2000 Fiscal Year Final Research Report Summary
Mechanisms of leukemogenesis caused by alterations of the structure of transcription factor PEBP2
| Project/Area Number |
09253220
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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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| Research Institution | Institute for Virus Research, Kyoto University |
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Principal Investigator |
ITO Yoshiaki Institute for Virus Research, Kyoto University : Professor, ウイルス研究所, 教授 (80004612)
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| Co-Investigator(Kenkyū-buntansha) |
MARUYAMA Mitsuo Institute for Virus Research, Kyoto University : Instructor, ウイルス研究所, 助手 (00212225)
KANNO Tomohiko Institute for Virus Research, Kyoto University : Instructor, ウイルス研究所, 助手 (10273525)
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| Project Period (FY) |
1994 – 1999
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| Keywords | RUNX1 / RUNX2 / RUNX3 / AML1 / PEBP2 / FPD-AML / TGF-β / BMP |
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| Research Abstract |
Transcription factor PEBP2 is composed of α and β subunits. There are three genes encoding the α subunit, RUNX1/AML1, RUNX2/CBFA1, RUNX3/PEBP2αC.We found that RUNX1 is required for generation of hematopoietic stem cells from endothelial cells. RUNX1 is the most frequent target of chromosome translocations associated with acute leukemia but we found sporadic loss-of-function point mutations without involving chimeric proteins. Later, familial cases of point mutations were reported which are called Familial Patelet Disorder with Predisposition to Acute Myeloid Leukemia (FPD-AML). Mice carrying heterozygously disrupted RUNX1 gene were found to be a good mouse model for FPD-AML.Haploinsufficiency of RUNX1 is being proved to be leukemogenic.
RUNX2 is essential for maturation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia (CCD). We found that RUNX2 is one of the major target of TGF-β/BMP signaling and mutations of RUNX2 impaired the BMP pathway to cause CCD.
We found that RUNX3 was expressed in epithelial cells of gastrointestinal tractand that the disruption of the gene caused hyperplasia of epithelial layer of glandular stomach. Possible involvement of RUNX3 in gastric cancer is being studied.
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