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    
Abstract/OtherAbstract:
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.
Authors:
A Slupianek; R Falinski; P Znojek; T Stoklosa; S Flis; V Doneddu; D Pytel; E Synowiec; J Blasiak; A Bellacosa; T Skorski
Related Documents :
21127195 - The tumor suppressor protein menin inhibits akt activation by regulating its cellular l...
11135355 - Therapeutic potential of purine analogue combinations in the treatment of lymphoid mali...
23799545 - Lentiviral-mediated p38 mapk rnai attenuates aldosterone-induced myocyte apoptosis.
23485815 - Phosphatidylinositol-3-kinase/protein kinase b is responsible for the protection of pae...
7896815 - Reduced light-dependent phosphorylation of an analog visual pigment containing 9-demeth...
9079685 - Direct t cell activation by chimeric single chain fv-syk promotes syk-cbl association a...
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    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cell Nucleus / genetics
Comet Assay
DNA Damage / genetics*
DNA, Neoplasm / genetics*
Fusion Proteins, bcr-abl / genetics,  metabolism*
Genomic Instability*
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*,  pathology
Mice
Mutagenesis
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
ID/Acronym/Agency:
P30 CA006927/CA/NCI NIH HHS; R01 CA078412/CA/NCI NIH HHS; R01 CA123014/CA/NCI NIH HHS; T32 CA009140/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Neoplasm; 0/Reactive Oxygen Species; EC 2.7.10.2/Fusion Proteins, bcr-abl; EC 3.2.2.-/Uracil-DNA Glycosidase; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Coronary Heart Disease Risk Factors: Concordance Between Patients and Partners Before and After Bypa...
Next Document:  B-lineage transcription factors and cooperating gene lesions required for leukemia development.