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Blood, 19 February 2009, Vol. 113, No. 8, pp. 1749-1755. Prepublished online as a Blood First Edition Paper on December 15, 2008; DOI 10.1182/blood-2008-04-152157. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-04-152157v1 113/8/1749    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tyner, J. W Articles by Loriaux, M. M Search for Related Content PubMed PubMed Citation Articles by Tyner, J. W Articles by Loriaux, M. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 17, 2008 Accepted November 10, 2008 High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients Jeffrey W Tyner, Heidi Erickson, Michael W.N. Deininger, Stephanie G. Willis, Christopher A. Eide, Ross L Levine, Michael C. Heinrich, Norbert Gattermann, D Gary Gilliland, Brian J. Druker, and Marc M Loriaux* Division of Hematology and Medical Oncology, Oregon Health & Science University, Knight Cancer Institute, Portland, OR, United States Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States Portland VA Medical Center, Portland, OR, United States Klinik fur Hamatologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States Howard Hughes Medical Institute, Portland, OR, United States Department of Pathology, Oregon Health & Science University, Portland, OR, United States * Corresponding author; email: loriauxm{at}ohsu.edu. Transforming mutations in NRAS, KRAS, and HRAS have been found in numerous malignancies, and these mutant alleles are thought to play a causative role in the development of cancer. In particular, myeloid malignancies have been shown to have a high incidence of transforming mutations in NRAS and KRAS. While mutations at amino acids 12, 13, or 61 account for the majority of oncogenic Ras variants, we hypothesized that less frequent mutations at alternate residues may account for disease in some patients with cancer of unexplained genetic etiology. Thus, to search for additional, novel RAS mutations, we sequenced all coding exons in NRAS, KRAS, and HRAS in 392 AML patients, 32 CMML patients, and 96 normal individuals. We detected four "non-canonical" point mutations in seven patients: N-RasG60E, K-RasV14I, K-RasT74P, and K-RasA146T. All four Ras mutants exhibited oncogenic properties in comparison to wild-type Ras in biochemical and functional assays. The presence of transforming RAS mutations outside of positions 12, 13, and 61 reveals that alternate mechanisms of transformation by RAS may be overlooked in screens designed to detect only the most common RAS mutations. Our results suggest that RAS mutations may play a greater role in leukemogenesis than currently believed and indicate that high-throughput screening for mutant RAS alleles in cancer should include analysis of the entire RAS coding region. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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