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
| Project/Area Number |
18591083
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
FURUKAWA Yusuke Jichi Medical University, School of Mediche, Professor (00199431)
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| 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)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Cancer / Gene / Transcription / Reaenerative medicine |
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| 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
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[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
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Journal Title
Cancer Res 68
Pages: 790-799
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Oncogene 27
Pages: 3102-3110
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
J. Invest. Dermatol 128
Pages: 1506-1516
Description
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[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
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Journal Title
Acta Derm. Venereol 88
Pages: 100-107
Description
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[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
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Journal Title
Hypertens. Res 31
Pages: 1001-1007
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Invest. New Drugs 25
Pages: 31-40
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Leukemia 21
Pages: 1005-1014
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
BMC Mol. Biol 8
Pages: 37-46
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Stem Cells 25
Pages: 2439-2447
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
JMU Journal 30
Pages: 89-95
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Oncogene 25
Pages: 512-524
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Acta Haematol 115
Pages: 78-90
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Oncol. Res 16
Pages: 85-95
Description
「研究成果報告書概要(欧文)」より
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