title: NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia.
abstract: Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction among PML/RARA, nucleophosmin (NPM), and topoisomerase II beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML); therefore, our model may be applicable to other more common leukemias driven by NPM.
authors.affiliation: Division of Experimental Medicine, Department of Oncology, Segal Cancer Centre and Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Nichol
authors.affiliation: Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular, and Developmental Biology and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80309, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galbraith
authors.affiliation: Department of Human Genetics, Segal Cancer Centre and Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Kleinman
authors.affiliation: Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular, and Developmental Biology and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80309, USA; Linda Crnic Institute for Down Syndrome, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Espinosa
authors.affiliation: Division of Experimental Medicine, Department of Oncology, Segal Cancer Centre and Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada. Electronic address: wmiller@ldi.jgh.mcgill.ca.
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000072482:Retinoic Acid Receptor alpha / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin / Q000633:toxicity*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D004268:DNA-Binding Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D034741:RNA, Small Interfering; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D000090243:Nucleophosmin; C070576:PML protein, human; D014212:Tretinoin; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human