Negative Regulation of Stat3 by ActivatingPTPN11Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia

摘要: Noonan syndrome (NS) is an autosomal dominant congenital disorder characterized by multiple birth defects including heart and myeloproliferative disease (MPD). Approximately 50% of NS patients have germline gain-of-function mutations in PTPN11, which encodes the protein-tyrosine phosphatase, Shp2. We provide evidence that conditional ablation Stat3 hematopoietic cells cardiac valvular tissues leads to myeloid progenitor hyperplasia pulmonary stenosis due leaflet thickening, respectively. Consistently, STAT3 activation significantly compromised peripheral blood from bearing Shp2-activating mutations. Biochemical functional analyses demonstrate activated Shp2 able down-regulate Tyr(P)-Stat3 constitutively active rescues activating mutant Shp2-induced granulocyte-macrophage colony-stimulating factor hypersensitivity bone marrow cells. Collectively, our work demonstrates essential signaling component potentially contributing pathogenesis juvenile myelomonocytic leukemia caused PTPN11