2004 Fiscal Year Final Research Report Summary
Molecular mechanisms of leukemogenesis and pathogenesis in adult T-cell leukemia
| Project/Area Number |
12213057
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyoto University |
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Principal Investigator |
MATSUOKA Kasao Institute for Virus Research, Professor, ウイルス研究所, 教授 (10244138)
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| Project Period (FY) |
2000 – 2004
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| Keywords | Adult T-cell leukemia / Retrovirus / Oncogenesis / HTLV-I / Methylation / Leukemogenesis |
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| Research Abstract |
After infection of human T-cell leukemia virus type I (HTLV-I), there is a long latent period before the onset of adult T-cell leukemia (ATL). I have studied the molecular mechanisms of leukemogenesis, and pathogenesis in ATL.
1) DNA methylation was first detected in the exon of p16 gene, and then it progressed to the promoter region. When the promoter region was methylated, the transcription of p16 gene was silenced. We found that DNA methylation of 5'-long terminal repeat (LTR) silenced the viral gene transcription. Within provirus, DNA methylation first occurred in the internal regions, such as gag, pol and env regions, and then spread to 5' and 3' directions. We isolated the aberrant methylated DNA regions in ATL cells by Methylated CpG island amplification/representative difference assay (MCA/RDA). MEL1S gene was identified as hypomethylated one in ATL cells. Aberrant expression of MEL1S gene was observed in ATL cells, which enabled ATL cells resistant to TGF-β. Therefore, MEL1S ex
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pression is considered to be one of mechanisms to confer the resistance to TGF-β. On the other hand, KLF4 and EGR3 genes were found to be hypermethylated in ATL cells. Silenced EGR3 gene transcription results in loss of Fas ligand expression, which enables ATL cells to escape from Fas-Fas ligand induced apoptosis.
2) ATL cells from hypercalcemic patients were found to express RANK ligand on their surfaces and produce M-CSF. RANK ligand and M-CSF have shown to co-operatively induce the differentiation of hematopoietic precursor cells into osteolcast. ATL cells from hypercalcemic patients could induce the differentiation to osteoclast in vitro.
3) Immunodeficiet state is observed in HTLV-I infected individuals and ATL patients. We analyzed the naive and memory T-cell subpopulation among HTLV-I carriers and ATL patients, and found that the number of naive T-cell decreased in HTLV-I infected individuals. Since T-cell receptor excision circles were decreased in HTLV-I infected individuals, decreased naive T-cell is thought to be due to suppressed production in the thymus.
4) Tax expression is frequently lost in ATL cells. We identified three mechanisms in inactivation of Tax expression : 1) genetic changes of tax gene, 2) DNA methylation of 5'-LTR and 3) deletion of 5'-LTR. Less
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