Document Detail

BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability.
MedLine Citation:
PMID:  23047475     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-09
Journal Detail:
Title:  Leukemia     Volume:  27     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-06     Completed Date:  2013-04-30     Revised Date:  2014-04-14    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  629-34     Citation Subset:  IM    
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MeSH Terms
Blotting, Western
Cell Nucleus / genetics
Comet Assay
DNA Damage / genetics*
DNA, Neoplasm / genetics*
Fusion Proteins, bcr-abl / genetics,  metabolism*
Genomic Instability*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*,  pathology
Neoplastic Stem Cells / metabolism*,  pathology
Point Mutation / genetics
Polymerase Chain Reaction
Reactive Oxygen Species / metabolism
Sodium-Potassium-Exchanging ATPase / genetics
Tumor Cells, Cultured
Uracil-DNA Glycosidase / genetics,  metabolism*
Grant Support
P30 CA006927/CA/NCI NIH HHS; R01 CA078412/CA/NCI NIH HHS; R01 CA123014/CA/NCI NIH HHS; T32 CA009140/CA/NCI NIH HHS
Reg. No./Substance:
0/DNA, Neoplasm; 0/Reactive Oxygen Species; EC Proteins, bcr-abl; EC 3.2.2.-/Uracil-DNA Glycosidase; EC ATPase

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