title: Identification of bromodomain-containing protein-4 as a novel marker and epigenetic target in mast cell leukemia.
abstract: Advanced systemic mastocytosis (SM) is a life-threatening neoplasm characterized by uncontrolled growth and accumulation of neoplastic mast cells (MCs) in various organs and a poor survival. So far, no curative treatment concept has been developed for these patients. We identified the epigenetic reader bromodomain-containing protein-4 (BRD4) as novel drug target in aggressive SM (ASM) and MC leukemia (MCL). As assessed by immunohistochemistry and PCR, neoplastic MCs expressed substantial amounts of BRD4 in ASM and MCL. The human MCL lines HMC-1 and ROSA also expressed BRD4, and their proliferation was blocked by a BRD4-specific short hairpin RNA. Correspondingly, the BRD4-targeting drug JQ1 induced dose-dependent growth inhibition and apoptosis in HMC-1 and ROSA cells, regardless of the presence or absence of KIT D816V. In addition, JQ1 suppressed the proliferation of primary neoplastic MCs obtained from patients with ASM or MCL (IC50: 100-500 nm). In drug combination experiments, midostaurin (PKC412) and all-trans retinoic acid were found to cooperate with JQ1 in producing synergistic effects on survival in HMC-1 and ROSA cells. Taken together, we have identified BRD4 as a promising drug target in advanced SM. Whether JQ1 or other BET-bromodomain inhibitors are effective in vivo in patients with advanced SM remains to be elucidated.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France.
authors.forename: G
authors.initials: G
authors.lastname: Wedeh
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Eisenwort
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.|Department of Radiotherapy, Medical University of Vienna, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Blatt
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Hadzijusufovic
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Sadovnik
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Müllauer
authors.affiliation: Third Medical Department, Division of Hematology, University of Heidelberg, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schwaab
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Hoffmann
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Guy's Hospital, Division of Clinical Haematology, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Radia
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: W R
authors.initials: WR
authors.lastname: Sperr
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Hoermann
authors.affiliation: Third Medical Department, Division of Hematology, University of Heidelberg, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reiter
authors.affiliation: Institute of Pathology, Ludwig Maximilian University, Munich, Germany.
authors.forename: H-P
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Zuber
authors.affiliation: LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France.
authors.forename: M
authors.initials: M
authors.lastname: Arock
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Valent
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007946:Leukemia, Mast-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D011990:Receptors, Transferrin / Q000032:analysis; D060149:Tetraspanin 30 / Q000032:analysis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D015703:Antigens, CD; D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D019009:Proto-Oncogene Proteins c-kit; D011990:Receptors, Transferrin; D060149:Tetraspanin 30; D014157:Transcription Factors; D014212:Tretinoin; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C554586:CD63 protein, human; C068126:CD71 antigen