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

Nature Genetics volume 23, pages 166–175 (1999)Cite this article

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.

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Figure 1: FPD/AML pedigrees.
Figure 2: The FPD/AML genomic region and informative recombination events in CBFA2.
Figure 3: CBFA2 mutations in FPD/AML pedigrees 2 and 3.
Figure 4: Summary of mutations in FPD/AML pedigrees 1–6.
Figure 5: Ribbon representation of the backbone of the NMR solution structure of the CBFA2 Runt domain.
Figure 6: Genotype and FISH analysis of FPD/AML pedigree 1.
Figure 7: RT-PCR of platelet RNA.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Woo-Joo Song, Melanie G. Sullivan, Sarah Hutchings, Xiaolian Tan, Mignon Loh & D. Gary Gilliland

  2. Dana-Farber Cancer Institute, Harvard Medical School, , Boston, Massachusetts, USA

    Frederick P. Li

  3. Program in Women's Oncology, Women and Infant's Hospital, Brown University,, Providence, Rhode Island, USA

    Robert D. Legare

  4. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Dubravka Kufrin, Isabel C. Resende, Carolyn Felix, Mortimer Poncz & John M. Maris

  5. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Janina Ratajczak & Alan M. Gewirtz

  6. Leicester Royal Infirmary,, Leicester, UK

    Catherine Haworth

  7. Children's Center for Cancer and Blood Diseases, St. Vincent Hospital,, Indianapolis, Indiana, USA

    Randy Hock

  8. Department of Hematology and Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, Quebec, Canada

    Denis-Claude Roy & Lambert Busque

  9. Departments of Pediatrics and Human Genetics, University of Michigan Medical Center, Ann Arbor, Michigan, USA

    David Kurnit

  10. Department of Pathology and the Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico , USA

    Cheryl Willman

  11. Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire, USA

    Nancy A. Speck

  12. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia , USA

    John H. Bushweller

  13. Eleanor Roosevelt Institute,, Denver, Colorado, USA

    Katheleen Gardiner

  14. Howard Hughes Medical Institute, Harvard Medical School, , Boston, 02115, Massachusetts, USA

    D. Gary Gilliland

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Song, WJ., Sullivan, M., Legare, R. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23, 166–175 (1999). https://doi.org/10.1038/13793

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