title: Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia.
abstract: Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: S
authors.identifier: 0000-0001-7036-1053
authors.initials: S
authors.lastname: Peirs
authors.affiliation: Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Frismantas
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Matthijssens
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Van Loocke
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.|Molecular and Cellular Oncology Lab, VIB Inflammation Research Center, Ghent University, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Pieters
authors.affiliation: Cancer Research Institute Ghent (CRIG), Ghent, Belgium.|Molecular and Cellular Oncology Lab, VIB Inflammation Research Center, Ghent University, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Vandamme
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Lintermans
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: M P
authors.initials: MP
authors.lastname: Dobay
authors.affiliation: Cancer Research Institute Ghent (CRIG), Ghent, Belgium.|Molecular and Cellular Oncology Lab, VIB Inflammation Research Center, Ghent University, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Berx
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.|Molecular and Cellular Oncology Lab, VIB Inflammation Research Center, Ghent University, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Goossens
authors.affiliation: Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: B C
authors.initials: BC
authors.lastname: Bornhauser
authors.affiliation: Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: J-P
authors.initials: JP
authors.lastname: Bourquin
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Van Vlierberghe
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11 / Q000096:biosynthesis / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D000072417:Protein Domains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D000072224:Bcl-2-Like Protein 11; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C000606775:BCL2L11 protein, human; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C579720:venetoclax