title: BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells.
abstract: The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples. Exposure to OTX015 lead to cell growth inhibition, cell cycle arrest and apoptosis at submicromolar concentrations in acute leukemia cell lines and patient-derived leukemic cells, as described with the canonical JQ1 BET inhibitor. Treatment with JQ1 and OTX15 induces similar gene expression profiles in sensitive cell lines, including a c-MYC decrease and an HEXIM1 increase. OTX015 exposure also induced a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression was unchanged. c-MYC, BRD2, BRD3, BRD4 and HEXIM1 mRNA levels did not correlate however with viability following exposure to OTX015. Sequential combinations of OTX015 with other epigenetic modifying drugs, panobinostat and azacitidine have a synergic effect on growth of the KASUMI cell line. Our results indicate that OTX015 and JQ1 have similar biological effects in leukemic cells, supporting OTX015 evaluation in a Phase Ib trial in relapsed/refractory leukemia patients.
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.|Laboratory of Hematology, Hôpital Saint-Louis (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France.
authors.forename: Marie-Magdelaine
authors.initials: MM
authors.lastname: Coudé
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.|Hematology Department, Hôpital Avicenne (Assistance Publique - Hôpitaux de Paris and University Paris XIII), Bobigny, France.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.
authors.forename: Jeannig
authors.initials: J
authors.lastname: Berrou
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Dupont
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.
authors.forename: Sibyl
authors.initials: S
authors.lastname: Bertrand
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Masse
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.|Leukemia Unit, Hematology Department, Hôpital Saint-Louis (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.|Leukemia Unit, Hematology Department, Hôpital Saint-Louis (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Itzykson
authors.affiliation: Bioinformatics, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Delord
authors.affiliation: Oncology Therapeutic Development, Clichy, France.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Riveiro
authors.affiliation: Oncoethix, Lausanne, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Herait
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.|Department of Pediatric Hemato-Immunology, Hôpital Robert Debré (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.|Leukemia Unit, Hematology Department, Hôpital Saint-Louis (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Laboratoire de Transfert des Leucémies, Institut Universitaire d'Hématologie, University Paris VII, Paris, France.|Hematology Department, Hôpital Avicenne (Assistance Publique - Hôpitaux de Paris and University Paris XIII), Bobigny, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Gardin
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D005260:Female; D005455:Fluorescent Antibody Technique; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000473:pathology*; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects; D059467:Transcriptome; D000092468:Bromodomain Containing Proteins
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006575:Heterocyclic Compounds, 3-Ring; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C489427:MYC protein, human; C000605331:OTX015
keywords: BET inhibitors; HEXIM1; OTX015; acute leukemias; c-MYC