Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells

S Schubbert, K Lieuw, SL Rowe, CM Lee, XX Li… - Blood, 2005 - ashpublications.org
S Schubbert, K Lieuw, SL Rowe, CM Lee, XX Li, ML Loh, DW Clapp, KM Shannon
Blood, 2005ashpublications.org
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 …
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.
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