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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2480-2489.
Prepublished online as a Blood First Edition Paper on December 4, 2003; DOI 10.1182/blood-2003-10-3383.
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Natural history of GATA1 mutations in Down syndrome
Momin Ahmed,
Alexander Sternberg,
Georgina Hall,
Angela Thomas,
Owen Smith,
Aengus O'Marcaigh,
Robert Wynn,
Richard Stevens,
Michael Addison,
Derek King,
Barbara Stewart,
Brenda Gibson,
Irene Roberts, and
Paresh Vyas
From the Departments of Hematology and Pediatric Hematology and Medical Research Council (MRC) Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, and the Department of Community Paediatrics, Oxford Radcliffe Hospital, Oxford, United Kingdom; the Department of Paediatric Hematology, Royal Hospital for Sick Children, Edinburgh, Scotland; the Department of Paediatric Hematology, Our Lady Hospital for Sick Children, Dublin, Ireland; the Department of Paediatric Hematology, Royal Manchester Children's University Hospital, Manchester, United Kingdom; the Department of Paediatric Hematology, Aberdeen Children's Hospital, Aberdeen, United Kingdom; the Department of Hematology, Royal Hospital for Sick Children Yorkhill Hospital National Health Service (NHS) Trust, Glasgow, Scotland; and the Department of Hematology, Hammersmith Hospital, Imperial College, London, United Kingdom.
Acquired mutations in megakaryocyte transcription factor GATA1 have recently been reported in Down syndrome (DS), transient myeloproliferative disorder (TMD), and acute megakaryoblastic leukemia (AMKL). To provide novel insight into GATA1 mutations in DS, genomic DNA was assayed from 12 AMKL and 4 TMD cases (including neonatal, prediagnosis samples in 4 of 16), neonatal blood spots from 21 DS children without clinically evident TMD or AMKL, and 62 non-DS cord blood samples, using techniques not previously employed with such samples. GATA1 mutations were present in all TMD and AMKL cases and at birth in 3 of 4 children without known clinical TMD, who later developed AMKL. They were present at birth in 2 of 21 DS neonates, who have not yet, but could still, develop AMKL (now 26 and 31 months). GATA1 mutations were not detected in 62 non-DS cord blood samples. In 4 AMKL patients multiple independent GATA1 mutations were observed. These data show GATA1 mutations occur in utero in most DS TMD and AMKL, that they may occur without clinical signs of disease, and that multiple separate GATA1 mutant clones can occur in an individual. The findings have implications for pathogenesis of DS TMD and AMKL and highlight parallels between DS AMKL and other childhood leukemias.
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