title: RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
abstract: Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Junwei
authors.initials: J
authors.lastname: Shi
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.forename: Amy R
authors.initials: AR
authors.lastname: Rappaport
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sison
authors.forename: Daniel
authors.initials: D
authors.lastname: Magoon
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatt
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Taylor
authors.forename: Christopher
authors.initials: C
authors.lastname: Johns
authors.forename: Agustin
authors.initials: A
authors.lastname: Chicas
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
mesh_terms: D000107:Acetylation; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins