title: High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia.
abstract: A high incidence of somatically acquired point mutations in the AML1/RUNX1 gene has been reported in poorly differentiated acute myeloid leukemia (AML, M0) and in radiation-associated and therapy-related myelodysplastic syndrome (MDS) or AML. The vast majority of AML1 mutations identified in these diseases were localized in the amino (N)-terminal region, especially in the DNA-binding Runt homology domain. In this report, we show that AML1 point mutations were found in 26 (23.6%) of 110 patients with refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt), and AML following MDS (defined these 3 disease categories as MDS/AML). Among them, 9 (8.2%) mutations occurred in the carboxy (C)-terminal region, which were exclusively found in MDS/AML and were strongly correlated with sporadic MDS/AML. All patients with MDS/AML with an AML1 mutation expressed wild-type AML1 protein and had a significantly worse prognosis than those without AML1 mutations. Most AML1 mutants lost trans-activation potential, regardless of their DNA binding potential. These data suggested that AML1 point mutation is one of the major driving forces of MDS/AML, and these mutations may represent a distinct clinicopathologic-genetic entity.
authors: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. herf1@hiroshima-u.ac.jp
authors: Hironori
authors: H
authors: Harada
authors: Yuka
authors: Y
authors: Harada
authors: Hiromasa
authors: H
authors: Niimi
authors: Taiichi
authors: T
authors: Kyo
authors: Akiro
authors: A
authors: Kimura
authors: Toshiya
authors: T
authors: Inaba
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019281:Dimerization; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006367:HeLa Cells; D006801:Humans; D015994:Incidence; D007951:Leukemia, Myeloid / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000453:epidemiology* / Q000235:genetics*; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors