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

Latif, A.-L. et al. (2021) BRD4-mediated repression of p53 is a target for combination therapy in AML. Nature Communications, 12(1), 241. (doi: 10.1038/s41467-020-20378-8) (PMID:33431824) (PMCID:PMC7801601)

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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.

Item Type:Articles
Additional Information:Work in the lab of P.D.A. was funded by CRUK program grant C10652/A16566. We thank support from Children with Cancer UK and the Howat Foundation (to Ka.Ke. and J.C.). Kr.Ki. was funded by Wellcome Trust (Grant number 105641/Z/14/Z). H.J.S.S. was supported by the Sussex Cancer Fund. Additional funding from CRUK Glasgow Centre (A25142) and Core Services at the Cancer Research UK Beatson Institute (A17196). This study was supported by the Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and the Chief Scientist’s Office, Scotland. Experiments in the lab of T.J.T.C. were supported by Sussex Cancer Fund. X.H. is a John Goldman Fellow [Leuka 2016/JGF/0005].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Abraham, Dr Sheela and Cole, Mr John and Clark, Mr William and Blyth, Professor Karen and Robertson, Mr Neil and Keeshan, Dr Karen and Adams, Professor Peter and Morton, Dr Jennifer and Huang, Dr Xu and Holyoake, Professor Tessa and Ryan, Professor Kevin and Latif, Dr Anne-Louise and Gilroy, Dr Kathryn and Kirschner, Dr Kristina and McGarry, Ms Lynn and Campos, Ms Joana and Tait, Professor Stephen and Lopez, Dr Jonathan and Newcombe, Ashley and Copland, Professor Mhairi and Terradas-Terradas, Miss Maria and Reid, Mrs Claire
Authors: Latif, A.-L., Newcombe, A., Li, S., Gilroy, K., Robertson, N. A., Lei, X., Stewart, H. J.S., Cole, J., Terradas, M. T., Rishi, L., McGarry, L., McKeeve, C., Reid, C., Clark, W., Campos, J., Kirschner, K., Davison, A., Lopez, J., Sakamaki, J.-i., Morton, J. P., Ryan, K. M., Tait, S. W.G., Abraham, S. A., Holyoake, T., Higgins, B., Huang, X., Blyth, K., Copland, M., Chevassut, T. J.T., Keeshan, K., and Adams, P. D.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12(1):241
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
168615Senescence-associated chromatin changes a barrier to tumor progression.Owen SansomCancer Research UK (CRUK)C10652/A16566CS - Epigenetics
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research
173450Delineation of the critical epigenetic regulatory machinery selective for acute myeloid leukaemia stem cell functionXu HuangLeuka (LEUKA)2016/JGF/0005CS - Paul O'Gorman Leukaemia Research Centre