@article{9e3b7400c3a146c49b84d9f0c25d3c61,
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/AM 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.",
author = "Song, {Woo Joo} and Sullivan, {Melanie G.} and Legare, {Robert D.} and Sarah Hutchings and Xiaolian Tan and Dubravka Kufrin and Janina Ratajczak and Resende, {Isabel C.} and Catherine Haworth and Randy Hock and Mignon Loh and Carolyn Felix and Roy, {Denis Claude} and Lambert Busque and David Kurnit and Cheryl Willman and Gewirtz, {Alan M.} and Speck, {Nancy A.} and Bushweller, {John H.} and Li, {Frederick P.} and Katheleen Gardiner and Mortimer Poncz and Maris, {John M.} and Gilliland, {D. Gary}",
note = "Funding Information: We thank patients, families and physicians for participation; S.C. Davies, J. Cogswell, T. Keating, C. Zerbini, K. Blanchard, R. Cote, P. Dunphy, K. Ferguson, B. Himelstein and A. Shapiro for clinical care of FPD/AML family members and for obtaining patient samples; D. Porter for evaluating the proband in pedigree 1; R. Lifton, T. Golub, J. Gusella and L. Kunkel for critical review of this manuscript and discussions, M. Ryan for administrative and secretarial assistance; S. Ontiveros and E. Motte for technical assistance; and J. Cheng for providing access to cDNA clones that localize to the FDP/AML region. This work was supported in part by American Cancer Society grant RPG-93-007-05-DHP, NIH RO1 CA81932 and the MarJo Foundation (S.H., M.S., W.-J.S. and D.G.G); NIH RO1 CA78545 (J.M.M.); NIH R29 AI39536, NIH K02 AI10481 and NIH AI42097 (J.H.B.); NIH HL40387 (M.P.), NIH R01CA58343 (N.A.S.). F.P.L. is Harry and Elsa Giles American Cancer Society Professor of Clinical Research and is supported in part by the Starr Foundation. L.B. and D.C.R are scholars of the FRSQ. D.G.G. is a Stephen Birnbaum Scholar of the Leukaemia Society of America and an Associate Investigator of the Howard Hughes Medical Institute.",
year = "1999",
month = oct,
doi = "10.1038/13793",
language = "English (US)",
volume = "23",
pages = "166--175",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",
}