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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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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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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Report
(3 results)
Research Products
(43 results)
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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
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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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Cancer Res 68
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Oncogene 27
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[Journal Article] Transcriptional Modulation Using HDACi Depsipeptide Promotes Immune Cell-Mediated Tumor Destruction of Murine B16 Melanoma2008
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Acta Derm. Venereol 88
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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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Invest. New Drugs 25
Pages: 31-40
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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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Leukemia 21
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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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BMC Mol. Biol 8
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[Journal Article] B-cell Lymphoma Showing Typical Features of Angioimmunoblastic T-cell Lymphoma2007
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JMU Journal 30
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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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Oncogene 25
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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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Acta Haematol 115
Pages: 78-90
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[Journal Article] Schedule-dependent Interactions between Pemetrexed and Cisplatin in Human Carcinoma Cell Lines in vitro2006
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