title: Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis.
abstract: Since the 19th century, arsenic (As2O3) has been used in the treatment of chronic myelogenous leukemia (CML) characterized by the t(9;22) translocation. As2O3 induces complete remissions in patients with acute promyelocytic leukemia. The response to As2O3 is genetically determined by the t(15;17)-or the t(9;22)-specific fusion proteins PML/RARalpha or BCR/ABL. The PML portion of PML/RARalpha is crucial for the sensitivity to As2O3. PML is nearly entirely contained in PML/RARalpha. PML is upregulated by oncogenic RAS in primary fibroblasts. The aberrant kinase activity of BCR/ABL leads to constitutive activation of RAS. Therefore, we hypothesized that BCR/ABL could increase sensitivity to As2O2-induced apoptosis by modifying PML expression. To disclose the mechanism of As2O3-induced apoptosis in PML/RARalpha- and BCR/ABL-expressing cells, we focused on the role of PML for As2O3-induced cell death. Here we report that (i) sensitivity to As2O3-induced apoptosis of U937 cells can be increased either by overexpression of PML, or by conditional expression of activated RAS; (ii) also the expression of the t(8;21)-related AML-1/ETO increased sensitivity to As2O3-induced apoptosis; (iii) both BCR/ABL and AML-1/ETO activated RAS and modified the PML expression pattern; (iv) the expression of either BCR/ABL or AML-1/ETO rendered U937 cells sensitive to interferon alpha-induced apoptosis. In summary, these data suggest a crucial role of factors able to upregulate PML for As2O2-induced cell death.
authors.affiliation: Med. Klinik III/Abtl. Hämatologie, Johann Wolfgang Goethe-Universität, D-60590 Frankfurt, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Puccetti
authors.forename: Tim
authors.initials: T
authors.lastname: Beissert
authors.forename: Saskia
authors.initials: S
authors.lastname: Güller
authors.forename: Jun E
authors.initials: JE
authors.lastname: Li
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D011905:Genes, ras; D006801:Humans; D000068877:Imatinib Mesylate; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D019076:Transgenes; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D001549:Benzamides; D004791:Enzyme Inhibitors; D010087:Oxides; D010879:Piperazines; D020033:Protein Isoforms; D011743:Pyrimidines; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl