Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia

Authors

  • Michael Kirwan,

    1. Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, United Kingdom
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    • The first two authors contributed equally to this article.

  • Tom Vulliamy,

    Corresponding author
    1. Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, United Kingdom
    • Centre for Paediatrics, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
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    • The first two authors contributed equally to this article.

  • Anna Marrone,

    1. MRC Clinical Sciences Centre, Imperial College School of Medicine, London, United Kingdom
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  • Amanda J. Walne,

    1. Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, United Kingdom
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  • Richard Beswick,

    1. Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, United Kingdom
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  • Peter Hillmen,

    1. Department of Haematology, Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
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  • Richard Kelly,

    1. Department of Haematology, Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
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  • Andrew Stewart,

    1. Central Pathology Laboratory, University Hospital of North Staffordshire, Stoke-on-Trent, United Kingdom
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  • David Bowen,

    1. Department of Haematology, Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
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  • Stefan O. Schonland,

    1. Department of Internal Medicine V, University Hospital Heidelberg, Germany
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  • Annika Maria Whittle,

    1. Department of Haematology, Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
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  • Anthony McVerry,

    1. Department of Haematology, Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
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  • Maria Gilleece,

    1. Department of Haematology, Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
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  • Inderjeet Dokal

    1. Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, United Kingdom
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  • Communicated by Christopher Mathew

Abstract

The primary pathology in many cases of myelodysplasia (MDS) and acute myeloid leukemia (AML) remains unknown. In some cases, two or more affected members have been identified in the same family. To date, mutations in two genes have been directly implicated: the hematopoietic transcription factors RUNX1 (runt-related transcription factor 1) and CEBPA (CCATT-box enhancer binding protein α). However, there are also other familial cases of MDS/AML where the genetic basis remains unknown. Both MDS, and to a lesser extent AML, have been observed in cases of the bone marrow failure syndrome dyskeratosis congenita, in which telomerase mutations have been identified. Recently, an increased incidence of telomerase reverse transcriptase mutations has been reported in a series of de novo AML. We have now identified novel mutations in the telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT) within 4 of 20 families presenting with familial MDS/AML. Functional analysis has demonstrated that all mutations adversely impact on telomerase activity in vitro, and affected individuals have short telomeres. These families, in conjunction with a review of previously published cases, help to further define the pathological role of telomerase mutations in MDS/AML and have implications for the biology, treatment and screening regimen of de novo cases. Hum Mutat 30:1–7, 2009. © 2009 Wiley-Liss, Inc.

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