Activation of p53 by SIRT1 inhibition enhances elimination of CML leukaemia stem cells in combination with imatinib

Li, L., Wang, L., Li, L., Wang, Z., Ho, Y., McDonald, T., Holyoake, T.L., Chen, W. and Bhatia, R. (2012) Activation of p53 by SIRT1 inhibition enhances elimination of CML leukaemia stem cells in combination with imatinib. Cancer Cell, 21(2), pp. 266-281. (doi: 10.1016/j.ccr.2011.12.020) (PMID:22340598) (PMCID:PMC3285436)

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Abstract

BCR-ABL tyrosine kinase inhibitors (TKI) fail to eliminate quiescent leukemia stem cells (LSC) in chronic myelogenous leukemia (CML). Thus, strategies targeting LSC are required to achieve cure. We show that the NAD+-dependent deacetylase SIRT1 is overexpressed in human CML LSC. Pharmacological inhibition of SIRT1 or SIRT1 knockdown increased apoptosis in LSC of chronic phase and blast crisis CML and reduced their growth in vitro and in vivo. SIRT1 effects were enhanced in combination with the BCR-ABL TKI imatinib. SIRT1 inhibition increased p53 acetylation and transcriptional activity in CML progenitors, and the inhibitory effects of SIRT1 targeting on CML cells depended on p53 expression and acetylation. Activation of p53 via SIRT1 inhibition represents a potential approach to target CML LSC.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa
Authors: Li, L., Wang, L., Li, L., Wang, Z., Ho, Y., McDonald, T., Holyoake, T.L., Chen, W., and Bhatia, R.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Cell
Publisher:Elsevier (Cell Press)
ISSN:15356108
ISSN (Online):1878-3686

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
498551Key survival pathways in chronic myeloid leukaemic (CML) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008Institute of Cancer Sciences