SEARCH:   Advanced

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 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 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 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 Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Genomics Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia Marc M. Loriaux*,1, Ross L. Levine*,2,3, Jeffrey W. Tyner1, Stefan Fröhling2, Claudia Scholl2, Eric P. Stoffregen1, Gerlinde Wernig2, Heidi Erickson1, Christopher A. Eide1, Roland Berger4, Olivier A. Bernard4, James D. Griffin3, Richard M. Stone3, Benjamin Lee3, Matthew Meyerson3,5, Michael C. Heinrich6, Michael W. Deininger1, D. Gary Gilliland2,3,7, and Brian J. Druker1,7 1 Division of Hematology and Medical Oncology, Oregon Health & Science University Cancer Institute, Portland, OR; 2 Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; 3 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 4 Inserm E0210, Institut Fédératif de Recherche Necker-Enfants Malades (IRNEM), Hopital Necker, Paris, France; 5 Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Boston, MA; 6 Portland Veterans Affairs (VA) Medical Center, Portland, OR; and 7 Howard Hughes Medical Institute, Boston, MA To determine whether aberrantly activated tyrosine kinases other than FLT3 and c-KIT contribute to acute myeloid leukemia (AML) pathogenesis, we used high-throughput (HT) DNA sequence ana-lysis to screen exons encoding the activation loop and juxtamembrane domains of 85 tyrosine kinase genes in 188 AML patients without FLT3 or c-KIT mutations. The screen identified 30 nonsynonymous sequence variations in 22 different kinases not previously reported in single-nucleotide polymorphism (SNP) databases. These included a novel FLT3 activating allele and a previously described activating mutation in MET (METT1010I). The majority of 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 nonsynonymous sequence variants identified in HT DNA sequencing screens may not have functional significance. Although 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. 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. 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] Z. Li, G. Beutel, M. Rhein, J. Meyer, C. Koenecke, T. Neumann, M. Yang, J. Krauter, N. von Neuhoff, M. Heuser, et al. High-affinity neurotrophin receptors and ligands promote leukemogenesis Blood, February 26, 2009; 113(9): 2028 - 2037. [Abstract] [Full Text] [PDF] J. W. Tyner, H. Erickson, M. W. N. Deininger, S. G. Willis, C. A. Eide, R. L. Levine, M. C. Heinrich, N. Gattermann, D. G. Gilliland, B. J. Druker, et al. High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients Blood, February 19, 2009; 113(8): 1749 - 1755. [Abstract] [Full Text] [PDF] B. J. Wouters, B. Lowenberg, and R. Delwel A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects Blood, January 8, 2009; 113(2): 291 - 298. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020