title: Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells.
abstract: The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1c+ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34(+) hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML.
authors.affiliation: Authors' Affiliations: Houston Methodist Research Institute, Houston, Texas; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; and Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: John A
authors.initials: JA
authors.lastname: Valenta
authors.forename: Leasha J
authors.initials: LJ
authors.lastname: Schaub
authors.forename: Bhavin
authors.initials: B
authors.lastname: Shah
authors.forename: Karissa
authors.initials: K
authors.lastname: Peth
authors.forename: Bryce P
authors.initials: BP
authors.lastname: Portier
authors.forename: Melissa
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Santhana G T
authors.initials: SG
authors.lastname: Devaraj
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.forename: Jianting
authors.initials: J
authors.lastname: Sheng
authors.forename: Swaminathan P
authors.initials: SP
authors.lastname: Iyer
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D019254:Genes, bcl-2; D016259:Genes, myc; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D000077767:Panobinostat; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D008565:Membrane Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000077767:Panobinostat; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C000606775:BCL2L11 protein, human; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000606776:Bcl2l11 protein, mouse