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Cell Stem Cell. 2014 Dec 4;15(6):775-90. doi: 10.1016/j.stem.2014.11.010.

Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy.

Author information

1
Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
2
The Finsen Laboratory, Bioinformatics Centre, Department of Biology, and Biotech Research and Innovation Center (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark.
3
Department of Hematology and Oncology, University Hospital, Otto-von-Guericke University, 39120 Magdeburg, Germany.
4
Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
5
Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia.
6
Queensland Children's Medical Research Institute, Brisbane, QLD 4029, Australia; University of Queensland, Brisbane, QLD 4072, Australia.
7
Department of Hematology and Oncology, University Hospital Ulm, 89081 Ulm, Germany.
8
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.
9
Department of Pediatrics, Memorial Sloan Kettering Leukemia Center, New York, NY 10065, USA.
10
Division of Hematology and Oncology, Dana-Farber Cancer Institute, Harvard Medical School and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
11
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.

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.

PMID:
25479751
PMCID:
PMC4317339
DOI:
10.1016/j.stem.2014.11.010
[Indexed for MEDLINE]
Free PMC Article

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