Latif, A.-L. et al. (2021) BRD4-mediated repression of p53 is a target for combination therapy in AML. Nature Communications, 12, 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 Terradas Terradas, Maria 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 Morton, Professor Jen and Tait, Professor Stephen and Lopez, Dr Jonathan and Newcombe, Ashley and Copland, Professor Mhairi 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 Terradas, M., 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 > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity 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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