The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia

• Published in: Oncogene 2016-01, Vol.35 (3), p.279-289
• Main Authors: Giotopoulos, G, Chan, W-I, Horton, S J, Ruau, D, Gallipoli, P, Fowler, A, Crawley, C, Papaemmanuil, E, Campbell, P J, Göttgens, B, Van Deursen, J M, Cole, P A, Huntly, B J P
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/31; 38/39; 631/67/1990/283/1897; 64/110; 64/60; Analysis; Animals; Apoptosis; Apoptosis - drug effects; Benzoates - administration & dosage; Cell Biology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; E1A-Associated p300 Protein - biosynthesis; E1A-Associated p300 Protein - genetics; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Female; Gene Expression Regulation, Leukemic - drug effects; Health aspects; Histone Acetyltransferases - antagonists & inhibitors; Histone Acetyltransferases - genetics; Human Genetics; Humans; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Male; Medicine; Medicine & Public Health; Mice; Nitrobenzenes; Oncology; original-article; Pathogenesis; Peptide Fragments - biosynthesis; Peptide Fragments - genetics; Protein expression; Pyrazoles - administration & dosage; Pyrazolones; Sialoglycoproteins - biosynthesis; Sialoglycoproteins - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.92

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.