title: Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis.
abstract: 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 beta (PEBP2beta/CBFbeta). On the other hand, the R139G mutant acts as a dominant negative inhibitor by competing with wild-type AML1 for interaction with PEBP2beta/CBFbeta. 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.
authors.affiliation: Department of Hematology and Oncology and the Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Imai
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
authors.forename: K
authors.initials: K
authors.lastname: Izutsu
authors.forename: A
authors.initials: A
authors.lastname: Hangaishi
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: K
authors.initials: K
authors.lastname: Maki
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Chiba
authors.forename: K
authors.initials: K
authors.lastname: Mitani
authors.forename: H
authors.initials: H
authors.lastname: Hirai
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D019281:Dimerization; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors