Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia

L. Kearney, D.G. De Castro, J. Yeung, J. Procter, S.W. Horsley, M. Eguchi-Ishimae, C.M. Bateman, K. Anderson, T. Chaplin, B.D. Young, C.J. Harrison, H. Kempski, C.W.E. So, A.M. Ford, M. Greaves

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Abstract

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. (Blood. 2009; 113: 646-648)
Original languageEnglish
Pages (from-to)646-648
Number of pages3
JournalBlood
Volume113
Issue number3
DOIs
Publication statusPublished - 15 Jan 2009

Keywords

  • MYELOPROLIFERATIVE DISORDERS
  • MEGAKARYOBLASTIC LEUKEMIA
  • CHILDHOOD
  • GATA1
  • DIFFERENTIATION
  • CHILDREN
  • DISEASE
  • LESIONS
  • FLT3

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    Kearney, L., De Castro, D. G., Yeung, J., Procter, J., Horsley, S. W., Eguchi-Ishimae, M., Bateman, C. M., Anderson, K., Chaplin, T., Young, B. D., Harrison, C. J., Kempski, H., So, C. W. E., Ford, A. M., & Greaves, M. (2009). Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood, 113(3), 646-648. https://doi.org/10.1182/blood-2008-08-170928