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

Item Type:	Article
Title:	Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy
Creators Name:	Bruedigam, C. and Bagger, F.O. and Heidel, F.H. and Paine Kuhn, C. and Guignes, S. and Song, A. and Austin, R. and Vu, T. and Lee, E. and Riyat, S. and Moore, A.S. and Lock, R.B. and Bullinger, L. and Hill, G.R. and Armstrong, S.A. and Williams, D.A. and Lane, S.W.
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.
Keywords:	Acute Myeloid Leukemia, Animal Disease Models, Apoptosis, Cell Cycle Checkpoints, Cultured Cells, Gene Knockout Techniques, Inbred C57BL Mice, Indoles, Neoplastic Gene Expression Regulation, Neoplastic Stem Cells, Niacinamide, Oligonucleotides, Recurrence, Small Interfering RNA, Telomerase, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, Animals, Mice
Source:	Cell Stem Cell
ISSN:	1934-5909
Publisher:	Cell Press
Volume:	15
Number:	6
Page Range:	775-90
Date:	4 December 2014
Official Publication:	https://doi.org/10.1016/j.stem.2014.11.010
PubMed:	View item in PubMed

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