Congenital amegakaryocytic thrombocytopenia iPS cells exhibit defective MPL-mediated signaling

摘要: Congenital amegakaryocytic thrombocytopenia (CAMT) is caused by the loss of thrombopoietin receptor-mediated (MPL-mediated) signaling, which causes severe pancytopenia leading to bone marrow failure with onset and anemia prior leukopenia. Because Mpl(-/-) mice do not exhibit human disease phenotype, we used an in vitro tracing system induced pluripotent stem cells (iPSCs) derived from a CAMT patient (CAMT iPSCs) normal iPSCs investigate role MPL signaling hematopoiesis. We found that essential for maintenance CD34+ multipotent hematopoietic progenitor (MPP) population development CD41+GPA+ megakaryocyte-erythrocyte (MEP) population, its fate decision differentiation toward megakaryopoiesis or erythropoiesis differs considerably between cells. Surprisingly, complimentary transduction into using retroviral vector showed overexpression promoted (HPCs), but impaired increased aberrant megakaryocyte production iPSC-derived HPCs, reflecting difference expression transcription factor FLI1. These results demonstrate transcriptional regulation normally governs underlies CAMT.