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

Oncogene volume 35, pages 279–289 (2016)Cite this article

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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.

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Acknowledgements

Funding in the Huntly laboratory comes from Cancer Research UK, Leukemia Lymphoma Research, the Kay Kendal Leukemia Fund, the Leukemia lymphoma Society of America, the Wellcome Trust, The Medical Research Council and an NIHR Cambridge Biomedical Research Centre grant. Patient samples were processed in the Cambridge Blood and Stem Cell Biobank.

Author Contributions

BH, GG and W-IC designed the experiments, GG, W-IC, SJH, PG, AF and EP performed experiments. GG, WI-C, DR, EP, PC, BG and BH analyzed data. CC, JMVD and PAC provided critical reagents. BH oversaw the study. BH, GG and W-IC wrote and all authors reviewed the manuscript.

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Author notes

  1. G Giotopoulos and W-I Chan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK

    G Giotopoulos, W-I Chan, S J Horton, D Ruau, P Gallipoli, A Fowler, C Crawley, P J Campbell, B Göttgens & B J P Huntly

  2. Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Cambridge,, UK

    G Giotopoulos, W-I Chan, S J Horton, D Ruau, P Gallipoli, B Göttgens & B J P Huntly

  3. State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau

    W-I Chan

  4. Wellcome Trust Sanger Institute, Hinxton, UK

    E Papaemmanuil & P J Campbell

  5. Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

    J M Van Deursen

  6. Department of Pharmacology and Molecular sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    P A Cole

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  1. G Giotopoulos
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Corresponding author

Correspondence to B J P Huntly.

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Competing interests

PA Cole is a cofounder, equity holder and paid consultant for Acylin Therapeutics which is developing p300 HAT inhibitors.

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Supplementary Information accompanies this paper on the Oncogene website

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Giotopoulos, G., Chan, WI., Horton, S. et al. The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia. Oncogene 35, 279–289 (2016). https://doi.org/10.1038/onc.2015.92

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