| BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability. | |
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MedLine Citation:
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PMID: 23047475 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of CML-CP. Unfortunately, 25% of TKI-naive patients and 50-90% of TKI-responding patients 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 (ROS), 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.Leukemia accepted article preview online, 10 October 2012; doi:10.1038/leu.2012.294. |
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Authors:
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A Slupianek; R Falinski; P Znojek; T Stoklosa; S Flis; V Doneddu; D Pytel; E Synowiec; J Blasiak; A Bellacosa; T Skorski |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-10 |
Journal Detail:
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Title: Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K Volume: - ISSN: 1476-5551 ISO Abbreviation: Leukemia Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8704895 Medline TA: Leukemia Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA, USA. |
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