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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 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 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 Chan, R. J. Articles by Kapur, R. Search for Related Content PubMed PubMed Citation Articles by Chan, R. J. Articles by Kapur, R. Related Collections Signal Transduction Hematopoiesis Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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 From the Departments of Pediatrics, Medical & Molecular Genetics, Biochemistry & Molecular Biology, Medicine (Division of Biostatistics), and the Herman B Wells Center for Pediatric Research; Indiana University School of Medicine, Indianapolis, IN. Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterized by hypersensitivity of hematopoietic progenitors to granulocyte-macrophage colony-stimulating factor (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–extracellular signal-regulated kinase (Erk) levels. To test this hypothesis, the wild-type (WT) and 3 mutant Ptpn11 cDNAs (E76K, D61V, and D61Y) were transduced into murine bone marrow cells to examine GM-CSF–stimulated granulocyte-macrophage colony-forming unit (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 with 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 with 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 with 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: S. Eminaga and A. M. Bennett Noonan Syndrome-associated SHP-2/Ptpn11 Mutants Enhance SIRP{alpha} and PZR Tyrosyl Phosphorylation and Promote Adhesion-mediated ERK Activation J. Biol. Chem., May 30, 2008; 283(22): 15328 - 15338. [Abstract] [Full Text] [PDF] M. M. Loriaux, R. L. Levine, J. W. Tyner, S. Frohling, C. Scholl, E. P. Stoffregen, G. Wernig, H. Erickson, C. A. Eide, R. Berger, et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia Blood, May 1, 2008; 111(9): 4788 - 4796. [Abstract] [Full Text] [PDF] Y. Ren, Z. Chen, L. Chen, N. T. Woods, G. W. Reuther, J. Q. Cheng, H.-g. Wang, and J. Wu Shp2E76K Mutant Confers Cytokine-independent Survival of TF-1 Myeloid Cells by Up-regulating Bcl-XL J. Biol. Chem., December 14, 2007; 282(50): 36463 - 36473. [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] D. Barua, J. R. Faeder, and J. M. Haugh Structure-Based Kinetic Models of Modular Signaling Protein Function: Focus on Shp2 Biophys. J., April 1, 2007; 92(7): 2290 - 2300. [Abstract] [Full Text] [PDF] W. Huang, E. Horvath, and E. A. Eklund PU.1, Interferon Regulatory Factor (IRF) 2, and the Interferon Consensus Sequence-binding Protein (ICSBP/IRF8) Cooperate to Activate NF1 Transcription in Differentiating Myeloid Cells J. Biol. Chem., March 2, 2007; 282(9): 6629 - 6643. [Abstract] [Full Text] [PDF] R. J. Chan and G.-S. Feng PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase Blood, February 1, 2007; 109(3): 862 - 867. [Abstract] [Full Text] [PDF] J. Chen, W.-M. Yu, H. Daino, H. E. Broxmeyer, B. J. Druker, and C.-K. Qu SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl Blood, January 15, 2007; 109(2): 778 - 785. [Abstract] [Full Text] [PDF] W. Huang, G. Saberwal, E. Horvath, C. Zhu, S. Lindsey, and E. A. Eklund Leukemia-Associated, Constitutively Active Mutants of SHP2 Protein Tyrosine Phosphatase Inhibit NF1 Transcriptional Activation by the Interferon Consensus Sequence Binding Protein. Mol. Cell. Biol., September 1, 2006; 26(17): 6311 - 6332. [Abstract] [Full Text] [PDF] L. Chen, S.-S. Sung, M. L. R. Yip, H. R. Lawrence, Y. Ren, W. C. Guida, S. M. Sebti, N. J. Lawrence, and J. Wu Discovery of a Novel Shp2 Protein Tyrosine Phosphatase Inhibitor Mol. Pharmacol., August 1, 2006; 70(2): 562 - 570. [Abstract] [Full Text] [PDF] A. Verbrugge, T. de Ruiter, C. Geest, P. J. Coffer, and L. Meyaard Differential expression of leukocyte-associated Ig-like receptor-1 during neutrophil differentiation and activation J. Leukoc. Biol., April 1, 2006; 79(4): 828 - 836. [Abstract] [Full Text] [PDF] M. I. Kontaridis, K. D. Swanson, F. S. David, D. Barford, and B. G. Neel PTPN11 (Shp2) Mutations in LEOPARD Syndrome Have Dominant Negative, Not Activating, Effects J. Biol. Chem., March 10, 2006; 281(10): 6785 - 6792. [Abstract] [Full Text] [PDF] W.-M. Yu, H. Daino, J. Chen, K. D. Bunting, and C.-K. Qu Effects of a Leukemia-associated Gain-of-Function Mutation of SHP-2 Phosphatase on Interleukin-3 Signaling J. Biol. Chem., March 3, 2006; 281(9): 5426 - 5434. [Abstract] [Full Text] [PDF] R. Xu, Y. Yu, S. Zheng, X. Zhao, Q. Dong, Z. He, Y. Liang, Q. Lu, Y. Fang, X. Gan, et al. Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia Blood, November 1, 2005; 106(9): 3142 - 3149. [Abstract] [Full Text] [PDF] C. P. Kratz, C. M. Niemeyer, R. P. Castleberry, M. Cetin, E. Bergstrasser, P. D. Emanuel, H. Hasle, G. Kardos, C. Klein, S. Kojima, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease Blood, September 15, 2005; 106(6): 2183 - 2185. [Abstract] [Full Text] [PDF] S. Schubbert, K. Lieuw, S. L. Rowe, C. M. Lee, X. Li, M. L. Loh, D. W. Clapp, and K. M. Shannon Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells Blood, July 1, 2005; 106(1): 311 - 317. [Abstract] [Full Text] [PDF]

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