Molecular mechanisms for regulation of hematopoietic and leukemia stem cell population by nucleolar molecules

• Project/Area Number: 18390281
• 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 Kanazawa University, がん研究所, 教授 (90343350)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,340,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥2,940,000); Fiscal Year 2008: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2007: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000)
• Keywords: 造血幹細胞 / 白血病 / 分化 / 核小体 / 細胞分化

Research Abstract

正常造血幹細胞と白血病幹細胞の共通性を解明するアプローチとして、核小体に焦点を当てて研究を進めた。核小体分子Nucleosteminは、未分化な造血幹細胞に高い発現が認められた。Nucleosteminの発現をGFPによってモニターするレポーターシステムを構築し、造血系で解析したところ、正常造血および骨髄性白血病において、未分化細胞を濃縮することができた。これらの知見は、将来の白血病治療薬の標的となる分子の特定に寄与することが期待された。

Research Products

• [Journal Article] Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity (2008)
  • Author(s): Ohmura M, Naka K, Hoshii T, Muraguchi T, Shugo H, Tamase A, Uema N, Ooshio T, Arai F, Takubo K, Nagamatsu G, Hamaguchi I, Takagi M, Ishihara M, Sakurada K, Miyaji H, Suda T, Hirao A.
  • Journal Title: Stem Cells 12 Pages: 3237-46
  • Peer Reviewed
• [Journal Article] Stem cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell cycle arrest (2008)
  • Author(s): Takubo K, Ohmura M, Azuma M, Nagamatsu G, Yamada W, Arai F, Hirao A, Suda T.
  • Journal Title: Cell Stem Cell 2 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells (2008)
  • Author(s): Oguma K, Oshima H, Aoki M, Uchio R, Naka K, Nakamura S, Hirao A, Saya H, Taketo MM, Oshima M.
  • Journal Title: EMBO J. 27 Pages: 1671-81
  • NAID: 120001670272
  • Peer Reviewed
• [Journal Article] Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells (2008)
  • Author(s): Naka K, Muraguchi T, Hoshii T, Hirao A.
  • Journal Title: Antioxid Redox Signal 10 Pages: 1883-94
  • Peer Reviewed
• [Journal Article] Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity. (2008)
  • Author(s): Ohmura M, et. al. (著者18名中18番)
  • Journal Title: Stem Cells. 39 Pages: 3237-46
  • Peer Reviewed
• [Journal Article] Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells. (2008)
  • Author(s): Naka K (著者4名中4番)
  • Journal Title: Antioxid Redox Signal. 11 Pages: 1883-94
  • Peer Reviewed
• [Journal Article] Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells. (2008)
  • Author(s): Oguma K, et al (著者1O名中7番)
  • Journal Title: EMBO J. 27 Pages: 1671-81
  • Peer Reviewed
• [Journal Article] Stem cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell cycle arrest (2008)
  • Author(s): Keiyo Takubo, 他
  • Journal Title: Cell Stem Cell 2 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Molecular bases for self-renewal and differentiation of leukemic stem cells (2008)
  • Author(s): Kazuhito Naka, 他
  • Journal Title: Curr. Cancer Therapy (掲載確定印刷中)
• [Journal Article] Foxo3a is essential for maintenance of the hematopoietic stem cell pool (2007)
  • Author(s): Miyamoto K, Araki YK, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, Nakauchi H, Nakayama K, Nakayama KI, Harada M, Motoyama N, Suda T, Hirao A.
  • Journal Title: Cell Stem Cell 1 Pages: 101-112
  • Peer Reviewed
• [Journal Article] Visualizing the dynamics of p21Waf1/Cip1 cyclin-dependent kinase inhibitor expression in living animals (2007)
  • Author(s): Ohtani N, Imamura Y, Yamakoshi K, Hirota F, Nakayama R, Kubo Y, Ishimaru N, Takahashi A, Hirao A, Shimizu T, Mann DJ, Saya H, Hayashi Y, Arase S, Matsumoto M, Kazuki N, Hara E.
  • Journal Title: Proc Natl Acad Sci USA 104 Pages: 15034-9
  • Peer Reviewed
• [Journal Article] Regulation of reactive oxygen species by atm is essential for proper response to DNA double-strand breaks in lymphocytes (2007)
  • Author(s): Ito K, Takubo K, Arai F, Satoh H, Matsuoka S, Ohmura M, Naka K, Azuma M, Miyamoto K, Hosokawa K, Ikeda Y, Mak TW, Suda T, Hirao A.
  • Journal Title: J Immunol 178 Pages: 103-10
  • Peer Reviewed
• [Journal Article] Cross-talk between Chk1 and Chk2 in double-mutant thymocytes (2007)
  • Author(s): Zaugg K, Su YW, Reilly PT, Moolani Y, Cheung CC, Hakem R, Hirao A, Liu Q, Elledge SJ, Mak TW.
  • Journal Title: Proc Natl Acad Sci U S A 104 Pages: 3805-10
  • Peer Reviewed
• [Journal Article] Neural-specific ablation of the scaffold protein JSAP1 in mice causes neonatal death (2007)
  • Author(s): Iwanaga A, Sato T, Sugihara K, Hirao A, Takakura N, Okamoto H, Asano M, Yoshioka K.
  • Journal Title: Neurosci Lett 429 Pages: 43-8
  • Peer Reviewed
• [Journal Article] Regulation of the self-renewal ability of tissue stem cells by tumor-related genes (2007)
  • Author(s): Naka K, Ohmura M, Hirao A.
  • Journal Title: Cancer Biomark 3 Pages: 193-201
  • Peer Reviewed
• [Journal Article] Foxo3a is essential for maintenance of the hematopoietic stem cell pool (2007)
  • Author(s): Kana Miyamoto, 他
  • Journal Title: Cell Stem Cell 1 Pages: 101-112
  • Peer Reviewed
• [Journal Article] Visualizing the dynamics of p21Waf1/Cip1 cyclin-dependent kinase inhibitor expression in living animals (2007)
  • Author(s): Naoko Ohtani, 他
  • Journal Title: Proc Natl Acad Sci U S A 104 Pages: 15034-9
  • Peer Reviewed
• [Journal Article] Neural-specific ablation of the scaffold protein JSAP1 in mice causes neonatal death (2007)
  • Author(s): Asuka Iwanaga
  • Journal Title: Neurosci Lett 429 Pages: 43-8
  • Peer Reviewed
• [Journal Article] Regulation of the self-renewal ability of tissue stem cells by tumor-related genes (2007)
  • Author(s): Kazuhito Naka, 他
  • Journal Title: Cancer Biomarkers 3 Pages: 193-201
• [Journal Article] Regulation of reactive oxygen species by atm is essential for proper response to DNA double-strand breaks in lymphocytes. (2007)
  • Author(s): Ito K., et al.Hirao A(計14名中14番)
  • Journal Title: J Immunol. 178 Pages: 103-10
• [Journal Article] Cross-talk between Chk1 and Chk2 in double-mutant thymocytes. (2007)
  • Author(s): Zaugg K., et al.Hirao A(計9名中7番)
  • Journal Title: Proc Natl Acad Sci U S A. 104 Pages: 3805-10
• [Journal Article] Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool. (2007)
  • Author(s): Miyamoto K.et al.Hirao A(計18名中18番)
  • Journal Title: Cell Stem Cell 1(印刷中)
• [Journal Article] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells (2006)
  • Author(s): Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, Suda T.
  • Journal Title: Nature Med. 12 Pages: 446-451
  • Peer Reviewed
• [Journal Article] Premeiotic germ cell defect in seminiferous tubules of Atm-null testis (2006)
  • Author(s): Takubo K, Hirao A, Ohmura M, Azuma M, Arai F, Nagamatsu G, Suda T.
  • Journal Title: Biochem Biophys Res Commun 351 Pages: 993-8
  • Peer Reviewed
• [Journal Article] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. (2006)
  • Author(s): Ito K., et al.Hirao A(計11名中2番)
  • Journal Title: Nature Med. 12 Pages: 446-451
• [Journal Article] Premeiotic germ cell defect in seminiferous tubules of Atm-null testis. (2006)
  • Author(s): Ito K., et al.Hirao A(計7名中2番)
  • Journal Title: Biochem Biophys Res Commun. 351 Pages: 993-8
• [Presentation] Roles of forkhead transcription factor Fox03a in normal hematopoiesis and leukemia. (2009)
  • Author(s): Hirao A
  • Organizer: USA-Japan Cooperative Cancer Workshop 2009
  • Place of Presentation: 米国ハワイ
  • Year and Date: 2009-03-27
• [Presentation] Effects of aging-or senescence-related factors on stem cell function and tissue homeostasis in vivo (2008)
  • Author(s): Hirao A.
  • Organizer: BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] Effects of aging- or senescence-related factors on stem cell function and tissue homeostasis in vivo. (2008)
  • Author(s): Hirao A
  • Organizer: BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] 正常および腫瘍組織における幹細胞システム (2008)
  • Author(s): 平尾敦
  • Organizer: 第45回日本婦人科腫瘍学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2008-11-22
• [Presentation] Stemness in normal and malignant tissues (2008)
  • Author(s): Hirao A
  • Organizer: 第67回日本癌学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-27
• [Presentation] Nucleosteminプロモーター活性による白血病幹細胞の同定 (2008)
  • Author(s): 仲一仁, 大村昌子, 石原正彦、宮地宏昌、須田年生、平尾敦
  • Organizer: 第67回日本癌学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-27
• [Presentation] Sternness in normal and malignant tissues. (2008)
  • Author(s): Hirao A
  • Organizer: 第67回日本癌学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-27
• [Presentation] 36th Congress of (2008)
  • Author(s): HIrao A, Stemness in normal, malignant tissues
  • Organizer: the International Society of Oncology & BioMarkers
  • Place of Presentation: Tokyo
  • Year and Date: 2008-10-07
• [Presentation] Sternness in normal and malignant tissues. (2008)
  • Author(s): Hirao A
  • Organizer: Mechanisms of Early Differentiation, Summer School
  • Place of Presentation: ドイツ
  • Year and Date: 2008-09-03
• [Presentation] Stemness in normal and malignant tissues (2008)
  • Author(s): Hirao A.
  • Organizer: The third International workshop on Cell Regulations in Division and Arrest
  • Place of Presentation: Okinawa
  • Year and Date: 2008-04-09
• [Presentation] Nucleostemin-GFPレポーターシステムによる白血病幹細胞の同定 (2008)
  • Author(s): 仲一仁, 大村昌子, 村口輝行, 星居孝之, 須田年生, 平尾敦
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Mechanisms of Early Differentiation (2008)
  • Author(s): Hirao A, Stemness in normal, malignant tissues
  • Organizer: Summer School
  • Place of Presentation: Barsinghausen, Germany
• [Presentation] Prospective identification of leukemic stem cells by promoter activity of nucleostemin gene (2008)
  • Author(s): Naka K, Ohmura M, Muraguchi T, Hoshii T, Hirao A.
  • Organizer: 6^<th> International Society of Stem Cell Research
  • Place of Presentation: Philadelphia, PA, USA
• [Presentation] Nucleostemin-GFPレポーターシステムによる白血病幹細胞の同定 (2008)
  • Author(s): 仲一仁, 大村昌子, 村口輝行, 星居孝之, 平尾敦
  • Organizer: 第6回幹細胞シンポジウム
  • Place of Presentation: 東京
• [Presentation] Identification of tumor-initiating cells by using Nucleostemin promoter activity (2008)
  • Author(s): Naka K, Ohmura M, Muraguchi T, Hoshii T, Hirao A.
  • Organizer: Keystone Symposia, Tumor suppressor and stem cell biology
  • Place of Presentation: Vancouver
• [Presentation] 幹細胞制御における組織間共通性 (2007)
  • Author(s): 平尾敦
  • Organizer: 第10回日本組織工学会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-08
• [Presentation] 造血幹細胞の自己複製と老化 (2007)
  • Author(s): 平尾敦
  • Organizer: 第69回日本血液学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-07
• [Presentation] Stemness genes in cancer (2007)
  • Author(s): 平尾敦
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] NucleosteminプロモーターGFPトランスジェニックマウスによる造血幹細胞標識システムの樹立 (2007)
  • Author(s): 仲 一仁, 他
  • Organizer: 第66回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] Establishment of a labeling system for hematopoietic stem cells by nucleostemin-enhancer/promoter driving GFP transgenic mice (2007)
  • Author(s): Kazuhito Naka, 他
  • Organizer: The 5th International Society of Stem Cell Research
  • Place of Presentation: Cairns, Australia
  • Year and Date: 2007-06-19
• [Presentation] Nucleosteminの発現による組織幹細胞の可視化と同定 (2007)
  • Author(s): 大村 昌子, 他
  • Organizer: 幹細胞シンポジウム
  • Place of Presentation: 兵庫
  • Year and Date: 2007-05-18
• [Presentation] The 49^<th> American Society (2007)
  • Author(s): Naka K, Ohmura M, Suda T, Hirao A
  • Organizer: of Hematology Annual Meeting and Exposition
  • Place of Presentation: Atlanta, USA
• [Presentation] NucleosteminプロモーターGFP トランスジェニックマウスによる造血幹細胞標識システムの樹立 (2007)
  • Author(s): 仲一仁, 大村昌子, 野口亜希, 石原正彦、宮地宏昌、須田年生, 平尾敦
  • Organizer: 第66回日本癌学会
  • Place of Presentation: 横浜
• [Presentation] The 5^<th> International Society (2007)
  • Author(s): Naka K, Ohmura M, Arai F, Suda T, Hirao A.
  • Organizer: of Stem Cell Research
  • Place of Presentation: Cairns,Australia
• [Presentation] Nucleosteminの発現による組織幹細胞の可視化と同定 (2007)
  • Author(s): 大村昌子、仲一仁、木下雅史、玉瀬玲、新井文用、永松剛、田久保圭誉、照田展大、須田年生、平尾敦
  • Organizer: 第5回幹細胞シンポジウム
  • Place of Presentation: 淡路島
• [Presentation] Regulation of stem cell self-renewal by aging related genes (2007)
  • Author(s): Hirao A
  • Organizer: The second International workshop on Cell Regulations in Division and Arrest
  • Place of Presentation: Okinawa
• [Presentation] Establishment of a Labeling System for Hematopoietic Stem Cells by Nucleostemin Enhancer/Promoter-GFP Transgenic Mice (2007)
  • Author(s): Kazuhito Naka, 他
  • Organizer: The 49th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Atlanta, USA
• [Presentation] Regulation of stem cell self-renewal by tumor related genes (2006)
  • Author(s): Hirao A
  • Organizer: Sixteenth International Symposium of the Hiroshima Cancer Seminar
  • Place of Presentation: Hiroshima
  • Year and Date: 2006-10-22
• [Presentation] 組織幹細胞マーキング法の開発 (2006)
  • Author(s): 大村昌子、仲一仁、新井文用、木下雅史、玉瀬玲、松岡佐保子、伊藤圭介、宮本佳奈、田久保圭誉、須田年生、平尾敦
  • Organizer: 第68回日本血液学会
  • Place of Presentation: 福岡
  • Year and Date: 2006-10-08
• [Presentation] Regulation of stem cell self-renewal by aging-related genes (2006)
  • Author(s): Hirao A
  • Organizer: 35^<th> Annual Scientific Meeting International Society for Experimental Hematology
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 2006-09-26
• [Presentation] ROS regulation and self-renewal capacity (2006)
  • Author(s): Hirao A
  • Organizer: International Symposium on Gas Biology : Hematopoietic stem cells
  • Place of Presentation: Tokyo
  • Year and Date: 2006-06-27
• [Presentation] 幹細胞自己複製制御と老化・寿命制御の共通性 (2006)
  • Author(s): 平尾敦
  • Organizer: 老年医学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2006-06-08
• [Presentation] 核小体分子Nucleosteminによる生殖幹細胞制御機構 (2006)
  • Author(s): 大村昌子、新井文用、仲一仁、田久保圭誉、東真樹、須田年生、平尾敦
  • Organizer: 第4回幹細胞シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2006-05-20
• [Presentation] The 19^<th> Naito Conference (2006)
  • Author(s): Hirao A
  • Organizer: Molecular Basis for Maintenance and Differentiation of Stem Cells[II]Nov
  • Place of Presentation: Kanagawa
  • Year and Date: 2006-01-05