Epigenetic landscape of the TERT promoter: a potential biomarker for high risk AML/MDS

Abstract

Although recent observations implicate the importance of telomerase activity in acute myeloid leukaemia (AML), the roles of epigenetic regulations of the TERT gene in leukaemogenesis, drug resistance and clinical prognosis in AML are not fully understood. We developed a quantitative pyrosequencing-based methylation assay covering the TERT proximal promoter and a partial exon 1 (hTERTpro/Ex1) region and tested both cell lines and primary leukaemia cells derived from AML and AML with preceding myelodysplastic syndrome (AML/MDS) patients (n = 43). Prognostic impact of methylation status of the upstream TERT promoter region was assessed by the Kaplan-Meier method. The activity of the telomerase inhibitor, imetelstat, was measured using leukaemia cell lines. The TERTpro/Ex1 region was highly methylated in all cell lines and primary leukaemia cells showed diverse methylation profiles. Most cases showed hypermethylated regions at the upstream TERTpro/Ex1 region that were associated with inferior patient survival. TERTpro/Ex1 methylation status was correlated with the cytotoxicity to imetelstat and its combination with hypomethylating agent enhanced the cytotoxicity of imetelstat. AML cell lines and primary blasts harbour distinct TERTpro/Ex1 methylation profiles that could serve as a prognostic biomarker of AML. However, validation in a large cohort of patients is necessary to confirm our findings.

TERTpromoter mutations are associated with poor prognosis and cell immortalization in meningioma

“…12 Additionally, TERT promoter methylation was correlated with worse prognosis in pediatric brain tumors, gastric cancer, and acute myeloid leukemia. 4,12,40,41 Corresponding data have been reported 1592 Spiegl-Kreinecker et al TERT promoter alterations of meningiomas for meningiomas, where TERT promoter methylation was associated with increasing tumor grade and upregulation of TERT mRNA expression. 13 In the latter study, a minor but significant impact of TERT promoter methylation on patient OS was detected in univariate analysis, which, however, lost significance in the multivariate setting.…”

Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis

“…40 Alternatively, the response to imetelstat could be influenced by the baseline levels of telomerase, which are reportedly elevated in MPN patients, 41,42 and/or by the epigenetic makeup of the TERT promoter as has been recently shown in AML/myelodysplastic syndromes. 43 Taken together, these observations indicate that TA inhibition might not be the only mode of action of imetelstat and the exact molecular mechanisms underlying its effects on normal and malignant MK require further investigation.…”

Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

“…THOR was further explored in prostate cancer and has shown its role as a potential marker with diagnostic and prognostic properties [ 139 ]. These findings have been expanded upon by multiple groups implicating h TERT promoter methylation in h TERT upregulation, and further demonstrating not only its diagnostic but, importantly, its clinical significance in cancer prognostic including thyroid cancer, acute myeloid leukemia/myelodisplastic syndrome, esophageal carcinoma, meningioma, pituitary adenomas, colorectal cancer and hepatocellular carcinoma) [ 72 , 82 , 139 , 152 – 157 ]. In these studies, h TERT promoter hypermethylation was positively correlated with high h TERT expression, telomerase reactivation and in the vast majority of the cases correlated with worse clinical outcomes.…”