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Background: Like T315I Bcr-Abl, T674I FIP1L1-PDGFRα existed in a subset of chronic eosinophilic leukemia (CEL) is also gatekeeper mutation that is resistant to tyrosine kinase inhibitors (TKIs, e.g., imatinib, nilotinib and dasatinib) approved by FDA.Therefore, novel TKIs against T674I FIP1L1-PDGFRα are still needed.Ponatinib is a novel orally bioavailable TKI against T315I Bcr-Abl.But it is not clear whether ponatinib is effective against T674I FIP1L1-PDGFRα.The purpose of this study was to examine the effect ofponatinib on T674I FIP1L1-PDGFRα.Methods: Molecular docking analysis in silico was first performed.The effects of ponatinib on PDGFRα signaling pathways, apoptosis and cell cycling were examined in EOL-1, BaF3 cells expressing either wild type (WT) or T674I FIP1L1-PDGFRα.The in vivo antitumor activity of ponatinib was measured with xenografted BaF3-T674I FIP1L1-PDGFRα cells in nude mice models.Results: Molecular docking analysis in silico revealed that ponatinib could bind to the DFG (Asp-Phe-Gly)-out state of T674I PDGFRα.Ponatinib potently inhibited the phosphorylation of WT and T674I FIP1L1-PDGFRα and their downstream signaling molecules (e.g., Stat3, Stat5).Ponatinib strikingly inhibited the growth of both WT and T674I FIP1L1-PDGFRα-carrying CEL cells.It induced apoptosis in CEL cells with caspase-3-dependent cleavage of Mcl-1, and inhibited tyrosine phosphorylation of β-catenin to decrease its stability and pro-survival functions.In vivo, ponatinib abrogated the growth of xenografted BaF3-T674I FIP1L1-PDGFRα cells in nude mice.Conclusions: Ponatinib is a pan-FIP1L1-PDGFRα inhibitor, and clinical trials are warranted to investigate its efficacy in imatinib-resistant CEL.