title: Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
abstract: Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Song
authors.forename: M G
authors.initials: MG
authors.lastname: Sullivan
authors.forename: R D
authors.initials: RD
authors.lastname: Legare
authors.forename: S
authors.initials: S
authors.lastname: Hutchings
authors.forename: X
authors.initials: X
authors.lastname: Tan
authors.forename: D
authors.initials: D
authors.lastname: Kufrin
authors.forename: J
authors.initials: J
authors.lastname: Ratajczak
authors.forename: I C
authors.initials: IC
authors.lastname: Resende
authors.forename: C
authors.initials: C
authors.lastname: Haworth
authors.forename: R
authors.initials: R
authors.lastname: Hock
authors.forename: M
authors.initials: M
authors.lastname: Loh
authors.forename: C
authors.initials: C
authors.lastname: Felix
authors.forename: D C
authors.initials: DC
authors.lastname: Roy
authors.forename: L
authors.initials: L
authors.lastname: Busque
authors.forename: D
authors.initials: D
authors.lastname: Kurnit
authors.forename: C
authors.initials: C
authors.lastname: Willman
authors.forename: A M
authors.initials: AM
authors.lastname: Gewirtz
authors.forename: N A
authors.initials: NA
authors.lastname: Speck
authors.forename: J H
authors.initials: JH
authors.lastname: Bushweller
authors.forename: F P
authors.initials: FP
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Gardiner
authors.forename: M
authors.initials: M
authors.lastname: Poncz
authors.forename: J M
authors.initials: JM
authors.lastname: Maris
authors.forename: D G
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism; D002874:Chromosome Mapping; D003114:Colony-Forming Units Assay; D050676:Core Binding Factor Alpha 2 Subunit; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006410:Hematopoiesis / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011518:Proto-Oncogene Proteins; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013921:Thrombocytopenia / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors; D012313:RNA