BRD4-mediated repression of p53 is a target for combination therapy in AML

Anne-Louise Latif, Ashley Newcombe, Sha Li, Kathryn Gilroy, Neil A. Robertson, Xue Lei, Helen J. S. Stewart, John Cole, Maria Terradas Terradas, Loveena Rishi, Lynn McGarry, Claire McKeeve, Claire Reid, William Clark, Joana Campos, Kristina Kirschner, Andrew Davis, Jonathan Lopez, Jun-ichi Sakamaki, Jennifer P. Morton, Kevin M. Ryan, Stephen W. G. Tait, Sheela A. Abraham, Tessa Holyoake, Brian Higgins, Xu Huang, Karen Blyth, Mhairi Copland, Timothy J. T. Chevassut, Karen Keeshan and Peter D. Adams ()
Additional contact information
Anne-Louise Latif: University of Glasgow
Ashley Newcombe: University of Glasgow
Sha Li: Sanford Burnham Prebys Medical Discovery Institute
Kathryn Gilroy: University of Glasgow
Neil A. Robertson: University of Glasgow
Xue Lei: Sanford Burnham Prebys Medical Discovery Institute
Helen J. S. Stewart: University of Sussex
John Cole: University of Glasgow
Maria Terradas Terradas: University of Glasgow
Loveena Rishi: University of Glasgow
Lynn McGarry: Cancer Research UK Beatson Institute
Claire McKeeve: Queen Elizabeth University Hospital
Claire Reid: University of Glasgow
William Clark: Cancer Research UK Beatson Institute
Joana Campos: College of Medical Veterinary and Life Sciences, University of Glasgow
Kristina Kirschner: University of Glasgow
Andrew Davis: Sanford Burnham Prebys Medical Discovery Institute
Jonathan Lopez: University of Glasgow
Jun-ichi Sakamaki: Cancer Research UK Beatson Institute
Jennifer P. Morton: University of Glasgow
Kevin M. Ryan: Cancer Research UK Beatson Institute
Stephen W. G. Tait: University of Glasgow
Sheela A. Abraham: College of Medical Veterinary and Life Sciences, University of Glasgow
Tessa Holyoake: College of Medical Veterinary and Life Sciences, University of Glasgow
Brian Higgins: Roche Innovation Center-New York
Xu Huang: College of Medical Veterinary and Life Sciences, University of Glasgow
Karen Blyth: University of Glasgow
Mhairi Copland: College of Medical Veterinary and Life Sciences, University of Glasgow
Timothy J. T. Chevassut: University of Sussex
Karen Keeshan: College of Medical Veterinary and Life Sciences, University of Glasgow
Peter D. Adams: University of Glasgow

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi’s ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-20378-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20378-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-20378-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().