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Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2002, Vol. 99, No. 4, pp. 1364-1372 NEOPLASIA 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 Joëlle Michaud, Feng Wu, Motomi Osato, Gregory M. Cottles, Masatoshi Yanagida, Norio Asou, Katsuya Shigesada, Yoshiaki Ito, Kathleen F. Benson, Wendy H. Raskind, Colette Rossier, Stylianos E. Antonarakis, Sara Israels, Archie McNicol, Harvey Weiss, Marshall Horwitz, and Hamish S. Scott From the Division of Medical Genetics, Geneva University Medical School, Switzerland and Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Victoria, Australia; Department of Viral Oncology and Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Japan; Second Department of Internal Medicine, Kumamoto University School of Medicine, Japan; Division of Medical Genetics, University of Washington School of Medicine, Seattle; Departments of Pediatrics and Oral Biology, University of Manitoba, Winnipeg, Canada; and Department of Medicine, Columbia University, New York, NY. 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 PEBP2/CBF and inhibited transactivation of a reporter gene by wild-type RUNX1. Colocalization of mutant RUNX1 and PEBP2/CBF in the cytoplasm was observed. These results suggest that the sequestration of PEBP2/CBF 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. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Edwards, C. Xie, K. M. LaFiura, A. A. Dombkowski, S. A. Buck, J. L. Boerner, J. W. Taub, L. H. Matherly, and Y. 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