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dc.contributor.authorScarpa, Mario
dc.contributor.authorKapoor, Shivani
dc.contributor.authorTvedte, Eric S
dc.contributor.authorDoshi, Kshama A
dc.contributor.authorZou, Ying S
dc.contributor.authorSingh, Prerna
dc.contributor.authorLee, Jonelle K
dc.contributor.authorChatterjee, Aditi
dc.contributor.authorAli, Moaath K Mustafa
dc.contributor.authorBromley, Robin E
dc.contributor.authorDunning Hotopp, Julie Cen_US
dc.contributor.authorRassool, Feyruz Ven_US
dc.contributor.authorBaer, Maria Ren_US
dc.date.accessioned2021-09-14T15:45:46Z
dc.date.available2021-09-14T15:45:46Z
dc.date.issued2021-08-31
dc.identifier.urihttp://hdl.handle.net/10713/16646
dc.description.abstractAcute myeloid leukemia (AML) with fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) relapses with new chromosome abnormalities following chemotherapy, implicating genomic instability. Error-prone alternative non-homologous end-joining (Alt-NHEJ) DNA double-strand break (DSB) repair is upregulated in FLT3-ITD-expresssing cells, driven by c-Myc. The serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD, and inhibiting Pim increases topoisomerase 2 (TOP2) inhibitor chemotherapy drug induction of DNA DSBs and apoptosis. We hypothesized that Pim inhibition increases DNA DSBs by downregulating Alt-NHEJ, also decreasing genomic instability. Alt-NHEJ activity, measured with a green fluorescent reporter construct, increased in FLT3-ITD-transfected Ba/F3-ITD cells treated with TOP2 inhibitors, and this increase was abrogated by Pim kinase inhibitor AZD1208 co-treatment. TOP2 inhibitor and AZD1208 co-treatment downregulated cellular and nuclear expression of c-Myc and Alt-NHEJ repair pathway proteins DNA polymerase θ, DNA ligase 3 and XRCC1 in FLT3-ITD cell lines and AML patient blasts. ALT-NHEJ protein downregulation was preceded by c-Myc downregulation, inhibited by c-Myc overexpression and induced by c-Myc knockdown or inhibition. TOP2 inhibitor treatment increased chromosome breaks in metaphase spreads in FLT3-ITD-expressing cells, and AZD1208 co-treatment abrogated these increases. Thus Pim kinase inhibitor co-treatment both enhances TOP2 inhibitor cytotoxicity and decreases TOP2 inhibitor-induced genomic instability in cells with FLT3-ITD. Copyright: © 2021 Scarpa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.description.urihttps://doi.org/10.18632/oncotarget.28042en_US
dc.language.isoenen_US
dc.publisherImpact Journals LLCen_US
dc.relation.ispartofOncotargeten_US
dc.rightsCopyright: © 2021 Scarpa et al.en_US
dc.subjectFLT3 internal tandem duplicationen_US
dc.subjectPim kinaseen_US
dc.subjectalternative non-homologous end-joining DNA repairen_US
dc.subjectgenomic instabilityen_US
dc.subjecttopoisomerase 2 inhibitorsen_US
dc.titlePim kinase inhibitor co-treatment decreases alternative non-homologous end-joining DNA repair and genomic instability induced by topoisomerase 2 inhibitors in cells with FLT3 internal tandem duplicationen_US
dc.typeArticleen_US
dc.identifier.doi10.18632/oncotarget.28042
dc.identifier.pmid34504649
dc.source.volume12
dc.source.issue18
dc.source.beginpage1763
dc.source.endpage1779
dc.source.countryUnited States


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