| 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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| 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
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, 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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