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

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.