Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence.
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.
Datta
Abhik
A
Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, 3025 Wahl Hall West, 3901 Rainbow Blvd, Kansas City, 66160, USA.
Bellon
Marcia
M
Sinha-Datta
Uma
U
Bazarbachi
Ali
A
Lepelletier
Yves
Y
Canioni
Danielle
D
Waldmann
Thomas A
TA
Hermine
Olivier
O
Nicot
Christophe
C
D045744:Cell Line, Tumor; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015368:Human T-lymphotropic virus 1; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell; D009154:Mutation; D012008:Recurrence; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015215:Zidovudine; D019098:Telomerase