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

G. Giotopoulos, W. I. Chan, S. J. Horton, D. Ruau, P. Gallipoli, A. Fowler, C. Crawley, E. Papaemmanuil, P. J. Campbell, B. Göttgens, Jan Van Deursen, P. A. Cole, B. J P Huntly

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)279-289
Number of pages11
JournalOncogene
Volume35
Issue number3
DOIs
StatePublished - Jan 21 2016

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Acute Myeloid Leukemia
Epigenomics
Therapeutics
Histone Acetyltransferases
Histone Deacetylases
Hematologic Neoplasms
Post Translational Protein Processing
Acetylation
Growth
Cell Cycle Checkpoints
Histones
Lysine
Tail
Leukemia
Maintenance
Apoptosis
DNA
Neoplasms
Lysine Acetyltransferases
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Giotopoulos, G., Chan, W. I., Horton, S. J., Ruau, D., Gallipoli, P., Fowler, A., ... Huntly, B. J. P. (2016). The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia. Oncogene, 35(3), 279-289. https://doi.org/10.1038/onc.2015.92

The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia. / 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, Jan; Cole, P. A.; Huntly, B. J P.

In: Oncogene, Vol. 35, No. 3, 21.01.2016, p. 279-289.

Research output: Contribution to journalArticle

Giotopoulos, G, Chan, WI, Horton, SJ, Ruau, D, Gallipoli, P, Fowler, A, Crawley, C, Papaemmanuil, E, Campbell, PJ, Göttgens, B, Van Deursen, J, Cole, PA & Huntly, BJP 2016, 'The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia', Oncogene, vol. 35, no. 3, pp. 279-289. https://doi.org/10.1038/onc.2015.92
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, Jan ; Cole, P. A. ; Huntly, B. J P. / The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia. In: Oncogene. 2016 ; Vol. 35, No. 3. pp. 279-289.
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