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Scientific article
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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

Published inBlood, vol. 99, no. 4, p. 1364-1372
Publication date2002
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/ genetics
  • Chromosomes, Human, Pair 21/genetics
  • Core Binding Factor Alpha 2 Subunit
  • DNA Mutational Analysis
  • DNA-Binding Proteins/ genetics/metabolism
  • Family Health
  • Female
  • Genes, Dominant
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Leukemia, Myeloid, Acute/etiology/ genetics
  • Linkage (Genetics)
  • Male
  • Pedigree
  • Point Mutation/ physiology
  • Protein Binding
  • Proto-Oncogene Proteins
  • Transcription Factor AP-2
  • Transcription Factors/ genetics/metabolism
  • Transcriptional Activation/drug effects
Citation (ISO format)
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. doi: 10.1182/blood.v99.4.1364
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ISSN of the journal0006-4971
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