Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

摘要: Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant characterized by qualitative and quantitative defects, propensity develop (AML). Informative recombination events in 6 FPD/AML pedigrees evidence of linkage markers on chromosome 21q identified 880-kb interval containing the disease gene. Mutational analysis regional candidate genes showed nonsense mutations or intragenic deletion one allele haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated four pedigrees. We heterozygous missense remaining two at phylogenetically conserved amino acids R166 R201, respectively. Analysis bone marrow peripheral blood cells from affected individuals a decrement megakaryocyte colony formation, demonstrating dosage affects megakaryopoiesis. Our findings support model for which haploinsufficiency causes congenital defect predisposes acquisition additional cause leukaemia.