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Blood, 15 January 2009, Vol. 113, No. 3, pp. 646-648.
Prepublished online as a Blood First Edition Paper on October 16, 2008; DOI 10.1182/blood-2008-08-170928.
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Submitted August 7, 2008
Accepted September 25, 2008
A specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukaemia
Lyndal Kearney*, David Gonzalez De Castro, Jenny Yeung, Julia Procter, Sharon W. Horsley, Minenori Eguchi-Ishimae, Caroline M. Bateman, Kristina Anderson, Tracy Chaplin, Bryan D. Young, Christine J. Harrison, Helena Kempski, Chi Wai Eric So, Anthony M. Ford, and Mel Greaves
Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, United Kingdom
Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan
Cancer Research UK Centre for Medical Oncology, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, United Kingdom
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom
Paediatric Malignancy Cytogenetics Unit, Great Ormond Street Hospital, London, United Kingdom
* Corresponding author; email: lyndal.kearney{at}icr.ac.uk.
Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukaemia (AMKL) and acute lymphoblastic leukaemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukaemogenesis in DS-ALL we undertook sequencing of candidate genes including FLT3, RAS, PTPN11, BRAF and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12/42 (28%) DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells demonstrated growth factor independence and constitutive activation of the JAK/STAT signalling pathway. High resolution SNP array analysis of nine DS-ALL cases identified additional submicroscopic deletions in key genes including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukaemogenesis, with trisomy 21 as an initiating or first hit and chromosome aneuploidy, gene deletions and activating JAK2 mutations as complementary genetic events.
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