Short-term treatment with imetelstat sensitizes hematopoietic malignant cells to a genotoxic agent via suppression of the telomerase-mediated DNA repair process

Abstract

Imetelstat is a specific and competitive inhibitor of telomerase enzymatic activity. We demonstrated that imetelstat could interfere with the DNA repair process and enhance the effect of DNA damaging agents using hematological tumor cell lines. Short-term administration of imetelstat enhanced growth suppression by anticancer agents and radiation. It also upregulated γH2AX expression induced by irradiation. Immunofluorescence staining showed that both human telomerase reverse transcriptase (hTERT) and γH2AX were upregulated and co-localized in the nucleus of peripheral blood mononuclear cells after irradiation, suggesting that hTERT was involved in the DNA-DSB repair process. Imetelstat enhanced growth inhibitory effect of cytotoxic agents in short-term culture without shortening of telomeres, indicating that this effect was attributed by telomere length independent mechanism. Our results suggest that the combination of short-term treatment with imetelstat and cytotoxic agent is a promising strategy to treat a wide variety of hematopoietic malignancies.

Keywords:

• Polymorphic telomere insertion
• interstitial telomeric sequences
• telomerase inhibition

Acknowledgements

We thank Y. Yamada, T. Hata, N. Arima for adult T cell leukemia/lymphoma cell lines.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was supported by the Japan Society for the Promotion of Science, grant-in aid for scientific research (C) 16K09836 (M.O.), the Japanese Society of Hematology Research Grant, SGH Foundation and Takeda Science Foundation.