title: The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.
abstract: Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Giotopoulos
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.|State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau.
authors.forename: W-I
authors.initials: WI
authors.lastname: Chan
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Horton
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
authors.forename: D
authors.initials: D
authors.lastname: Ruau
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
authors.forename: P
authors.initials: P
authors.lastname: Gallipoli
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Fowler
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
authors.forename: C
authors.initials: C
authors.lastname: Crawley
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: E
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
authors.forename: B
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Van Deursen
authors.affiliation: Department of Pharmacology and Molecular sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Cole
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
authors.forename: B J P
authors.initials: BJ
authors.lastname: Huntly
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000008:administration & dosage; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000096:biosynthesis / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009578:Nitrobenzenes; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage; D047069:Pyrazolones; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C584509:4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid; D001565:Benzoates; D009578:Nitrobenzenes; D010446:Peptide Fragments; D011720:Pyrazoles; D047069:Pyrazolones; D012795:Sialoglycoproteins; C571744:bone sialoprotein (35-62), human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases