title: RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma.
abstract: Multiple myeloma (MM) is a plasma cell cancer with poor survival, characterized by the expansion of multiple myeloma cells (MMCs) in the bone marrow. Using a microarray-based genome-wide screen for genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 among the most downregulated genes. RecQ helicases are DNA unwinding enzymes involved in the maintenance of chromosome stability. Here we show that RECQ1 is significantly overexpressed in MMCs compared to normal plasma cells and that increased RECQ1 expression is associated with poor prognosis in three independent cohorts of patients. Interestingly, RECQ1 knockdown inhibits cells growth and induces apoptosis in MMCs. Moreover, RECQ1 depletion promotes the development of DNA double-strand breaks, as evidenced by the formation of 53BP1 foci and the phosphorylation of ataxia-telangiectasia mutated (ATM) and histone variant H2A.X (H2AX). In contrast, RECQ1 overexpression protects MMCs from melphalan and bortezomib cytotoxicity. RECQ1 interacts with PARP1 in MMCs exposed to treatment and RECQ1 depletion sensitizes MMCs to poly(ADP-ribose) polymerase (PARP) inhibitor. DNMT inhibitor treatment results in RECQ1 downregulation through miR-203 deregulation in MMC. Altogether, these data suggest that association of DNA damaging agents and/or PARP inhibitors with DNMT inhibitors may represent a therapeutic approach in patients with high RECQ1 expression associated with a poor prognosis.
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: E
authors.initials: E
authors.lastname: Viziteu
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.|Department of Biological Hematology, CHU Montpellier, Montpellier, France.|University of Montpellier, UFR de Médecine, Montpellier, France.
authors.forename: B
authors.initials: B
authors.lastname: Klein
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: J
authors.initials: J
authors.lastname: Basbous
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Clinical Proteomic Platform, CHU Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Hirtz
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Gourzones
authors.affiliation: Clinical Proteomic Platform, CHU Montpellier, Montpellier, France.
authors.forename: L
authors.initials: L
authors.lastname: Tiers
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: A
authors.initials: A
authors.lastname: Bruyer
authors.affiliation: Department of Clinical Hematology, CHU Montpellier, Montpellier, France.
authors.forename: L
authors.identifier: 0000-0001-5904-1286
authors.initials: L
authors.lastname: Vincent
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Grandmougin
authors.affiliation: Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.|Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Seckinger
authors.affiliation: Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.|Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: A
authors.initials: A
authors.lastname: Constantinou
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.
authors.forename: P
authors.initials: P
authors.lastname: Pasero
authors.affiliation: Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.|Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hose
authors.affiliation: Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France.|Department of Biological Hematology, CHU Montpellier, Montpellier, France.|University of Montpellier, UFR de Médecine, Montpellier, France.
authors.forename: J
authors.identifier: 0000-0002-5717-3207
authors.initials: J
authors.lastname: Moreaux
mesh_terms: D000069286:Bortezomib / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008558:Melphalan / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D010950:Plasma Cells / Q000187:drug effects / Q000201:enzymology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D053484:RecQ Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000069286:Bortezomib; D015257:DNA-Cytosine Methylases; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C506725:RECQL protein, human; D053484:RecQ Helicases; D008558:Melphalan