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Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells


Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before γ-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl−/− murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response.

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We are grateful to Tabea Peußer and Kerstin Willecke for technical assistance. The MEFs were a kind gift from Dr JY Wang (UCSD, San Diego, CA, USA).

Research Grants and other Financial Support: This work was financially supported by the Robert Bosch foundation project O2A and the Deutsche Forschungsgemeinschaft project KU 2338/1-1.

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Correspondence to H van der Kuip.

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Fanta, S., Sonnenberg, M., Skorta, I. et al. Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells. Oncogene 27, 4380–4384 (2008).

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