘッド転写因子FoxOによる造血幹細胞および白血病幹細胞制御 (2009)
  • Author(s): 平尾敦
  • Organizer: 第82回日本生化学大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2009-10-21
• [Presentation] Roles of FoxO3a in normal hematopoiesis and leukemia (2009)
  • Author(s): Hirao A
  • Organizer: The 8th Japan-China Joint Conference for Cancer Research
  • Place of Presentation: リーガロイヤルホテル大阪(大阪)
  • Year and Date: 2009-10-05
• [Presentation] Roles of FoxO3a in normal hematopoiesis and leukemia. (2009)
  • Author(s): 平尾敦
  • Organizer: The 8th Japan-China Joint Conference for Cancer Research
  • Place of Presentation: リーガロイヤルホテル大阪(大阪府)
  • Year and Date: 2009-10-05
• [Presentation] Regulation of stem cell homeostasis and tumorigenesis by microenvironmental factors (2009)
  • Author(s): 平尾敦
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2009-10-01
• [Presentation] Regulation of stem cell homeostasis and tumorigenesis by microenvirc nmental factors (2009)
  • Author(s): 平尾敦
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-10-01
• [Presentation] 寿命制御シグナルと幹細胞 (2009)
  • Author(s): 平尾敦
  • Organizer: 第51回日本老年医学会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2009-06-19
• [Presentation] 寿命制御シグナルと幹細胞 (2009)
  • Author(s): 平尾敦
  • Organizer: 第51回日本老年医学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-06-19
• [Presentation] 幹細胞可視化システムを用いたがん組織不均一性の解析 (2009)
  • Author(s): 平尾敦
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2009-05-01
• [Presentation] 幹細胞可視化システムを用いたがん組織不均一性の解析 (2009)
  • Author(s): 平尾敦
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2009-05-01