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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 18, 2006 Accepted December 18, 2006 K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells Margaret E. M. Van Meter, Ernesto Diaz-Flores, Joehleen A. Archard, Emmanuelle Passegue, Jonathan M. Irish, Nikesh Kotecha, Garry P. Nolan, Kevin Shannon, and Benjamin S. Braun* Departments of Pediatrics and Medicine, and the Program in Developmental and Stem Cell Biology, University of California, San Francisco, CA Departments of Microbiology & Immunology, and Bioinformatics, Stanford University School of Medicine, Stanford, CA * Corresponding author; email: braunb{at}peds.ucsf.edu. 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 K-RasG12D 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 K-RasG12D 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 multiparameter 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: T. B. Campbell, S. Basu, G. Hangoc, W. Tao, and H. E. Broxmeyer Overexpression of Rheb2 enhances mouse hematopoietic progenitor cell growth while impairing stem cell repopulation Blood, October 15, 2009; 114(16): 3392 - 3401. [Abstract] [Full Text] [PDF] G. Chan, D. Kalaitzidis, T. Usenko, J. L. Kutok, W. Yang, M. G. Mohi, and B. G. Neel Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis Blood, April 30, 2009; 113(18): 4414 - 4424. [Abstract] [Full Text] [PDF] J. Zuber, I. Radtke, T. S. Pardee, Z. Zhao, A. R. Rappaport, W. Luo, M. E. McCurrach, M.-M. Yang, M. E. Dolan, S. C. Kogan, et al. 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