Journal
CANCER CELL
Volume 21, Issue 2, Pages 266-281Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2011.12.020
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Funding
- National Institutes of Health [R01 HL77847, R01 CA95684, R01 CA143421]
- Samuel Waxman Cancer Research Foundation
- Leukemia and Lymphoma Society
- V Foundation
- Cancer Research UK [C11074/A11008]
- Glasgow Experimental Cancer Medicine Centre (ECMC)
- Cancer Research UK
- Chief Scientist's Office (Scotland)
- Cancer Research UK [11008] Funding Source: researchfish
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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.
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