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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4797-4808. Prepublished online as a Blood First Edition Paper on February 12, 2008; DOI 10.1182/blood-2007-09-113027. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2007-09-113027v1 111/9/4797    most recent Alert me when this article is cited Alert me if a correction is posted 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 Tomasson, M. H Articles by Ley, T. J Search for Related Content PubMed PubMed Citation Articles by Tomasson, M. H Articles by Ley, T. J Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 17, 2007 Accepted December 19, 2007 Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia Michael H Tomasson*, Zhifu Xiang, Richard Walgren, Yu Zhao, Yumi Kasai, Tracie Miner, Rhonda E Ries, Olga Lubman, Daved Fremont, Michael D McLellan, Jacqueline E Payton, Peter Westervelt, John F DiPersio, Daniel C Link, Matthew J Walter, Timothy A Graubert, Mark Watson, Jack Baty, Sharon Heath, William D Shannon, Rakesh Nagarajan, Clara D. Bloomfield, Elaine R. Mardis, Richard K Wilson, and Timothy J Ley Division of Oncology, Department of Medicine, Washington University, St. Louis, MO, United States Genome Sequencing Center, Washington University, St. Louis, MO, United States Department of Pathology and Immunology, Washington University, St. Louis, MO, United States Division of Biostatistics, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States Cancer and Leukemia Group B, Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States * Corresponding author; email: tomasson{at}wustl.edu. Activating mutations in tyrosine kinase (TK) genes (e.g. FLT3 and KIT) are found in more than 30% of patients with de novo acute myeloid leukemia (AML); many groups have speculated that mutations in other TK genes may be present in the remaining 70%. We performed high-throughput re-sequencing of the kinase domains of 26 TK genes (11 receptor TK and 15 cytoplasmic TK) that are expressed in most AML patients, using genomic DNA from the bone marrow (tumor) and matched skin biopsy samples ("germline") from 94 patients with de novo AML; sequence variants were validated in an additional 94 AML tumor samples (14.3 million base pairs of sequence were obtained and analyzed). We identified known somatic mutations in FLT3, KIT, and JAK2 TK genes at the expected frequencies, and found four novel somatic mutations, JAK1V623A, JAK1T478S, DDR1A803V and NTRK1S677N, once each in four respective patients out of 188 tested. We also identified novel germline sequence changes encoding amino acid substitutions (i.e. non-synonymous changes) in 14 TK genes, including TYK2, which had the largest number of non-synonymous sequence variants (11 total detected). Additional studies will be required to define the roles that these somatic and germline TK gene variants play in AML pathogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Hitchhikers' guide to the leukemia genome Nicholas C. P. Cross Blood 2008 111: 4428-4429. [Full Text] [PDF] This article has been cited by other articles: H. J. M. de Jonge, E. S. J. M. de Bont, P. J. M. Valk, J. J. Schuringa, M. Kies, C. M. Woolthuis, R. Delwel, N. J. G. M. Veeger, E. Vellenga, B. Lowenberg, et al. AML at older age: age-related gene expression profiles reveal a paradoxical down-regulation of p16INK4A mRNA with prognostic significance Blood, October 1, 2009; 114(14): 2869 - 2877. [Abstract] [Full Text] [PDF] O. Fuster, E. Barragan, P. Bolufer, J. Cervera, M. J. Larrayoz, A. Jimenez-Velasco, J. Martinez-Lopez, A. Valencia, F. Moscardo, and M. A. Sanz Rapid Detection of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia Using High-Resolution Melting Analysis J. Mol. Diagn., September 1, 2009; 11(5): 458 - 463. [Abstract] [Full Text] [PDF] Y. Shiotsu, H. Kiyoi, Y. Ishikawa, R. Tanizaki, M. Shimizu, H. Umehara, K. Ishii, Y. Mori, K. Ozeki, Y. Minami, et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation Blood, August 20, 2009; 114(8): 1607 - 1617. [Abstract] [Full Text] [PDF] M. J. Walter, J. E. Payton, R. E. Ries, W. D. Shannon, H. Deshmukh, Y. Zhao, J. Baty, S. Heath, P. Westervelt, M. A. Watson, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes PNAS, August 4, 2009; 106(31): 12950 - 12955. [Abstract] [Full Text] [PDF] O. Abdel-Wahab, A. Mullally, C. Hedvat, G. Garcia-Manero, J. Patel, M. Wadleigh, S. Malinge, J. Yao, O. Kilpivaara, R. Bhat, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies Blood, July 2, 2009; 114(1): 144 - 147. [Abstract] [Full Text] [PDF] E. J. Fox, J. J. Salk, and L. A. Loeb Cancer Genome Sequencing--An Interim Analysis Cancer Res., June 15, 2009; 69(12): 4948 - 4950. [Abstract] [Full Text] [PDF] J. A. Knight, A. D. Skol, A. Shinde, D. Hastings, R. A. Walgren, J. Shao, T. R. Tennant, M. Banerjee, J. M. Allan, M. M. Le Beau, et al. Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility Blood, May 28, 2009; 113(22): 5575 - 5582. [Abstract] [Full Text] [PDF] J. W. Tyner, M. W. Deininger, M. M. Loriaux, B. H. Chang, J. R. Gotlib, S. G. Willis, H. Erickson, T. Kovacsovics, T. O'Hare, M. C. Heinrich, et al. RNAi screen for rapid therapeutic target identification in leukemia patients PNAS, May 26, 2009; 106(21): 8695 - 8700. [Abstract] [Full Text] [PDF] J. V. Abella and M. 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