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2007 Fiscal Year Final Research Report Summary

Elucidation of the de of histone deacetylases (HDACs) in leukemogenesis and its impfication in the treatment of leukemia

Research Project

Project/Area Number 18591083
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionJichi Medical University

Principal Investigator

FURUKAWA Yusuke  Jichi Medical University, School of Mediche, Professor (00199431)

Co-Investigator(Kenkyū-buntansha) KIKUCHI Jiro  Jichi Medical University, School of Medicine, Associate Professor (60371035)
WADA Taeko  Jichi Medical University, School of Medicine, Research Fellow (30382956)
Project Period (FY) 2006 – 2007
KeywordsCancer / Gene / Transcription / Reaenerative medicine
Research Abstract

Histone deacetylases (HDACs) negatively regulate the transcription of eukaryotic genes by deacetylating core histones at promoter regions. Recent investigations have demonstrated the involvement of HDACs in leukemogenesis : Leukemic fusion proteins such as PML-RARa and AML1-ETO recruit HDACs to repress the expression of genes required for differentiation in hematopoietic stem/progenitor cells (HSC). However, little is known about the role of HDACs in normal hematopoiesis and leukemogenesis in the absence of fusion genes. In this study, we examined the expression of HDACs in normal hematopoietic cells and acute myeloblastic leukemia (AML) cells, and analyzed their function using allogenic transplantation of HDAC1- overexpressing HSC in the murine system.
The expression of major HDACs (HDAC1, 2, and 3) was below the detection limit of immunoblotting and immunocytochemistry in CD34-positive human HSC. It was readily detected in CD34-negative common myeloid progenitors (CMP) and lymphocytes … More , but was very weak or absent in monocytes and granulocytes. In contrast, AML cells expressed HDACs far stronger than their normal counterparts : HSC and CMP. HDACs were down-regulated along with myeloid differentiation in vitro, whereas their expression level was retained during erythroid and megakaryocytic differentiation. Reporter assays revealed that transcription of the HDAC1 gene was repressed by GATA-2 and MZF-1 in HSC, activated by GATA-1 in CMP and throughout erythroid/megakaryocytic differentiation, and inactivated by C/EBPa during terminal myeloid differentiation. Myeloid differentiation was perturbed when c-kit-positive murine HSC were transplanted into lethally-irradiated congenic mice after transducing HDAC1 using retrovirus expression vector. Leukemic transformation of transplanted HSC was not observed up to 28 weeks after transplantation.
According to the two-hit theory, two independent genetic abnormalities, class I and class II mutations, are required to transform HSC. Prototype abnormalities of class I and II are FLT3-ITD and PML-RARa, respectively. It is believed that leukemia develops when a class I mutation confers a growth advantage to HSC in which differentiation is blocked by a class II mutation. Our present study suggests that HDAC1 acts as a novel class II transforming gene upon overexpression in HSC. To confirm this hypothesis, we have performed transplantation of HSC overexpressing both HDAC1 and FLT3-ITD into congenic mice. Less

  • Research Products

    (31 results)

All 2008 2007 2006 Other

All Journal Article (26 results) (of which Peer Reviewed: 13 results) Presentation (2 results) Book (1 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] CD43,but not P-selectin Glycoprotein Ligand-1,Functions as an E-Selectin Counter-Receptor in Human Pre-B-Cell Leukemia NALL-12008

    • Author(s)
      Nonomura, C., et. al.
    • Journal Title

      Cancer Res 68

      Pages: 790-799

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] The FLT3 Inhibitor PKC412 Exerts Differential Cell Cycle Effects on Leukemic Cells Depending on the Presence of FLT3 Mutations2008

    • Author(s)
      Odgerel, T., et. al.
    • Journal Title

      Oncogene 27

      Pages: 3102-3110

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Transcriptional Modulation Using HDACi Depsipeptide Promotes Immune Cell-Mediated Tumor Destruction of Murine B16 Melanoma2008

    • Author(s)
      Murakami, T., et. al.
    • Journal Title

      J.Invest.Dermatol 128

      Pages: 1506-1516

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Activation of Focal Adhesion Kinase in Detached Human Epidermal Cancer Cells and Their Long-term Survival Might be Associated with Cell Surface Expression of Laminin-52008

    • Author(s)
      Katayama, H., et. al.
    • Journal Title

      Acta Derm.Venereol 88

      Pages: 100-107

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Cholesterol Reduction and Atherosclerosis Inhibition by Bezafibrate in Low-Density Lipoprotein Receptor Knockout Mice2008

    • Author(s)
      Inaba, T., et. al.
    • Journal Title

      Hypertens.Res 31

      Pages: 1001-1007

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] CD43, but not P-selectin Glycoprotein Ligand-1, Functions as an E-Selectin Counter-Receptor in Human Pre-B-Cell Leukemia NALL-12008

    • Author(s)
      Nonomura, C., Kikuchi, J., Kiyokawa, N., Ozaki, H., Mitsunaga, K., Ando, H., Kanamori, A., Kannagi, .R., Fujimoto, J., Muroi, K., Furukawa., Y., Nakamura, M
    • Journal Title

      Cancer Res 68

      Pages: 790-799

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The FLT3 Inhibitor PKC412 Exerts Differential Cell Cycle Effects on Leukemic Cells Depending on the Presence of FLT3 Mutations2008

    • Author(s)
      Odgerel, T., Kikuchi, J., Wada, T., Shimizu, R., Futaki, K., Kano, Y., Furukawa., Y
    • Journal Title

      Oncogene 27

      Pages: 3102-3110

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Transcriptional Modulation Using HDACi Depsipeptide Promotes Immune Cell-Mediated Tumor Destruction of Murine B16 Melanoma2008

    • Author(s)
      Murakami, T., Sato, A., Chun, N. A. L., Hara, M., Naito, Y., Kobayashi, Y., Kano, Y., Ohtsuki, M., Furukawa., Y., Kobayashi, E
    • Journal Title

      J. Invest. Dermatol 128

      Pages: 1506-1516

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Activation of Focal Adhesion Kinase in Detached Human Epidermal Cancer Cells and Their Long-term Survival Might be Associated with Cell Surface Expression of Laminin-52008

    • Author(s)
      Katayama, H., Yamane, Y., Furukawa, Y., Kitagawa, S., Nakamura, Y., Yoshino, K
    • Journal Title

      Acta Derm. Venereol 88

      Pages: 100-107

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Cholesterol Reduction and Atherosclerosis Inhibition by Bezafibrate in Low-Density Lipoprotein Receptor Knockout Mice2008

    • Author(s)
      Inaba, T., Yagyu, H., Itabashi, N., Tazoe, F., Fujita, N., Nagashima, S., Okada, K., Okazaki, M., Furukawa., Y., Ishibashi, S
    • Journal Title

      Hypertens. Res 31

      Pages: 1001-1007

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Cytotoxic Effects of Histone Deacetylase Inhibitor FK228(Depsipeptide,Formally Named FR901228)in Combination with Conventional Anti-leuke mia/lymphoma Agents against Human Leukemia/lymphoma Cell Lines2007

    • Author(s)
      Kano, Y., et. al.
    • Journal Title

      Invest.New Drugs 25

      Pages: 31-40

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Divergent Cytotoxic Effects of PKC412 in Combination with Conventional Antileukemic Agents in FLT3 Mutation-positive versus Negative Leukemia Cell Lines2007

    • Author(s)
      Furukawa, Y., et. al.
    • Journal Title

      Leukemia 21

      Pages: 1005-1014

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Rad9 Modulates the p21^<WAF1> Pathway by Direct Association with p532007

    • Author(s)
      Ishikawa, K., et. al.
    • Journal Title

      BMC Mol.Biol 8

      Pages: 37-46

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] E2F-6 Suppresses Growth-associated Apoptosis of Human Hematopoietic Progenitor Cells by Counteracting Proapoptotic Activity of E2F-12007

    • Author(s)
      Kikuchi, J., et. al.
    • Journal Title

      Stem Cells 25

      Pages: 2439-2447

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] B-cell Lymphoma Showing Typical Features of Angioimmunoblastic T-cell Lymphoma2007

    • Author(s)
      Mori, M., et. al.
    • Journal Title

      JMu Journal 30

      Pages: 89-95

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Cytotoxic Effects of Histone Deacetylase Inhibitor FK228(Depsipeptide, Formally Named FR901228) in Combination with Conventional Anti-leukemia/lymphoma Agents against Human Leukemia/lymphoma Cell Lines2007

    • Author(s)
      Kano, Y., Akutsu, M., Tsunoda, S., Izumi, T., Kobayashi, H., Mano, H., Furukawa. Y
    • Journal Title

      Invest. New Drugs 25

      Pages: 31-40

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Divergent Cytotoxic Effects of PKC412 in Combination with Conventional Antileukemic Agents in FLT3 Mutation-positive versus Negative Leukemia Cell Lines2007

    • Author(s)
      Furukawa, Y., Vu, H. A., Akutsu, M., Odgerel, T., Izumi, T., Tsunoda, S., Matsuo, Y., Kirito, K., Sato, Y., Mano, H., Kano, Y
    • Journal Title

      Leukemia 21

      Pages: 1005-1014

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Rad9 Modulates the p21^<WAF1> Pathway by Direct Association with p532007

    • Author(s)
      Ishikawa, K., Ishii, H., Murakumo, Y., Mimori, K., Kobayashi, M., Yamamoto, K.-I., Mon, M., Nishino, H., Furukawa., Y., Ichimura, K
    • Journal Title

      BMC Mol. Biol 8

      Pages: 37-46

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] E2F-6 Suppresses Growth-associated Apoptosis of Human Hematopoietic Progenitor Cells by Counteracting Proapoptotic Activity of E2F-12007

    • Author(s)
      Kikuchi, J., Shimizu, R., Wada, T., Ando, H., Nakamura, M., Ozawa, K., Furukawa., Y
    • Journal Title

      Stem Cells 25

      Pages: 2439-2447

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] B-cell Lymphoma Showing Typical Features of Angioimmunoblastic T-cell Lymphoma2007

    • Author(s)
      Mori, M., Furukawa., Y., Takatoku, M., Nagai, T., Muroi, K., Ozawa, K
    • Journal Title

      JMU Journal 30

      Pages: 89-95

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Histone Deacetylase Inhibitor FK228 Suppresses the Ras-MAP kinase Signaling Pathway by Up-regulating Rapl and Induces Apoptosis in Malignant Melanoma2006

    • Author(s)
      Kobayashi, Y., et. al.
    • Journal Title

      Oncogene 25

      Pages: 512-524

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Histone Deacetylase Inhibitor Depsipeptide(FK228)Induces Apoptosis in Leukemic Cells by Facilitating Mitochondrial Translocation of Bax,which Is Enhanced by Proteasome Inhibitor Bortezomib2006

    • Author(s)
      Sutheesophon, K., et. al.
    • Journal Title

      Acta Haematolo 115

      Pages: 78-90

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Schedule-dependent Interactions between Pemetrexed and Cisplatin in Human Carcinoma Cell Lines in vitro2006

    • Author(s)
      Kano, Y., et. al.
    • Journal Title

      Oncol.Res 16

      Pages: 85-95

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Histone Deacetylase Inhibitor FK228 Suppresses the Ras-MAP kinase Signaling Pathway by Up-regulating Rap1 and Induces Apoptosis in Malignant Melanoma2006

    • Author(s)
      Kobayashi, Y., Ohtsuki, M., Murakami, T., Kobayashi, T., Sutheesophon, K., Kitayama, H., Kano, Y., Kusano, E., Nakagawa, H., Furukawa., Y
    • Journal Title

      Oncogene 25

      Pages: 512-524

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Histone Deacetylase Inhibitor Depsipeptide(FK228) Induces Apoptosis in Leukemic Cells by Facilitating Mitochondrial Translocation of Bax, which Is Enhanced by Proteasome Inhibitor Bortezomib2006

    • Author(s)
      Sutheesophon, K., Kobayashi, Y., Takatoku, M., Ozawa, K., Kano, Y., Ishii, H., Furukawa, Y
    • Journal Title

      Acta Haematol 115

      Pages: 78-90

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Schedule-dependent Interactions between Pemetrexed and Cisplatin in Human Carcinoma Cell Lines in vitro2006

    • Author(s)
      Kano, Y., Akutsu, M., Tsunoda, S., Izumi, T., Kobayashi, H., Inoue, K., Mori, K., Fujii, H., Mano, H., Odgerel, T., Furukawa, Y
    • Journal Title

      Oncol. Res 16

      Pages: 85-95

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Histone Deacetylase 1 Acts as a Class II Transforming Gene in AcuteMyeloblastic Leukemia2007

    • Author(s)
      Furukawa, Y.
    • Organizer
      The 4th Nikko Intenational Symposium
    • Place of Presentation
      栃木県下野市
    • Year and Date
      2007-09-29
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Histone Deacetylase 1 Acts as a Class II Transforming Gene in Acute Myeloblastic Leukemia2007

    • Author(s)
      Furukawa. Y
    • Organizer
      The 4th Nikko Intenational Symposium
    • Place of Presentation
      Shimotuke, Tochigi, Japan
    • Year and Date
      2007-09-29
    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] 血液疾患と細胞周期〜基礎から臨床まで〜(血液フロンティア特集号)2007

    • Author(s)
      古川 雄祐
    • Total Pages
      144
    • Publisher
      医薬ジャーナル社
    • Description
      「研究成果報告書概要(和文)」より
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.jichi.ac.jp/stem/index.html

  • [Patent(Industrial Property Rights)] 腎疾患の予防および治療剤2007

    • Inventor(s)
      古川 雄祐
    • Industrial Property Rights Holder
      古川 雄祐
    • Industrial Property Number
      特07-01号
    • Filing Date
      2007-04-06
    • Description
      「研究成果報告書概要(和文)」より

URL: 

Published: 2010-02-04  

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