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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 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 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 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. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients Jeffrey W. Tyner1,*, Heidi Erickson1,*, Michael W. N. Deininger1, Stephanie G. Willis1, Christopher A. Eide1, Ross L. Levine2,3, Michael C. Heinrich1,4, Norbert Gattermann5, D. Gary Gilliland2,3,6, Brian J. Druker1,6, and Marc M. Loriaux1,7 1 Division of Hematology and Medical Oncology, Oregon Health & Science University (OSHU) Knight Cancer Institute, Portland; 2 Brigham and Women's Hospital, Howard Hughes Medical Institute, and 3 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 4 Portland VA Medical Center, OR; 5 Klinik für Hämatologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; 6 Howard Hughes Medical Institute, Portland, OR; and 7 Department of Pathology, Oregon Health & Science University, Portland Transforming mutations in NRAS and KRAS are thought to play a causative role in the development of numerous cancers, including myeloid malignancies. Although 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. To search for additional, novel RAS mutations, we sequenced all coding exons in NRAS, KRAS, and HRAS in 329 acute myeloid leukemia (AML) patients, 32 chronic myelomonocytic leukemia (CMML) patients, and 96 healthy individuals. We detected 4 "noncanonical" point mutations in 7 patients: N-RasG60E, K-RasV14I, K-RasT74P, and K-RasA146T. All 4 Ras mutants exhibited oncogenic properties in comparison with 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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