title: Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of California at San Francisco, 513 Parnassus Ave, HSE 302, San Francisco, CA 94143, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Schubbert
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lieuw
authors.forename: Sara L
authors.initials: SL
authors.lastname: Rowe
authors.forename: Connie M
authors.initials: CM
authors.lastname: Lee
authors.forename: Xiaxin
authors.initials: X
authors.lastname: Li
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shannon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D005260:Female; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; D018631:ras Proteins