Abstract
Imatinib mesylate has shown remarkable efficacy in the treatment of patients in the chronic phase of chronic myeloid leukemia. However, despite an overall significant hematological and cytogenetic response, imatinib therapy may favor the emergence of drug-resistant clones, ultimately leading to relapse. Some imatinib resistance mechanisms had not been fully elucidated yet. In this study we used sensitive and resistant sublines from a Bcr-Abl positive cell line to investigate the putative involvement of telomerase in the promotion of imatinib resistance. We showed that sensitivity to imatinib can be partly restored in imatinib-resistant cells by targeting telomerase expression, either by the introduction of a dominant-negative form of the catalytic protein subunit of the telomerase (hTERT) or by the treatment with all-trans-retinoic acid, a clinically used drug. Furthermore, we showed that hTERT overexpression favors the development of imatinib resistance through both its antiapoptotic and telomere maintenance functions. Therefore, combining antitelomerase strategies to imatinib treatment at the beginning of the treatment should be promoted to reduce the risk of imatinib resistance development and increase the probability of eradicating the disease.
Highlights
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by t(9;22) chromosomal translocation, which results in the generation of p210Bcr-Abl, a chimeric protein endowed with constitutive active tyrosine kinase activity [1]
We showed that imatinib sensitivity can be restored in resistant cells by antitelomerase strategies and showed that overexpression of human telomerase reverse transcriptase (hTERT), first, protected sensitive cells from apoptosis induced by low concentration of imatinib and second, facilitated the establishment of imatinib resistance
We did a kinetic analysis to evaluate whether the effects of imatinib at high concentrations on hTERT expression could result from apoptosis induction (Fig. 1B)
Summary
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by t(9;22) chromosomal translocation, which results in the generation of p210Bcr-Abl, a chimeric protein endowed with constitutive active tyrosine kinase activity [1]. This activity is essential for the induction of in vitro cellular transformation and in vivo leukemogenesis. A competitive inhibitor of the ATP-binding site of the Bcr-Abl enzyme, has revolutionized the treatment of this particular type of leukemia [2]. In vitro studies have shown that imatinib induces apoptosis in Bcr-Abl positive cell lines [3].
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