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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3945-3952. Prepublished online as a Blood First Edition Paper on December 27, 2006; DOI 10.1182/blood-2006-09-047530. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-09-047530v1 109/9/3945    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 Van Meter, M. E. M. Articles by Braun, B. S. Search for Related Content PubMed PubMed Citation Articles by Van Meter, M. E. M. Articles by Braun, B. S. Related Collections Hematopoiesis and Stem Cells Neoplasia Signal Transduction Stem Cells in Hematology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells Margaret E. M. Van Meter1, Ernesto Díaz-Flores1, Joehleen A. Archard1, Emmanuelle Passegué2,3, Jonathan M. Irish4, Nikesh Kotecha4, Garry P. Nolan4, Kevin Shannon1, and Benjamin S. Braun1 Departments of1 Pediatrics and 2 Medicine and 3 the Program in Developmental and Stem Cell Biology, University of California, San Francisco, CA; 4 Departments of Microbiology and Immunology, and Bioinformatics, Stanford University School of Medicine, Stanford, CA Defining how cancer-associated mutations perturb signaling networks in stem/progenitor populations that are integral to tumor formation and maintenance is a fundamental problem with biologic and clinical implications. Point mutations in RAS genes contribute to many cancers, including myeloid malignancies. We investigated the effects of an oncogenic KrasG12D allele on phosphorylated signaling molecules in primary c-kit+ lin–/low hematopoietic stem/progenitor cells. Comparison of wild-type and KrasG12D c-kit+ lin–/low cells shows that K-RasG12D expression causes hyperproliferation in vivo and results in abnormal levels of phosphorylated STAT5, ERK, and S6 under basal and stimulated conditions. Whereas KrasG12D cells demonstrate hyperactive signaling after exposure to granulocyte-macrophage colony-stimulating factor, we unexpectedly observe a paradoxical attenuation of ERK and S6 phosphorylation in response to stem cell factor. These studies provide direct biochemical evidence that cancer stem/progenitor cells remodel signaling networks in response to oncogenic stress and demonstrate that multi-parameter flow cytometry can be used to monitor the effects of targeted therapeutics in vivo. This strategy has broad implications for defining the architecture of signaling networks in primary cancer cells and for implementing stem cell–targeted interventions. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Wahlstrom, B. A. Cutts, M. Liu, A. Lindskog, C. Karlsson, A.-K. M. Sjogren, K. M. E. Andersson, S. G. Young, and M. O. Bergo Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease Blood, August 15, 2008; 112(4): 1357 - 1365. [Abstract] [Full Text] [PDF] B. S. Braun and K. Shannon Targeting Ras in Myeloid Leukemias Clin. Cancer Res., April 15, 2008; 14(8): 2249 - 2252. [Abstract] [Full Text] [PDF] S. Schubbert, G. Bollag, N. Lyubynska, H. Nguyen, C. P. Kratz, M. Zenker, C. M. Niemeyer, A. Molven, and K. Shannon Biochemical and Functional Characterization of Germ Line KRAS Mutations Mol. Cell. Biol., November 15, 2007; 27(22): 7765 - 7770. [Abstract] [Full Text] [PDF]

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