| Project/Area Number |
10670958
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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 | Kumamoto University |
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Principal Investigator |
ASOU Norio Kumamoto University School of Medicine, Associate Professor, 医学部, 講師 (50175171)
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| Co-Investigator(Kenkyū-buntansha) |
麻生 範雄 熊本大学, 医学部, 講師 (50175171)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1998: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | acute myeloblastic leukemia / AML1 gene / point mutation / transcriptional factor / runt family / PEBP2β / mechanism of leukemogenesis / AML1-MTG8 fusion gene / MTG8融合遺伝子 / ルント領域 |
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| Research Abstract |
The AML1 gene is known as the most frequent target of chromosomal translocations associated with leukemia. It encodes the α-subunit in the Runt domain family of heterodimeric transcriptional factors and acts to regulate the expression of various gene specific to hematopoiesis. The Translocations involving AML1 produce chimeric proteins such as AML1-ETO (MTG8) in acute myeloblastic leukemia (AML) with t(8;21)(q22;q22) and ETV6 (TEL)-AML1 in pediatric acute lymphoblastic leukemia(ALL)with t(12;21). A11 of these chimeric proteins retain thc entire Runt domain which is responsible for DNA binding and heterodimerization withβsubunit (PEBP2β). We round point mutations of the AML1 gene in 8 of 160 leukemias; 2 silent mutations, 4 heterozygous missense mutations, and 2 biallelic nonsense or frameshift mutations. Missense mutations in 3 patients showed neither DNA binding nor transactivation. The biallelic nonsense mutants encoding truncated AML1 proteins lost almost all functions and may play a role in leukemogenesis leading to AML. On the other hand,we found no mutation of the PEBP2βgene in 120 leukemias. In this study, we also examined mutation of the AML1 gene in AML M0 subtype to verify relationship between subtype and the AML1 gene mutation. In 6 of 30 patients with M0, we detected frameshift mutations of the AML1 gene, resulting in haploinsufficiency of the AML1. It was recently demonstrated that haploinsufficiency of AML1 causes familial platelet disorder associated with propensity to develop AML. Therefore, the haploinsufficiency of the AML1 is relevant to the predisposition or progression of leukemia.
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