Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor

摘要: Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterized by hypersensitivity hematopoietic progenitors to granulocyte-macrophage colony-stimulating factor (GM-CSF). Mutations in PTPN11, which encodes the protein tyrosine phosphatase Shp-2, are common JMML. We hypothesized that PTPN11 mutations induce GM-CSF and confer increased GM-CSF–stimulated phospho–extracellular signal-regulated kinase (Erk) levels. To test this hypothesis, wild-type (WT) 3 mutant Ptpn11 cDNAs (E76K, D61V, D61Y) were transduced into murine bone marrow cells examine colony-forming unit (CFU-GM) growth, macrophage progenitor proliferation, activation Ras signaling pathway. Expression Shp-2 mutants induced cell compared with vector alone or WT Shp-2. Macrophage expressing displayed both basal hyperproliferation Consistently, demonstrated constitutively elevated phospho-Erk levels sustained following stimulation These data support hypothesis due hyperactivation axis provide basis for pathway as target rational drug design