The telomerase complex is responsible for telomere maintenance and represents a 
promising neoplasia therapeutic target. In order to determine whether 
G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might 
have effects on telomere dynamics and to evaluate the clinical utility, we 
assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. 
We found that treatment with telomestatin reproducibly inhibited telomerase 
activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting 
in telomere shortening. Inhibition of telomerase activity by telomestatin 
disrupts telomere maintenance and ultimately results in telomere dysfunction. 
Telomestatin completely suppressed the plating efficiency of K562 cells at 1 
microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony 
formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity 
toward imatinib and chemotherapeutic agents was also observed in 
telomestatin-treated K562 cells. Further, the combination of telomestatin plus 
imatinib more effectively inhibited hematopoietic colony formation by primary 
human chronic myelogenous leukemia cells. Last, telomestatin induced the 
activation of ATM and Chk2, and subsequently increased the expression of 
p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction 
induced by telomestatin activates the ATM-dependent DNA damage response. We 
conclude that telomerase inhibitors combined with the use of imatinib and other 
chemotherapeutic agents may be very useful for the treatment of human leukemia.