In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis
- Author(s)
- Michaud, J; Wu, F; Osato, M; Cotties, GM; Yanagida, M; Asou, N; Shigesada, K; Ito, Y; Benson, KF; Raskind, WH; Rossier, C; Antonarakis, SE; Israels, S; McNicol, A; Weiss, H; Horwitz, M; Scott, HS;
- Details
- Publication Year 2002-02-15,Volume 99,Issue #4,Page 1364-1372
- Journal Title
- BLOOD
- Publication Type
- Journal Article
- Abstract
- Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML) Is an autosomal dominant familial platelet disorder characterized by thrombocytopenia and a propensity to develop AML. Mutation analyses of RUNX1 in 3 families with FPD/AML showing linkage to chromosome 21q22.1 revealed 3 novel heterozygous point mutations (K83E, R135fsX177 (IVS4 + 3deIA), and Y260X). Functional investigations of the 7 FPD/AML RUNX1 Runt domain point mutations described to date (2 frameshift, 2 nonsense, and 3 missense mutations) were performed. Consistent with the position of the mutations in the Runt domain at the RUNX1-DNA interface, DNA binding of all mutant RUNX1 proteins was absent or significantly decreased. In general, missense and nonsense RUNX1 proteins retained the ability to heterodimerize with PEBP2beta/CBFbeta and inhibited transactivation of a reporter gene by wild-type RUNX1. Colocalization of mutant RUNX1 and PEBP2beta/CBFbeta in the cytoplasm was observed. These results suggest that the sequestration of PEBP2beta/CBFbeta by mutant RUNX1 may cause the inhibitory effects. While haploinsufficiency of RUNX1 causes FPD/AML in some families (deletions and frameshifts), mutant RUNX1 proteins (missense and nonsense) may also inhibit wild-type RUNX1, possibly creating a higher propensity to develop leukemia. This is consistent with the hypothesis that a second mutation has to occur, either in RUNX1 or another gene, to cause leukemia among Individuals harboring RUNX1 FPD/AML mutations and that the propensity to acquire these additional mutations is determined, at least partially, by the Initial RUNX1 mutation. (C) 2002 by The American Society of Hematology.
- Publisher
- AMER SOC HEMATOLOGY
- Keywords
- ACUTE MYELOID-LEUKEMIA; STORAGE POOL DEFICIENCY; CORE-BINDING-FACTOR; GASTROINTESTINAL STROMAL TUMORS; TRANSCRIPTION FACTOR PEBP2/CBF; FACTOR-RECEPTOR PROMOTER; CLEIDOCRANIAL DYSPLASIA; RUNT DOMAIN; DNA-BINDING; ALPHA-SUBUNIT
- Publisher's Version
- https://doi.org/10.1182/blood.V99.4.1364
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2002-02-15 12:00:00