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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3737-3742. Prepublished online as a Blood First Edition Paper on January 11, 2005; DOI 10.1182/blood-2004-10-4002. This Article Full Text (PDF) All Versions of this Article: 2004-10-4002v1 105/9/3737    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 Chan, R. J Articles by Kapur, R. Search for Related Content PubMed PubMed Citation Articles by Chan, R. J Articles by Kapur, R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 19, 2004 Accepted January 6, 2005 Human somatic PTPN11 mutations induce hematopoietic cell hypersensitivity to granulocyte-macrophage colony stimulating factor Rebecca J Chan*, Melissa B Leedy, Veerendra Munugalavadla, Cara S Voorhorst, Yanjun Li, Menggang Yu, and Reuben Kapur Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medicine (Division of Biostatistics), Indiana University School of Medicine, Indianapolis, IN, USA Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA * Corresponding author; email: rchan{at}iupui.edu. Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterized by hypersensitivity of hematopoietic progenitors to GM-CSF. Mutations in PTPN11, which encodes the protein tyrosine phosphatase Shp-2, are common in JMML. We hypothesized that PTPN11 mutations induce hypersensitivity of hematopoietic progenitors to GM-CSF and confer increased GM-CSF-stimulated phospho-Erk levels. To test this hypothesis, the WT and three mutant Ptpn11 cDNAs (E76K, D61V, and D61Y) were transduced into murine bone marrow cells to examine GM-CSF-stimulated CFU-GM growth, macrophage progenitor proliferation, and activation of the Ras signaling pathway. Expression of the Shp-2 mutants induced progenitor cell hypersensitivity to GM-CSF compared to cells transduced with vector alone or WT Shp-2. Macrophage progenitors expressing the Shp-2 mutants displayed both basal and GM-CSF-stimulated hyperproliferation compared to cells transduced with vector alone or WT Shp-2. Consistently, macrophage progenitors transduced with the Shp-2 mutants demonstrated constitutively elevated phospho-Erk levels and sustained activation of phospho-Erk following GM-CSF stimulation compared to vector alone or WT Shp-2. These data support the hypothesis that PTPN11 mutations induce hematopoietic progenitor hypersensitivity to GM-CSF due to hyperactivation of the Ras signaling axis and provide a basis for the GM-CSF signaling pathway as a target for rational drug design in JMML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Heuser, L. M. Sly, B. Argiropoulos, F. Kuchenbauer, C. Lai, A. Weng, M. Leung, G. Lin, C. Brookes, S. Fung, et al. Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal Blood, November 5, 2009; 114(19): 3983 - 3993. [Abstract] [Full Text] [PDF] Z. Yang, T. Kondo, C. S. Voorhorst, S. C. Nabinger, L. Ndong, F. 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