title: The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression.
abstract: DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for treatment of acute myeloid leukemia (AML) and other malignancies. Although inhibiting global/gene-specific DNA methylation is widely accepted as a key mechanism behind DNMTI anti-tumor activity, other mechanisms are likely involved in DNMTI's action. Because telomerase reverse transcriptase (TERT) plays key roles in cancer through telomere elongation and telomere lengthening-independent activities, and TERT 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. Down-regulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZA-mediated DNA damage, telomere dysfunction and apoptosis of AML cells. Collectively, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction, which consequently exerts an anti-tumor activity.
authors: Department of Medicine, Division of Hematology and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Xiaolu
authors: X
authors: Zhang
authors: Department of Medicine, Division of Hematology and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Bingnan
authors: B
authors: Li
authors: Department of Medicine, Division of Hematology and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Nick
authors: N
authors: de Jonge
authors: Department of Medicine, Division of Hematology and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Magnus
authors: M
authors: Björkholm
authors: Department of Medicine, Division of Hematology and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Dawei
authors: D
authors: Xu
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D016615:Telomere / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C509186:TERT protein, human; D019098:Telomerase; D001374:Azacitidine
keywords: AML; DNMT inhibitors; TERT; apoptosis; telomerase; telomere