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.
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.
authors.affiliation: Division of Medical Genetics, Geneva University Medical School, Switzerland.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Michaud
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cottles
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yanagida
authors.forename: Norio
authors.initials: N
authors.lastname: Asou
authors.forename: Katsuya
authors.initials: K
authors.lastname: Shigesada
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Benson
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.forename: Colette
authors.initials: C
authors.lastname: Rossier
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Sara
authors.initials: S
authors.lastname: Israels
authors.forename: Archie
authors.initials: A
authors.lastname: McNicol
authors.forename: Harvey
authors.initials: H
authors.lastname: Weiss
authors.forename: Marshall
authors.initials: M
authors.lastname: Horwitz
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
mesh_terms: D001791:Blood Platelet Disorders / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D008297:Male; D010375:Pedigree; D017354:Point Mutation / Q000502:physiology*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
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