title: Regain control of p53: Targeting leukemia stem cells by isoform-specific HDAC inhibition.
abstract: Leukemia stem cells (LSCs) are self-renewable, leukemia-initiating populations that are often resistant to traditional chemotherapy and tyrosine kinase inhibitors currently used for treatment of acute or chronic myeloid leukemia. The persistence and continued acquisition of mutations in resistant LSCs represent a major cause of refractory disease and/or relapse after remission. Understanding the mechanisms regulating LSC growth and survival is critical in devising effective therapies that will improve treatment response and outcome. Several recent studies indicate that the p53 tumor suppressor pathway is often inactivated in de novo myeloid leukemia through oncogenic-specific mechanisms, which converge on aberrant p53 protein deacetylation. Here, we summarize our current understanding of the various mechanisms underlying deregulation of histone deacetylases (HDACs), which could be exploited to restore p53 activity and enhance targeting of LSCs in molecularly defined patient subsets.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Norbert Gehr and Family Leukemia Center, City of Hope Medical Center, Duarte, CA. Electronic address: YKuo@coh.org.
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Norbert Gehr and Family Leukemia Center, City of Hope Medical Center, Duarte, CA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Norbert Gehr and Family Leukemia Center, City of Hope Medical Center, Duarte, CA.
authors.forename: Guerry J
authors.initials: GJ
authors.lastname: Cook
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000208:Acute Disease; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C409470:HDAC8 protein, human; D006655:Histone Deacetylases