Abstract 3816: The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression

Abstract

Abstract DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for the treatment of acute myeloid leukemia (AML) and other malignancies, and inhibition of global/gene-specific DNA methylation is widely accepted as a key mechanism behind their anti-tumor activity. It is currently unclear whether other mechanisms are involved in DNMTI's action. Because telomerase or telomerase reverse transcriptase (TERT) plays a key role in malignant transformation and progression through telomere elongation and other telomere lengthening-independent activities, and TERT or telomerase has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Downregulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZAmediated DNA damage, telomere dysfunction and apoptosis of AML cells. Taken together, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction,which consequently exerts an anti-tumor activity. These findings may have implications in DNMTI and telomerase-based strategies for cancer therapeutics. Citation Format: Bingnan Li, Xiaolu Zhang, Nick de Jonge, Magnus Björkholm, Dawei Xu. The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3816. doi:10.1158/1538-7445.AM2015-3816