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• W2078444319 endingPage "7069" @default.
• W2078444319 startingPage "7055" @default.
• W2078444319 abstract "Chronic myelogenous leukemia (CML) is driven by Bcr-Abl, a constitutively active protein-tyrosine kinase that stimulates proliferation and survival of myeloid progenitors. Global inhibition of myeloid Src family kinase (SFK) activity with the broad-spectrum pyrrolo-pyrimidine inhibitor, A-419259, blocks proliferation and induces apoptosis in CML cell lines, suggesting that transformation by Bcr-Abl requires SFK activity. However, the contribution of Hck and other individual SFKs to Bcr-Abl signaling is less clear. Here, we developed an A-419259-resistant mutant of Hck by replacing the gatekeeper residue (Thr-338; c-Src numbering) in the inhibitor-binding site with a bulkier methionine residue (Hck-T338M). This substitution reduced Hck sensitivity to A-419259 by more than 30-fold without significantly affecting kinase activity in vitro. Expression of Hck-T338M protected K-562 CML cells and Bcr-Abl-transformed TF-1 myeloid cells from the apoptotic and antiproliferative effects of A-419259. These effects correlated with persistence of Hck-T338M kinase activity in the presence of the compound, and were accompanied by sustained Erk and Stat5 activation. In contrast, control cells expressing equivalent levels of wild-type Hck retained sensitivity to the inhibitor. We also show for the first time that A-419259 induces cell-cycle arrest and apoptosis in primary CD34+ CML cells with equal potency to imatinib. These data suggest that Hck has a nonredundant function as a key downstream signaling partner for Bcr-Abl and may represent a potential drug target in CML." @default.
• W2078444319 created "2016-06-24" @default.
• W2078444319 creator A5042246776 @default.
• W2078444319 creator A5073045604 @default.
• W2078444319 creator A5079044019 @default.
• W2078444319 creator A5082059304 @default.
• W2078444319 date "2008-09-15" @default.
• W2078444319 modified "2023-10-12" @default.
• W2078444319 title "An inhibitor-resistant mutant of Hck protects CML cells against the antiproliferative and apoptotic effects of the broad-spectrum Src family kinase inhibitor A-419259" @default.
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• W2078444319 doi "https://doi.org/10.1038/onc.2008.330" @default.
• W2078444319 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2738638" @default.
• W2078444319 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18794796" @default.
• W2078444319 hasPublicationYear "2008" @default.
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