A small molecule compound IX inhibits telomere and attenuates oncogenesis of drug-resistant leukemia cells

Area of Science:

• Oncology
• Hematology
• Pharmacology

Background:

• Drug resistance and leukemia stem cell (LSC) persistence are major challenges in leukemia treatment, leading to relapse.
• Telomerase activity is linked to the uncontrolled self-renewal of LSCs.

Purpose of the Study:

• To identify and evaluate a novel compound (IX) for its efficacy against drug-resistant leukemia stem cells.
• To investigate the mechanisms by which compound IX targets LSCs.

Main Methods:

• Compound IX, an imatinib derivative with telomerase inhibitory properties, was tested against drug-resistant leukemia cell lines and primary patient cells.
• In vitro assays assessed LSC viability, colony formation, and frequency.
• In vivo studies utilized patient-derived xenograft (PDX) models to evaluate tumor burden and survival.
• Mechanistic studies examined telomerase activity, alternative lengthening of telomeres (ALT), and Wnt signaling pathways.

Main Results:

• Compound IX reduced the viability of drug-resistant K562/G cells and blast crisis CML patient cells.
• IX decreased LSC survival, colony-forming ability, and frequency.
• In vivo, IX alleviated tumor burden in PDX models and prolonged survival.
• Compound IX inhibited telomerase activity, affected alternative lengthening of telomeres, and suppressed both canonical and non-canonical Wnt pathways.

Conclusions:

• Compound IX demonstrates potent activity against leukemia stem cells, including drug-resistant populations.
• The compound targets key pathways involved in LSC survival and self-renewal, including telomere maintenance and Wnt signaling.
• Compound IX represents a promising therapeutic candidate for overcoming drug resistance in leukemia.