title: 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 (TERTpro/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, which 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.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Cantilena
authors.affiliation: Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Strickland
authors.affiliation: Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.affiliation: Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xingmin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Dunavin
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Townsley
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Minoo
authors.initials: M
authors.lastname: Battiwalla
authors.affiliation: Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. itos2@nhlbi.nih.gov.
authors.forename: Sawa
authors.initials: S
authors.lastname: Ito
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics*; D059505:Telomere Homeostasis; D024363:Transcription Initiation Site; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D019098:Telomerase
keywords: acute myeloid leukaemia; methylation profile; mutation analysis; survival curve; telomerase reverse transcriptase promoter