Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence
Open accessAbstract
The antiviral thymidine analog azidothymidine (AZT) is used to treat several virus-associated human cancers. However, to date the mechanism of AZT action remains unclear and thus, reasons for treatment failure are unknown. Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of poor prognosis. Here, we report that enduring AZT treatment of T-cell leukemia virus I-infected cells, in vitro and in vivo in ATL patients, results in inhibition of telomerase activity, progressive telomere shortening, and increased p14(ARF) expression. In turn, this elicits stabilization and reactivation of the tumor suppressor p53-dependent transcription, increased expression of the cyclin-dependent kinase inhibitor p21(Waf1), and accumulation of p27(kip1), thereby inducing cellular senescence and tumor cell death. While ATL patients carrying a wild-type p53 enter remission following treatment with AZT, those with a mutated p53 did not respond, and patients' disease relapse was associated with the selection of a tumor clone carrying mutated inactive p53.
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Other studies have suggested that the use of NRTIs may potentially activate the tumour suppressor gene p53 in healthy cells, inhibiting telomerase to cause cell death.
“Contrastingly, other studies have suggested that the use of NRTIs may potentially activate the tumour suppressor gene p53 in healthy cells, inhibiting telomerase to cause cell death [183,184,185].”
From Current State of Therapeutics for HTLV-1 (2024) · cites this paper as [183]
Cites
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MDM2 promotes ubiquitination and degradation of MDMX
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Small molecule compounds that induce cellular senescence.
Petrova, N. V., Velichko, A. K., Razin, S. V., & Kantidze, O. L. (2016) · Aging Cell · doi:10.1111/acel.12518 · Cited by 240 · see citing works
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Current State of Therapeutics for HTLV-1
Wang, T. T., Hirons, A., Doerflinger, M., Morris, K. V., Ledger, S., Purcell, D. F. J., Kelleher, A. D., & Ahlenstiel, C. L. (2024) · Viruses · doi:10.3390/v16101616 · Cited by 22 · see citing works
“This will be discussed further in Section 2.2.”
BackgroundInfluential
- Authors
- Datta, A., Bellon, M., Sinha-Datta, U., Bazarbachi, A., Lepelletier, Y., Canioni, D., Waldmann, T. A., Hermine, O., & Nicot, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-08-01
- Volume
- 108
- Issue
- 3
- Pages
- 1021-1029
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895862
- OpenAlex
- W2038982713
- Cited by
- 139
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 9 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 11 · 2014: 5 · 2013: 9 · 2012: 11
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Cancer Institute (R01CA106258)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- adult T-cell leukemia/lymphoma, zidovudine, telomerase inhibition, telomere shortening, p14ARF, p21, p27, TP53 mutation, treatment resistance, recurrence
- MeSH terms
- Humans, Mutation, Recurrence, Transcription, Genetic, Tumor Cells, Cultured, Zidovudine, Human T-lymphotropic virus 1, Leukemia-Lymphoma, Adult T-Cell, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Telomerase, Tumor Suppressor Protein p14ARF, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27
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