Analysis on the molecular mechanisms for the self renewal of the leukemic stem cells and for the leukemcgenesis

• Project/Area Number: 18390278
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Mie University
• Principal Investigator: NOSAKA Tetsuya Mie University, Graduate School of Medicine, Professor (30218309)
• Co-Investigator(Kenkyū-buntansha): KITAMURA Toshio The University of Tokyo, The Institute of Medical Science, Professor (20282527) ; ONO Ryoichi Mie University, Graduate School of Medicine, Assistant Professor (40422414)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥17,580,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2007: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2006: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: leukemic stem cell / 11q23 chromosomal translocation / MLL / infant leukemia / Ras / mouse bone marrow transplantation / retroviral vector / Hox / 白血病肝細胞 / Raf / MAPK / STAT5

Research Abstract

A variety of reciprocal 11q23 translocations generating fusions of MLL(Mixed Lineage Leukemia) with partner genes are frequently found in infant acute leukemia. However, little has been clarified regarding the pathway through which MLL fusion proteins lead to leukemia. We have recently reported the two-step leukemogenesis by MLL fusion proteins in mice models(Ono R, et. al. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J. Clin. Invest 115, 919-929, 2005 ; selected as one of the highlight papers in the April 2005 issue of the Nature Reviews/Cancer). By comparing the effects of two kinds of FLT3 mutants, and constitutively active mutant molecules of Ras, Raf, and STATS, we first identified Ras/Raf/MAPK as synergistic collaborative pathway for MLL fusion proteins to induce acute leukemia. Furthermore, expression of Hoxa9, one of the upregulated molecules in MLL-related human leukemia, and Ras activation were found to recapitulate MLL-fusion-mediated acute leukemia in mice. Hoxa9 is considered to contribute to confer self-renewal activity on leukemic cells, and Ras activation is inferred to induce proliferation of the leukemic cells.
Thus this study unveiled the molecular mechanism of MLL-fusion-mediated leukemogenesis, and may help develop the MLL-fusion-targeted therapy in future.

Research Products

• [Journal Article] AML1 mutations induced MDS and MDS/AML in a mouse BMT model. (2008)
  • Author(s): Watanabe-Okochi N, Kitaura J, Ono R, Harada H, Harada Y, Komeno Y, Nakajima H, Nosaka T, Inaba T, Kitamura T.
  • Journal Title: Blood 111 Pages: 4297-4308
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Identification of leukemia-related gene alterations: Molecular pathogenesis of leukemia, myeloproliferative disorders(MPD), and myelodysplastic syndromes(MDS). (2008)
  • Author(s): Kitamura T, Oki T, Watanabe-Okochi N, Komeno Y, Kato N, Yuji K, Ono RNakajima H, Tojo A, Nosaka T, Kitaura J.
  • Journal Title: Blood Cells, Molecules and Diseases. (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human parainfluenza virus type 2 V protein inhibits genome replication by binding to the L protein; a possible role in promoting viral fitness. (2008)
  • Author(s): Nishio M, Ohtsuka J, Tsurudome M, Nosaka T, Kolakofsky D.
  • Journal Title: Journal of Virology (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 造血器腫瘍マウスモデル (2008)
  • Author(s): 野阪哲哉
  • Journal Title: がん分子標的治療 6(2)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] AML1 mutations induced MDS and MDS/AML in a mouse BMT model (2008)
  • Author(s): Watanabe-Okochi, N. kitaura, J. Ono, R. Harada, H. Harada, Y. Komeno, Y. Nakajima, H. Nosaka, T. Inaba, T. Kitamura, T
  • Journal Title: Blood 111 Pages: 4297-4308
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human parainfluenza virus type 2 V protein inhibits genome replication by binding to the L protein ; a possible role in promoting viral fitness (2008)
  • Author(s): Nishio, M. Ohtsuka, J. Tsurudome, M. Nosaka, T. Kolakofsky, D
  • Journal Title: J Virol (Epub ahead of print)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] AML1 mutations induced MDS and MDS/AML in a mouse BMT model. (2008)
  • Author(s): Watanabe-Okochi N, Kitaura J, Ono R, Harada H, Harada Y, Komeno Y, Nakajima H, Nosaka T, Inaba T, Kitamura T.
  • Journal Title: Blood (印刷中)
  • Peer Reviewed
• [Journal Article] 造血器腫瘍マウスモデル (2008)
  • Author(s): 野阪 哲哉
  • Journal Title: がん分子標的治療 (印刷中)
• [Journal Article] Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD. (2007)
  • Author(s): Lu Y, Kitaura J, Oki T, Komeno Y, Ozaki K, Kiyono M, Kumagai H, Nakajima H, Nosaka T, Aburatani H, Kitamura T.
  • Journal Title: Leukemia 21 Pages: 2246-2257
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD (2007)
  • Author(s): Lu, Y. Kitaura, J. Oki, T. Komeno, Y. Ozaki, K. Kiyono, M. Kumagai, H. Nakajima, H. Nosaka, T. Aburatani, H. Kitamura, T
  • Journal Title: Leukemia 21 Pages: 2246-2257
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD (2007)
  • Author(s): Lu Y, Kitaura J, Oki T, Komeno Y, Ozaki K, Kiyono M, Kumagai H, Nakajima H, Nosaka T, Aburatani H, Kitamura T.
  • Journal Title: Leukemia 21 Pages: 2246-2257
  • Peer Reviewed
• [Journal Article] Overexpression of Interleukin 21 induces expansion of hematopoietic progenitor cells. (2006)
  • Author(s): Ozaki K, Hishiya A, Hatanaka K, Nakajima H, Wang G, Hwu P, Kitamura T, Ozawa K, Leonard WJ, Nosaka T.
  • Journal Title: International Journal of Hematology 84 Pages: 224-230
  • NAID: 10018303983
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Rac 1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcriptionfactors. (2006)
  • Author(s): Kawashima T, Bao YC, Moon Y, Tonozuka Y, Minoshima Y, Hatori T, Kiyono M, Nosaka T, Nakajima H, Williams DA, Kitamura T.
  • Journal Title: Journal of Cell Biology 175 Pages: 937-946
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] MLL関連白血病の分子病態 (2006)
  • Author(s): 小埜良一、野阪哲哉
  • Journal Title: 血液・腫瘍科 52(6) Pages: 615-624
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of Interleukin 21 induces expansion of hematopoietic progenitor cells (2006)
  • Author(s): Ozaki, K. Hishiya, A. Hatanaka, K. Nakajima, H. Wang, G. Hwu, P. Kitamura, T. Ozawa, K. Leonard, WJ. Nosaka, T
  • Journal Title: Int J Hematol 84 Pages: 224-230
  • NAID: 10018303983
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rae 1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors (2006)
  • Author(s): Kawashima, T. Bao, YC. Moon, Y. Tonozuka, Y. Minoshima, Y. Hatori, T. Kiyono, M. Nosaka, T. Nakajima, H. Williams, DA. Kitamura, T
  • Journal Title: J Cell Biol 175 Pages: 937-946
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rac 1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors. (2006)
  • Author(s): Kawashima T, Bao YC, Moon Y, Tonozuka Y, Minoshima Y, Hatori T, Kiyono M, Nosaka T, Nakajima H, Williams DA, Kitamura T.
  • Journal Title: Journal of Cell Biology 175 Pages: 937-946
• [Journal Article] MLL関連白血病の分子病態 (2006)
  • Author(s): 小埜良一, 野阪哲哉
  • Journal Title: 血液・腫瘍科 52(6) Pages: 615-624
• [Journal Article] Identification of leukemia-related gene alterations : Molecular pathogenesis of leukemia, myeloproliferative disorders (MPD), and myelodysplastic syndromes (MDS)
  • Author(s): Kitamura, T. Oki, T. Watanabe-Okochi, N. Komeno, Y. Kato, N. Yuji, K. Ono, R. Nakajima, H. Tojo, A. Nosaka, T. Kitaura, J
  • Journal Title: Blood Cells, Molecules and Diseases (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] MLL融合蛋白による多段階発癌におけるRaf-MAPキナーゼ系活性化の重要性 (2007)
  • Author(s): 小埜良一、北村俊雄、野阪哲哉(演者)
  • Organizer: 日本プロテインホスファターゼ研究会 第3回 国内集会
  • Place of Presentation: 津
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] AML1点変異はマウスBMTモデルにおいてMDS/AMLを発症させる (2007)
  • Author(s): 渡辺-大河内直子、北浦次郎、小埜良一、原田浩徳、原田結花、中島秀明、野阪哲哉、稲葉俊哉、北村俊雄
  • Organizer: 第5回幹細胞シンポジウム
  • Place of Presentation: 淡路島
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Hoxa9とRas-MAPキナーゼ系の協調作用がMLL融合蛋白による急性白血病の発症に重要である (2007)
  • Author(s): 小埜良一、熊谷英敏、中島秀明、殿塚行雄、菱谷愛、滝智彦、林泰秀、北村俊雄、野阪哲哉
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 白血病およびMDSの分子病態:マウス骨髄移植モデルおよび発現クローニング法を利用した解析 (2007)
  • Author(s): 北村俊雄、野阪哲哉
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] RasGRP4と変異型AML1はマウスBMTモデルにおいて協調的に働き、T細胞性白血病を誘発する (2007)
  • Author(s): 渡辺(大河内)直子、沖俊彦、小埜良一、原田浩徳、湯地晃一郎、東條有伸、中島秀明、野阪哲哉、稲葉俊哉、北浦次郎、北村俊雄
  • Organizer: 第69回日本血液学会総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 活性誘導型C/EBPαおよびC/EBPεによるMLLキメラ遺伝子を有する骨髄単球性白血病細胞の単球系分化 (2007)
  • Author(s): 松下弘道、中島秀明、中村嘉彦、塚本秀雄、田中由美子、浅井さとみ、小埜良一、野阪哲哉、安藤潔、宮地勇人
  • Organizer: 第69回日本血液学会総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] MLL融合蛋白はRas-MAPキナーゼ系の活性化と相乗的に協調して急性白血病を発症する (2007)
  • Author(s): 小埜良一、熊谷英敏、中島秀明、殿塚行雄、菱谷愛、滝智彦、林泰秀、北村俊雄、野阪哲哉
  • Organizer: 第69回日本血液学会総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] A BMT model mouse for myelodysplastic syndromes(MDS)and MDS/overt leukemia (2006)
  • Author(s): Watanabe-Okochi N, Kitaura J, Harada H, Ono R, Inaba T, Nakajima H, Nosaka T, Kitamura T
  • Organizer: 35th Annual Meeting of the International Society For Experimental Hematology
  • Place of Presentation: Minneapolis
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] C/EBPα and C/EBPε induce monocytic differentiation of myelomonocytic cells with MLL chimeric fusion gene (2006)
  • Author(s): Matsushita H, Nakajima H, Nakamura Y, Tsukamoto H, Tanaka Y, Asai S, Nosaka T, Ando K, Miyachi H
  • Organizer: 48th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Orlando
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] MAP kinase activation is essential for the development of acute leukemia by MLL fusion protein and FLT3 tyrosine kinase mutation (2006)
  • Author(s): Ono R, Kumagai H, Nakajima H, Tonozuka Y, Hishiya A, Taki T, Hayashi Y, Kitamura T, Nosaka T
  • Organizer: 48th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Orlando
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] A BMT model mice for myelodysplastic syndromes(MDS)and transformation to AML (2006)
  • Author(s): Watanabe-Okochi N, Kitaura J, Harada H, Ono R, Nakajima H, Nosaka T, Inaba T, Kitamura T
  • Organizer: 48th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Orlando
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] MLL融合蛋白による多段階発癌モデルマウス:MAPキナーゼの重要性 (2006)
  • Author(s): 小埜良一、熊谷英敏、中島秀明、殿塚行雄、菱谷愛、滝智彦、林泰秀、北村俊雄、野阪哲哉
  • Organizer: 第65回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] MLL融合蛋白による多段階発癌にはMAPキナーゼ系の活性化が重要である (2006)
  • Author(s): 小埜良一、熊谷英敏、中島秀明、殿塚行雄、菱谷愛、滝智彦、林泰秀、北村俊雄、野阪哲哉
  • Organizer: 第68回日本血液学会総会
  • Place of Presentation: 福岡
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] AML1点変異はマウスBMTモデルにおいてMDS/AMLを発症させる (2006)
  • Author(s): 渡辺直子、北浦次郎、原田浩徳、小埜良一、米野由希子、佐藤均、稲葉俊哉、中島秀明、野阪哲哉、北村俊雄
  • Organizer: 第68回日本血液学会総会
  • Place of Presentation: 福岡
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] A BMT model mouse for myelodysplastic syndromes (MDS) and MDS/overt leukemia (2006)
  • Author(s): Watanabe-Okochi, N. Kitaura, J. Harada, H. Ono, R. Inaba, T. Nakajima, H. Nosaka, T. Kitamura, T
  • Organizer: 35th Annual Meeting of the International Society For Experimental Hematology
  • Place of Presentation: Minneapolis
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A BMT model mice for myelodysplastic syndromes (MDS) and transformation to AML (2006)
  • Author(s): Watanabe-Okochi, N. Kitaura, J. Harada, H. Ono, R. Nakajima, H. Nosaka, T. Inaba, T. Kitamura, T
  • Organizer: 48th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Orlando
  • Description: 「研究成果報告書概要(欧文)」より