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Chronic Myeloproliferative Neoplasias

BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability

Leukemia volume 27, pages 629–634 (2013)Cite this article

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Abstract

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in chronic phase (CML-CP). Unfortunately, 25% of TKI-naive patients and 50–90% of patients developing TKI-resistance carry CML clones expressing TKI-resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species, which may result in accumulation of uracil derivatives in genomic DNA. Unfaithful and/or inefficient repair of these lesions generates TKI-resistant point mutations in BCR-ABL1 kinase. Using an array of specific substrates and inhibitors/blocking antibodies we found that uracil DNA glycosylase UNG2 were inhibited in BCR-ABL1-transformed cell lines and CD34+ CML cells. The inhibitory effect was not accompanied by downregulation of nuclear expression and/or chromatin association of UNG2. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI, we found that reduction of UNG2 activity increased the number of uracil derivatives in genomic DNA detected by modified comet assay and facilitated accumulation of ouabain-resistant point mutations in reporter gene Na+/K+ATPase. In conclusion, we postulate that BCR-ABL1 kinase-mediated inhibition of UNG2 contributes to accumulation of point mutations responsible for TKI resistance causing the disease relapse, and perhaps also other point mutations facilitating malignant progression of CML.

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Acknowledgements

This work was supported by NCI R01 CA123014 from the National Cancer Institute.

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Author notes

  1. D Pytel

    Present address: 5Present address: Department of Cancer Biology, The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia PA 19104, USA.,

Authors and Affiliations

  1. Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA, USA

    A Slupianek, R Falinski, P Znojek, T Stoklosa, S Flis, D Pytel & T Skorski

  2. Department of Immunology, Center of Biostructure Research, Banacha 1A, Bldg F, Medical University of Warsaw, Warsaw, Poland

    T Stoklosa

  3. Cancer Biology Program and Epigenetics and Progenitor Cells Keystone Program, Fox Chase Cancer Center, Temple University, Philadelphia, PA, USA

    V Doneddu & A Bellacosa

  4. Department of Molecular Genetics, University of Lodz, Lodz, Poland

    E Synowiec & J Blasiak

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Slupianek, A., Falinski, R., Znojek, P. et al. BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability. Leukemia 27, 629–634 (2013). https://doi.org/10.1038/leu.2012.294

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