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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4788-4796. Prepublished online as a Blood First Edition Paper on February 5, 2008; DOI 10.1182/blood-2007-07-101394. This Article Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2007-07-101394v1 111/9/4788    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 Loriaux, M. M Articles by Druker, B. J Search for Related Content PubMed PubMed Citation Articles by Loriaux, M. M Articles by Druker, B. J Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 30, 2007 Accepted January 27, 2008 High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia Marc M Loriaux, Ross L Levine, Jeffrey W Tyner, Stefan Frohling, Claudia Scholl, Eric P Stoffregen, Gerlinde Wernig, Heidi Erickson, Christopher A Eide, Roland Berger, Olivier A. Bernard, James D. Griffin, Richard M Stone, Benjamin Lee, Matthew Meyerson, Michael C Heinrich, Michael W Deininger, D Gary Gilliland, and Brian J Druker* Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, OR, United States Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States INSERM, IRNEM, Hopital Necker, Paris, France Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States Broad Institute of Harvard and MIT, Boston, MA, United States Portland VA Medical Center, Portland, OR, United States Howard Hughes Medical Institute, Boston, MA, United States Howard Hughes Medical Institute, Portland, OR, United States * Corresponding author; email: drukerb{at}ohsu.edu. To determine whether aberrantly activated tyrosine kinases other than FLT3 and c-KIT contribute to acute myeloid leukemia (AML) pathogenesis, we employed high throughput (HT) DNA sequence analysis to screen exons encoding the activation loop and juxtamembrane domains of 85 tyrosine kinase genes in 192 AML patients without FLT3 or c-KIT mutations. The screen identified 30 non-synonymous sequence variations in 22 different kinases not previously reported in single-nucleotide polymorphism databases. These included a novel FLT3 activating allele and a previously described activating mutation in MET (METT1010I). The majority of the novel sequence variants were stably expressed in factor-dependent Ba/F3 cells. Apart from one FLT3 allele, none of the novel variants showed constitutive phosphorylation by immunoblot analysis and none transformed Ba/F3 cells to factor-independent growth. These findings indicate the majority of these alleles are not potent tyrosine kinase activators in this cellular context and that a significant proportion of non-synonymous sequence variants identified in HT DNA sequencing screens may not have functional significance. Though some sequence variants may represent SNPs, these data are consistent with recent reports that a significant fraction of such sequence variants are "passenger" rather than "driver" alleles and underscore the importance of functional assessment of candidate disease alleles. 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: O. Abdel-Wahab, A. Mullally, C. Hedvat, G. Garcia-Manero, J. Patel, M. Wadleigh, S. Malinge, J. Yao, O. Kilpivaara, R. Bhat, et al. 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