title: Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy.
abstract: Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs.
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bruedigam
authors.affiliation: The Finsen Laboratory, Bioinformatics Centre, Department of Biology, and Biotech Research and Innovation Center (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark.
authors.forename: Frederik O
authors.initials: FO
authors.lastname: Bagger
authors.affiliation: Department of Hematology and Oncology, University Hospital, Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Florian H
authors.initials: FH
authors.lastname: Heidel
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Paine Kuhn
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Solene
authors.initials: S
authors.lastname: Guignes
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Axia
authors.initials: A
authors.lastname: Song
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Austin
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
authors.forename: Therese
authors.initials: T
authors.lastname: Vu
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Erwin
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia.
authors.forename: Sarbjit
authors.initials: S
authors.lastname: Riyat
authors.affiliation: Queensland Children's Medical Research Institute, Brisbane, QLD 4029, Australia; University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Moore
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Department of Hematology and Oncology, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia; University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Leukemia Center, New York, NY 10065, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Division of Hematology and Oncology, Dana-Farber Cancer Institute, Harvard Medical School and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia; University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: steven.lane@qimrberghofer.edu.au.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055786:Gene Knockout Techniques; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology / Q000637:transplantation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009841:Oligonucleotides; D034741:RNA, Small Interfering / Q000235:genetics; D012008:Recurrence; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D019098:Telomerase; C519562:imetelstat