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Title: | A specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukaemia |
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List of authors: | Kearney, L; Gonzalez-de Castro, D; Yeung, J; Procter, J; Horsley, SW; Eguchi-Ishimae, M; Bateman, CM; Anderson, K; Chaplin, T; Young, BD; Harrison, CJ; Kempski, H; So, CWE; Ford, AM; Mel Greaves, M |
Reference: | Blood, 2008 (Epub ahead of print) |
Year of Publication: | 2008 |
Abstract: | 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. |
PMID: | 18927438 |
Supplementary Data: |
Supplementary Tables Table S3: High-resolution SNP array analysis of DS-ALL cases showing regions of loss or gain SNP Genotype Data The SNP Genotype Data Tables for the patients detailed in Supplementary Table S3 are listed below. The following key deciphers the file names. Key: PT = Patient PRES = Leukaemic bone marrow/blood at presentation of ALL REM = Remission bone marrow/blood as germline control NSP = Affymetrix 250K Nsp1 array STY = Affymetrix 250K Sty1 array
PT#1_PRES_STY_CHP PT#1_REM_NSP_CHP PT#1_REM_STY_CHP PT#3_PRES_NSP_CHP PT#3_PRES_STY_CHP PT#4_PRES_NSP_CHP PT#4_PRES_STY_CHP PT#4_REM 250K NSP_CHP PT#4_REM 250K STY_CHP PT#13_PRES_NSP_CHP PT#13_PRES_STY_CHP PT#13_REM_NSP_CHP PT#13_REM_STY_CHP PT#14_PRES_NSP_CHP PT#14_PRES_STY_CHP PT#15_PRES_NSP_CHP PT#15_PRES_STY_CHP PT#15_REM_NSP_CHP PT#15_REM_STY_CHP PT#16_PRES_NSP_CHP PT#16_PRES_STY_CHP PT#16_REM_NSP_CHP PT#16_REM_STY_CHP PT#17_PRES_NSP_CHP PT#17_PRES_STY_CHP PT#17_REM 250K NSP_CHP PT#17_REM 250K STY_CHP PT#18_PRES_NSP_CHP PT#18_PRES_STY_CHP PT#18_REM 250K NSP_CHP PT#18_REM 250K STY_CHP |