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Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis

The AML1 gene encodes a DNA-binding protein that contains the runt domain and is the most frequent target of translocations associated with human leukemias. Here, point mutations of the AML1 gene, V105ter (single-letter amino acid code) and R139G, (single-letter amino acid codes) were identified in...

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Bibliographic Details
Published in:Blood 2000-11, Vol.96 (9), p.3154-3160
Main Authors: Imai, Yoichi, Kurokawa, Mineo, Izutsu, Koji, Hangaishi, Akira, Takeuchi, Kengo, Maki, Kazuhiro, Ogawa, Seishi, Chiba, Shigeru, Mitani, Kinuko, Hirai, Hisamaru
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Language:English
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Summary:The AML1 gene encodes a DNA-binding protein that contains the runt domain and is the most frequent target of translocations associated with human leukemias. Here, point mutations of the AML1 gene, V105ter (single-letter amino acid code) and R139G, (single-letter amino acid codes) were identified in 2 cases of myelodysplastic syndrome (MDS) by means of the reverse transcriptase–polymerase chain reaction single-strand conformation polymorphism method. Both mutations are present in the region encoding the runt domain of AML1 and cause loss of the DNA-binding ability of the resultant products. Of these mutants, V105ter has also lost the ability to heterodimerize with polyomavirus enhancer binding protein 2/core binding factor β (PEBP2β/CBFβ). On the other hand, the R139G mutant acts as a dominant negative inhibitor by competing with wild-type AML1 for interaction with PEBP2β/CBFβ. This study is the first report that describes mutations of AML1 in patients with MDS and the mechanism whereby the mutant acts as a dominant negative inhibitor of wild-type AML1.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V96.9.3154