The impressive advances carried out in designing pharmacological strategies with the aim of telomerase inhibition in cancers emerged a consensus that telomerase-targeted therapies could be exciting prospect in repertoire of future cancer strategies. The results of the present study indicated that targeting telomerase using an oligonucleotide-based molecule against human telomerase RNA template (hTR ASODN) reduced the survival rate of NB4 cells and induced a caspase-3-dependent apoptosis. Our finding was even noticeable in the synergistic experiments, where we found an enhanced reduction in the viability of the cells after short-term treatment with ATO in combination with the inhibitor. The resulting data delineated that short-term treatment of the cells with hTR ASODN either as single agent or in combination with ATO resulted in apoptotic cell death through activation of DNA damage response via up-regulation of p73 and ATM coupled with down-regulation of c-Myc. Moreover, we found that induction of p21 and subsequent disturbance of the death promoter to death repressor genes may contribute to the enhanced growth suppressive effect of the drugs combination. Overall, our findings support the idea that telomerase activity may have pivotal role in attenuating ATO effectiveness and combination of ATO with telomerase inhibitor seems to be a novel promising strategy, which may increase APL cure rates.