title: Role of SIRT1 in the growth and regulation of normal hematopoietic and leukemia stem cells.
abstract: OBJECTIVE
  Recent studies have enhanced our understanding of the role of the SIRT1 deacetylase in regulation of normal hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), and its importance in regulating autophagy and epigenetic reprogramming in response to metabolic alterations.
  
  
  RESULTS
  Studies employing conditional deletion mouse models indicate an important role of SIRT1 in maintenance of adult HSCs under conditions of stress. SIRT1 is significantly overexpressed in LSC populations from acute myeloid leukemia (AML) patients with the FLT3-ITD mutation, and maintains their survival, growth and drug resistance, as previously described for chronic myelogenous leukemia (CML). SIRT1 can also enhance leukemia evolution and drug resistance by promoting genetic instability. Recent studies indicate an important role of SIRT1 in regulating autophagy in response to oxidative stress and nutrient requirements, and have elucidated complex mechanisms by which SIRT1 regulates epigenetic reprogramming of stem cells.
  
  
  CONCLUSIONS
  SIRT1 inhibition holds promise as a novel approach for ablation of LSCs in chronic phase CML or FLT3-ITD-associated AML. Additional studies to understand the role of SIRT1 in linking metabolic alterations to genomic stability, autophagy and epigenetic reprogramming of stem cells are warranted.
authors.affiliation: aDivision of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, California bDivision of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C447939:SIRT1 protein, human; D056564:Sirtuin 1