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Blood, 1 August 2006, Vol. 108, No. 3, pp. 1021-1029.
Prepublished online as a Blood First Edition Paper on March 28, 2006; DOI 10.1182/blood-2006-01-0067.
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NEOPLASIA
Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence
Abhik Datta,
Marcia Bellon,
Uma Sinha-Datta,
Ali Bazarbachi,
Yves Lepelletier,
Danielle Canioni,
Thomas A. Waldmann,
Olivier Hermine, and
Christophe Nicot
From the University of Kansas Medical Center, Department of Microbiology, Immunology, and Molecular Genetics, Kansas City, KS; the American University of Beirut, Department of Internal Medicine, Beirut, Lebanon; Hopital Necker Universite Paris V, Centre National de la Recherche Scientifique Unite Mixte de Recherche 8603, Paris, France; and the National Cancer Institute, National Institutes of Health, Metabolism Branch, Center for Cancer Research, Bethesda, MD.
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 p14ARF expression. In turn, this elicits stabilization and reactivation of the tumor suppressor p53-dependent transcription, increased expression of the cyclin-dependent kinase inhibitor p21Waf1, and accumulation of p27kip1, 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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