@article{da02033fd66547509e038b553e8ea0e4,
title = "Pim 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 duplication",
abstract = "Acute 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.",
keywords = "Alternative non-homologous end-joining DNA repair, FLT3 internal tandem duplication, Genomic instability, Pim kinase, Topoisomerase 2 inhibitors",
author = "Mario Scarpa and Shivani Kapoor and Tvedte, {Eric S.} and Doshi, {Kshama A.} and Zou, {Ying S.} and Prerna Singh and Lee, {Jonelle K.} and Aditi Chatterjee and {Mustafa Ali}, {Moaath K.} and Bromley, {Robin E.} and {Dunning Hotopp}, {Julie C.} and Rassool, {Feyruz V.} and Baer, {Maria R.}",
note = "Funding Information: Supported by Merit Review Award BX002184 from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service (M.R.B.), Leukemia and Lymphoma Society Translational Research Awards (M.R.B., F.V.R.), NIH NCI and OD (Office of the Director{\textquoteright}s) R01 CA206188 (J.C.D.H.), NIH-NCI grant P30 CA134274, University of Maryland, Baltimore UMMG Cancer Research Grant #CH 649 CRF issued by the State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program, the Valanda Wilson Leukemia Research Fund and Mary Ellen{\textquoteright}s Angelic Fund for Leukemia Research. Funding Information: Supported by Merit Review Award BX002184 from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service (M.R.B.), Leukemia and Lymphoma Society Translational Research Awards (M.R.B., F.V.R.), NIH NCI and OD (Office of the Director's) R01 CA206188 (J.C.D.H.), NIH-NCI grant P30 CA134274, University of Maryland, Baltimore UMMG Cancer Research Grant #CH 649 CRF issued by the State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program, the Valanda Wilson Leukemia Research Fund and Mary Ellen's Angelic Fund for Leukemia Research. Publisher Copyright: Copyright: {\textcopyright} 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.",
year = "2021",
month = aug,
day = "31",
doi = "10.18632/oncotarget.28042",
language = "English (US)",
volume = "12",
pages = "1763--1779",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "18",
}