title: RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells.
abstract: In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.
authors.affiliation: Institute of Research in Immunology and Cancer (IRIC), Molecular Biology Program, and Department of Pharmacology, University of Montreal, Montreal, QC, Canada H3C 3J7.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Girard
authors.forename: Mathieu
authors.initials: M
authors.lastname: Tremblay
authors.forename: Magali
authors.initials: M
authors.lastname: Humbert
authors.forename: Benoît
authors.initials: B
authors.lastname: Grondin
authors.forename: André
authors.initials: A
authors.lastname: Haman
authors.forename: Jean
authors.initials: J
authors.lastname: Labrecque
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Trang
authors.initials: T
authors.lastname: Hoang
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D018014:Gene Transfer Techniques; D042381:Granulocyte Precursor Cells; D006098:Granulocytes / Q000502:physiology; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D006657:Histones; D051741:Kruppel-Like Transcription Factors; D015514:Oncogene Proteins, Fusion; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C092037:ZBTB16 protein, human; D056284:Histone Deacetylase 1
keywords: APL; granulocyte differentiation; histone modification; protein interaction; transcription inhibition
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