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- Title
Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
- Authors
Song, W J; Sullivan, M G; Legare, R D; Hutchings, S; Tan, X; Kufrin, D; Ratajczak, J; Resende, I C; Haworth, C; Hock, R; Loh, M; Felix, C; Roy, D C; Busque, L; Kurnit, D; Willman, C; Gewirtz, A M; Speck, N A; Bushweller, J H; Li, F P; Gardiner, K; Poncz, M; Maris, J M; Gilliland, D G
- 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.
- Publication
Nature genetics, 1999, Vol 23, Issue 2, p166
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/13793