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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2325-2331. Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-09-3287. This Article Full Text (PDF) All Versions of this Article: 2003-09-3287v1 103/6/2325    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 Loh, M. L Articles by Shannon, K. M Search for Related Content PubMed PubMed Citation Articles by Loh, M. L Articles by Shannon, K. M Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted September 25, 2003 Accepted November 11, 2003 Somatic mutations in PTPN11 implicate the protein tyrosine phosphatase SHP-2 in leukemogenesis Mignon L Loh*, Shashaank Vattikuti, Suzanne Schubbert, Melissa G Reynolds, Elaine Carlson, Kenneth H Lieuw, Jennifer W Cheng, Connie M Lee, David Stokoe, Jeannette M Bonifas, Nicole P Curtiss, Jason Gotlib, Soheil Meshinchi, Michelle M Le Beau, Peter D Emanuel, and Kevin M Shannon Department of Pediatrics, University of California, San Francisco, CA, USA; Comprehensive Cancer Center, University of California, San Francisco, CA, USA Program in Human Genetics, University of California, San Francisco, CA, USA Cancer Research Institute, University of California, San Francisco, CA, USA Division of Hematology, Stanford University, Stanford, CA, USA Department of Pediatrics, University of Washington, Seattle, WA, USA Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA Division of Hematology/Oncology, University of Alabama, Birmingham, AL, USA * Corresponding author; email: lohm{at}itsa.ucsf.edu. The PTPN11 gene encodes SHP-2, a non-receptor tyrosine PTPase that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome(NS), a developmental disorder characterized by cardiac and skeletal defects, and dysmorphism. NS is also associated with a spectrum of hematologic disorders including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that germline and somatic PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Somatic missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but were less common in other myeloid malignancies. Almost all of the mutations are located in the N-SH2 domain, and are predicted to activate SHP-2 PTPase activity. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth-factor independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors ERK or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these leukemia-associated mutant proteins interact with the Ras and other effectors to deregulate myeloid growth control. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mutated SHP and AML in leukemias Gen-Sheng Feng Blood 2004 103: 1982-1983. [Full Text] [PDF] This article has been cited by other articles: A. K. Purdy and K. S. 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