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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.
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