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Inhibition of Human Telomerase Enhances the Effect of the Tyrosine Kinase Inhibitor, Imatinib, in BCR-ABL-positive Leukemia Cells¹

First Department of Internal Medicine, Tokyo Medical University, Tokyo, 160-0023 [T. T., A. N., G. S., T. S., K. O.]; Intractable Disease Research Center, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023 [J. H. O.]; and Department of Virology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8519 [K. A., K. Y.], Japan

Purpose: Telomerase is a ribonucleoprotein enzyme that maintains protective structures at the ends of eukaryotic chromosomes. Earlier findings have supported an association between progressive telomere shortening in the chronic phase of chronic myelogenous leukemia and the up-regulation of telomerase activity occurring late in the evolution of the disease. We examined the impact of telomerase inhibition by dominant negative-human telomerase reverse transcriptase (DN-hTERT) on the biological features of BCR-ABL-transformed cells.

Experimental Design: We introduced vectors encoding DN-hTERT, wild-type (WT)-hTERT, or a control vector expressing only a drug-resistant marker into Philadelphia chromosome-positive K562 cells and OM9;22 cells and assessed the biological effect of telomerase inhibition on cellular immortality.

Results: Ectopic expression of DN-hTERT resulted in complete inhibition of telomerase activity and reduction of telomere length. The entire population of telomerase-inhibited K562 cells exhibited cytoplasmic blebbling and chromatin condensation, features of apoptosis. In contrast, K562 cells expressing WT-hTERT, which differ from the mutants by only two amino acids, exhibited normal morphology. The evidence of apoptosis in the telomerase-inhibited cells was determined by flow cytometric analysis with APO2.7 monoclonal antibody. We also observed enhanced induction of apoptosis by imatinib seen in DN-hTERT-expressing K562 cells, as compared with WT-hTERT-expressing cells.

Conclusions: These results demonstrate that disruption of telomere maintenance limits the cellular life span of leukemia cells and show that the combined use of imatinib and telomere maintenance inhibition may be effective in the treatment of BCR-ABL-positive leukemia.

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