Antisense inhibition of Bcr‐Abl/c‐Abl synthesis promotes telomerase activity and upregulates tankyrase in human leukemia cells1

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Abstract
Clinical studies in chronic myelogenous leukemia demonstrate that the overexpression of Bcr‐Abl tyrosine kinase is usually accompanied by relatively low telomerase activity in the chronic phase, which reverts to a high activity in blast crisis. The present study was designed to investigate the cross‐talk between both enzymes, using Bcr‐Abl‐positive K‐562 and Bcr‐Abl‐negative Jurkat cell lines, treated with antisense oligodeoxyribonucleotides (ODNs) against Bcr‐Abl/c‐Abl mRNA. The decreased amount and enzyme activity of Bcr‐Abl/c‐Abl provoked telomerase activation in both cell lines. After short‐term treatment with anti‐Bcr‐Abl/c‐Abl ODNs (6 days), no variations in hTERT and phospho‐hTERT were detected. The decreased amount of Bcr‐Abl/c‐Abl was accompanied by: alterations in telomeric associated proteins–overexpression of tankyrase and decreased amount of TRF1/Tin2, cell growth arrest of K‐562 cells, reaching a plateau after 6 days treatment, and increased proliferating activity of Jurkat cells. No changes in telomere length were detected after short‐term treatment. In contrast, after long‐term treatment with anti‐Bcr‐Abl/c‐Abl ODNs (36 days), a significant elongation of telomeres and enhancement of hTERT were established, accompanied by an increased proliferating activity of both cell lines. These data provide evidence that the inhibition of Bcr‐Abl or c‐Abl synthesis keeps a potential to restore or induce cell proliferation through telomere lengthening control and telomerase activation.