LAUSR

The drug resistance is the most often obstacle in leukemia treatment and failing to eradicating the quiescent leukemia stem cell (LSCs) is believed as the main reason of relapse. Numerous studies have indicated that abnormal maintenance of telomere is related to the sensitivity of cancer cells to therapy. Based on these facts, we designed a lot of compounds and conducted large scale screening. In this study, we identified a small molecule compound IX, an imatinib derivative, as a potential therapeutic candidate of drug-resistant leukemia treatment. IX can eradicate drug-resistant leukemia cells or LSCs, while has little effect on the normal progenitor cells in vitro. We also showed that IX can relive the tumor burden of CML xenograft mice model and prolong the life span of them. Meanwhile, it can inhibit the abnormal elongation of telomere not only by effectively decreases the telomerase activity of drug-resistant leukemia cells, but also by affecting ALT mechanism. Besides, the suppression of Wnt signaling pathway by IX may plays an important role in eradicating drug-resistant cells. Taken together, our findings suggest that IX could be a novel therapeutic agent for the treatment of refractory leukemia.