title: Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib.
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.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Yinwei
authors.initials: Y
authors.lastname: Ho
authors.forename: Tinisha
authors.initials: T
authors.lastname: McDonald
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: WenYong
authors.initials: W
authors.lastname: Chen
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D004359:Drug Therapy, Combination; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; C447939:SIRT1 protein, human; D056564:Sirtuin 1