ArticleLeukemia2013
BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability.
Article in Leukemia, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 48 citations in OpenAlex.
- Secondary malignancies after chronic myeloid leukaemia upon TKI treatment: Population trends and outcomes.British journal of haematology · 2025Article
- Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients.International journal of molecular sciences · 2025Article
- Article
- Review
- Oxidative Stress and Chronic Myeloid Leukemia: A Balance between ROS-Mediated Pro- and Anti-Apoptotic Effects of Tyrosine Kinase Inhibitors.Antioxidants (Basel, Switzerland) · 2024Review
- Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance.Cancers · 2021Review
- Transcriptional control of CBX5 by the RNA binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia.Nature cancer · 2021Article
- Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review.World journal of clinical oncology · 2021Review
- Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update.International journal of molecular sciences · 2019Review
- Low numbers of pre-leukemic fusion genes are frequently present in umbilical cord blood without affecting DNA damage response.Oncotarget · 2017Article
- Cellular and Molecular Networks in Chronic Myeloid Leukemia: The Leukemic Stem, Progenitor and Stromal Cell Interplay.Current drug targets · 2017Review
- Tracking of Normal and Malignant Progenitor Cell Cycle Transit in a Defined Niche.Scientific reports · 2016Article
- DNA Repair--A Double-Edged Sword in the Genomic Stability of Cancer Cells--The Case of Chronic Myeloid Leukemia.International journal of molecular sciences · 2015Review
- UV Differentially Induces Oxidative Stress, DNA Damage and Apoptosis in BCR-ABL1-Positive Cells Sensitive and Resistant to Imatinib.International journal of molecular sciences · 2015Article
- Leukemia stem cells: the root of chronic myeloid leukemia.Protein & cell · 2015Review
- BMI1 reprogrammes histone acetylation and enhances c-fos pathway via directly binding to Zmym3 in malignant myeloid progression.Journal of cellular and molecular medicine · 2014Article
- Article
- Vpr expression abolishes the capacity of HIV-1 infected cells to repair uracilated DNA.Nucleic acids research · 2014Article
- Reactive oxygen species in normal and tumor stem cells.Advances in cancer research · 2014Article
- Current management of chronic myeloid leukemia with tyrosine kinase inhibitors.Turkish journal of haematology : official journal of Turkish Society of Haematology · 2013Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.