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Title

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

Authors
Michaud, Joelle
Wu, Feng
Osato, Motomi
Cottles, G. M.
Yanagida, Masatoshi
Asou, Norio
Shigesada, Katsuya
Ito, Yoshiaki
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Published in Blood. 2002, vol. 99, no. 4, p. 1364-1372
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.
Keywords Blood Platelet Disorders/ geneticsChromosomes, Human, Pair 21/geneticsCore Binding Factor Alpha 2 SubunitDNA Mutational AnalysisDNA-Binding Proteins/ genetics/metabolismFamily HealthFemaleGenes, DominantGenetic Predisposition to DiseaseHaplotypesHumansLeukemia, Myeloid, Acute/etiology/ geneticsLinkage (Genetics)MalePedigreePoint Mutation/ physiologyProtein BindingProto-Oncogene ProteinsTranscription Factor AP-2Transcription Factors/ genetics/metabolismTranscriptional Activation/drug effects
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PMID: 11830488
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MICHAUD, Joelle et al. 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. In: Blood, 2002, vol. 99, n° 4, p. 1364-1372. https://archive-ouverte.unige.ch/unige:8900

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Deposited on : 2010-07-12

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