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Blood, 1 July 2005, Vol. 106, No. 1, pp. 311-317. Prepublished online as a Blood First Edition Paper on March 10, 2005; DOI 10.1182/blood-2004-11-4207. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4207v1 106/1/311    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 Schubbert, S. Articles by Shannon, K. M. Search for Related Content PubMed PubMed Citation Articles by Schubbert, S. Articles by Shannon, K. M. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells Suzanne Schubbert, Kenneth Lieuw, Sara L. Rowe, Connie M. Lee, XiaXin Li, Mignon L. Loh, D. Wade Clapp, and Kevin M. Shannon From the Department of Pediatrics, University of California at San Francisco (UCSF), San Francisco, CA; Department of Pediatrics and Herman B. Wells Center, Indiana University School of Medicine, Indianapolis, IN; and Comprehensive Cancer Center, University of California, San Francisco, CA. PTPN11 encodes the protein tyrosine phosphatase SHP-2, which relays signals from growth factor receptors to Ras and other effectors. Germline PTPN11 mutations underlie about 50% of Noonan syndrome (NS), a developmental disorder that is associated with an elevated risk of juvenile myelomonocytic leukemia (JMML). Somatic PTPN11 mutations were recently identified in about 35% of patients with JMML; these mutations introduce amino acid substitutions that are largely distinct from those found in NS. We assessed the functional consequences of leukemia-associated PTPN11 mutations in murine hematopoietic cells. Expressing an E76K SHP-2 protein induced a hypersensitive pattern of granulocyte-macrophage colony-forming unit (CFU-GM) colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) that was dependent on SHP-2 catalytic activity. E76K SHP-2 expression also enhanced the growth of immature progenitor cells with high replating potential, perturbed erythroid growth, and impaired normal differentiation in liquid cultures. In addition, leukemia-associated SHP-2 mutations conferred a stronger phenotype than a germline mutation found in patients with NS. Mutant SHP-2 proteins induce aberrant growth in multiple hematopoietic compartments, which supports a primary role of hyperactive Ras in the pathogenesis of JMML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. Yang, T. Kondo, C. S. Voorhorst, S. C. Nabinger, L. Ndong, F. Yin, E. M. Chan, M. Yu, O. Wurstlin, C. P. Kratz, et al. Increased c-Jun Expression and Reduced GATA2 Expression Promote Aberrant Monocytic Differentiation Induced by Activating PTPN11 Mutants Mol. Cell. Biol., August 15, 2009; 29(16): 4376 - 4393. [Abstract] [Full Text] [PDF] W. Zhang, R. J. Chan, H. Chen, Z. Yang, Y. He, X. Zhang, Y. Luo, F. Yin, A. Moh, L. C. Miller, et al. Negative Regulation of Stat3 by Activating PTPN11 Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia J. Biol. Chem., August 14, 2009; 284(33): 22353 - 22363. [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. W. Tyner, H. Erickson, M. W. N. Deininger, S. G. Willis, C. A. Eide, R. L. Levine, M. C. Heinrich, N. Gattermann, D. G. Gilliland, B. J. Druker, et al. High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients Blood, February 19, 2009; 113(8): 1749 - 1755. [Abstract] [Full Text] [PDF] S. Wang, W.-M. Yu, W. Zhang, K. R. McCrae, B. G. Neel, and C.-K. Qu Noonan Syndrome/Leukemia-associated Gain-of-function Mutations in SHP-2 Phosphatase (PTPN11) Enhance Cell Migration and Angiogenesis J. Biol. Chem., January 9, 2009; 284(2): 913 - 920. [Abstract] [Full Text] [PDF] M. I. Kontaridis, W. Yang, K. K. Bence, D. Cullen, B. Wang, N. Bodyak, Q. Ke, A. Hinek, P. M. Kang, R. Liao, et al. Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways Circulation, March 18, 2008; 117(11): 1423 - 1435. [Abstract] [Full Text] [PDF] C. Zhu, S. Lindsey, I. Konieczna, and E. A. Eklund Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation J. Leukoc. Biol., March 1, 2008; 83(3): 680 - 691. [Abstract] [Full Text] [PDF] N. Ohnishi, H. Yuasa, S. Tanaka, H. Sawa, M. Miura, A. Matsui, H. Higashi, M. Musashi, K. Iwabuchi, M. Suzuki, et al. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse PNAS, January 22, 2008; 105(3): 1003 - 1008. [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] C. Flotho, C. P. Kratz, and C. M. Niemeyer How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia Haematologica, November 1, 2007; 92(11): 1441 - 1446. [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] S. Lindsey, W. Huang, H. Wang, E. Horvath, C. Zhu, and E. A. Eklund Activation of SHP2 Protein-tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91PHOX and p67PHOX J. Biol. Chem., January 26, 2007; 282(4): 2237 - 2249. [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] B. D. Gelb and M. Tartaglia Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R220 - R226. [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] 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] H. Keilhack, F. S. David, M. McGregor, L. C. Cantley, and B. G. Neel Diverse Biochemical Properties of Shp2 Mutants: IMPLICATIONS FOR DISEASE PHENOTYPES J. Biol. Chem., September 2, 2005; 280(35): 30984 - 30993. [Abstract] [Full Text] [PDF]

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