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Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias

Abstract

Resistance to imatinib (IM) and other tyrosine kinase inhibitors (TKI)s is an increasing problem in leukemias caused by expression of BCR-ABL1. As chronic myeloid leukemia (CML) cell lines expressing BCR-ABL1 utilize an alternative non-homologous end-joining pathway (ALT NHEJ) to repair DNA double-strand breaks (DSB)s, we asked whether this repair pathway is a novel therapeutic target in TKI-resistant disease. Notably, the steady state levels of two ALT NHEJ proteins, poly-(ADP-ribose) polymerase 1 (PARP1) and DNA ligase IIIα, were increased in the BCR-ABL1-positive CML cell line K562 and, to a greater extent, in its imatinib-resistant (IMR) derivative. Incubation of these cell lines with a combination of DNA ligase and PARP inhibitors inhibited ALT NHEJ and selectively decreased survival with the effect being greater in the IMR derivative. Similar results were obtained with TKI-resistant derivatives of two hematopoietic cell lines that had been engineered to stably express BCR-ABL1. Together our results show that the sensitivity of cell lines expressing BCR-ABL1 to the combination of DNA ligase and PARP inhibitors correlates with the steady state levels of PARP1 and DNA ligase IIIα, and ALT NHEJ activity. Importantly, analysis of clinical samples from CML patients confirmed that the expression levels of PARP1 and DNA ligase IIIα correlated with the sensitivity to the DNA repair inhibitor combination. Thus, the expression levels of PARP1 and DNA ligase IIIα serve as biomarkers to identify a subgroup of CML patients who may be candidates for therapies that target the ALT NHEJ pathway when treatment with TKIs has failed.

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Acknowledgements

We would like to thank Professor Stephen Baylin (JHU) for insightful comments and careful reading of our manuscript. CML patient samples were collected under IMRB no. H25314. These studies were supported by the Cigarette Restitution Funds of Maryland (FR and LT), the Leukemia Lymphoma Society (FR, CR and LT), the V Foundation (FR, LT and AET) and NIH Grants ES 012512 and CA92584 (AET).

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Correspondence to F V Rassool.

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AET and FVR are co-inventors on a patent application that covers the use of PARP1 and DNA ligase III alpha as biomarkers of abnormal ALT NHEJ in solid tumors.

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Tobin, L., Robert, C., Rapoport, A. et al. Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias. Oncogene 32, 1784–1793 (2013). https://doi.org/10.1038/onc.2012.203

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