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BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint
Open accessAbstract
Chronic myelogeneous leukemia (CML) is a two-stage disease associated with expression of the BCR/ABL tyrosine kinase protein. However, whether BCR/ABL expression directly causes blast crisis, and if so by what mechanism, is unknown. We have found that BCR/ABL translocates from the cytoplasm to the nucleus after genotoxic stress. Furthermore, BCR/ABL increases DNA double-strand damage after etoposide treatment and leads to a defect in an intra-S phase checkpoint, causing a radioresistant DNA synthesis (RDS) phenotype. In the nucleus, BCR/ABL associates with the ataxia-telangiectasia and rad 3-related protein (ATR) and disrupts ATR-dependent signal transduction. Overexpression of ATR in a BCR/ABL-expressing cell line corrects the DNA damage phenotype. These results demonstrate a nuclear role for BCR/ABL in altering the cellular response to DNA damage.
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“The oncogenic BCR-ABL fusion protein disrupts ATR-dependent intra-S phase checkpoint in chronic myeloid leukemia after etoposide treatment, by causing DNA strand break formation [33].”
From The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia (2017) · cites this paper as [33]
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Metadata
- Authors
- Dierov, J., Dierova, R., & Carroll, M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Carroll, Martin
- ORCID
- Carroll, Martin
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 5
- Issue
- 3
- Pages
- 275-285
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2035713316
- Cited by
- 117
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 9
- FWCI
- 7.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- BCR-ABL, chronic myeloid leukemia, nuclear translocation, ATR, S-phase checkpoint, DNA damage response, radioresistant DNA synthesis, etoposide, DNA double-strand breaks, blast crisis, tyrosine kinase
- MeSH terms
- Cell Nucleus, Cells, Cultured, Cytoplasm, DNA Damage, DNA Topoisomerases, Type II, DNA Repair, Enzyme Inhibitors, Etoposide, Humans, Signal Transduction, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Protein Transport, Ataxia Telangiectasia Mutated Proteins
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