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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. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2008-08-170928v1 113/3/646    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kearney, L. Articles by Greaves, M. Search for Related Content PubMed PubMed Citation Articles by Kearney, L. Articles by Greaves, M. Related Collections Lymphoid Neoplasia Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Brief report Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia Lyndal Kearney1, David Gonzalez De Castro1, Jenny Yeung1, Julia Procter1, Sharon W. Horsley1, Minenori Eguchi-Ishimae1,2, Caroline M. Bateman1, Kristina Anderson1, Tracy Chaplin3, Bryan D. Young3, Christine J. Harrison4, Helena Kempski5, Chi Wai E. So1, Anthony M. Ford1, and Mel Greaves1 1 Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, United Kingdom; 2 Department of Pediatrics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan; 3 Cancer Research UK Centre for Medical Oncology, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, United Kingdom; 4 Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom; and 5 Paediatric Malignancy Cytogenetics Unit, Great Ormond Street Hospital, London, United Kingdom Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis 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 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 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 leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. J. Russell, M. Capasso, I. Vater, T. Akasaka, O. A. Bernard, M. J. Calasanz, T. Chandrasekaran, E. Chapiro, S. Gesk, M. Griffiths, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia Blood, September 24, 2009; 114(13): 2688 - 2698. [Abstract] [Full Text] [PDF] A. C. Xavier, Y. Ge, and J. W. Taub Down Syndrome and Malignancies: A Unique Clinical Relationship: A Paper from the 2008 William Beaumont Hospital Symposium on Molecular Pathology J. Mol. Diagn., September 1, 2009; 11(5): 371 - 380. [Abstract] [Full Text] [PDF] I. Ganmore, G. Smooha, and S. Izraeli Constitutional aneuploidy and cancer predisposition Hum. Mol. Genet., April 15, 2009; 18(R1): R84 - R93. [Abstract] [Full Text] [PDF] S. Malinge, S. Izraeli, and J. D. Crispino Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome Blood, March 19, 2009; 113(12): 2619 - 2628. [Abstract] [Full Text] [PDF]

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