Activation of p53 by SIRT1 Inhibition Enhances Elimination of CML Leukemia Stem Cells in Combination with Imatinib

SummaryBCR-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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (183 K)Download as PowerPoint slideHighlights► SIRT1 expression and activity is enhanced in CML compared to normal stem cells ► SIRT1 inhibition cooperates with Imatinib to increase elimination of CML stem cells ► SIRT1 inhibition acetylates p53 and activates p53 signaling in CML cells ► The effects of SIRT1 inhibition on CML stem cells are p53 dependent