Distinct effects of V617F and exon12-mutated JAK2 expressions on erythropoiesis in a human induced pluripotent stem cell (iPSC)-based model.

摘要: Activating mutations affecting the JAK-STAT signal transduction is genetic driver of myeloproliferative neoplasms (MPNs) which comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis. The JAK2p.V617F mutation can produce both erythrocytosis in PV thrombocytosis ET, while JAK2 exon 12 cause only erythrocytosis. We hypothesized that these two activated different intracellular signals. In this study, induced pluripotent stem cells (iPSCs) were used to model JAK2-mutated MPNs. Normal iPSCs underwent lentiviral overexpress or JAK2p.N542_E543del (JAK2exon12) under a doxycycline-inducible system. modified differentiated into erythroid cells. Compared with JAK2V617F-iPSCs, JAK2exon12-iPSCs yielded more total CD71+GlycophorinA+ cells, displayed mature morphology expressed adult hemoglobin after doxycycline induction. Capillary Western immunoassay revealed significantly higher phospho-STAT1 but lower phospho-STAT3 Phospho-AKT compared those JAK2V617F-iPSCs response erythropoietin. Furthermore, interferon alpha arsenic trioxide tested on explore their potentials for MPN therapy. Both agents preferentially inhibited proliferation promoted apoptosis expressing mutant without conclusion, iPSC be investigate mechanisms search new therapy