Research Papers:
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
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Abstract
Mario Scarpa1,2, Shivani Kapoor1, Eric S. Tvedte3, Kshama A. Doshi1, Ying S. Zou1,4, Prerna Singh1, Jonelle K. Lee1, Aditi Chatterjee1,2, Moaath K. Mustafa Ali1,2, Robin E. Bromley3, Julie C. Dunning Hotopp1,3,5, Feyruz V. Rassool1,6 and Maria R. Baer1,2,7
1 University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
2 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
3 Institute for Genome Sciences, Baltimore, MD, USA
4 Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
5 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
6 Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
7 Veterans Affairs Medical Center, Baltimore, MD, USA
Correspondence to:
Maria R. Baer, | email: | mbaer@umm.edu |
Keywords: FLT3 internal tandem duplication; Pim kinase; alternative non-homologous end-joining DNA repair; genomic instability; topoisomerase 2 inhibitors
Received: June 22, 2021 Accepted: July 28, 2021 Published: August 31, 2021
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.
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