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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.
- Source :
-
Blood [Blood] 2002 Feb 15; Vol. 99 (4), pp. 1364-72. - Publication Year :
- 2002
-
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 + 3delA), 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.
- Subjects :
- Chromosomes, Human, Pair 21 genetics
Core Binding Factor Alpha 2 Subunit
DNA Mutational Analysis
DNA-Binding Proteins metabolism
Family Health
Female
Genes, Dominant
Genetic Linkage
Genetic Predisposition to Disease
Haplotypes
Humans
Leukemia, Myeloid, Acute etiology
Male
Pedigree
Protein Binding
Transcription Factor AP-2
Transcription Factors metabolism
Transcriptional Activation drug effects
Blood Platelet Disorders genetics
DNA-Binding Proteins genetics
Leukemia, Myeloid, Acute genetics
Point Mutation physiology
Proto-Oncogene Proteins
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 99
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 11830488
- Full Text :
- https://doi.org/10.1182/blood.v99.4.1364