BRD4-mediated repression of p53 is a target for combination therapy in AML.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33431824.
- Also identified by DOI 10.1038/s41467-020-20378-8 and PMC identifier 7801601.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antineoplastic Combined Chemotherapy Protocols
- Cell Cycle Proteins
- Leukemia, Myeloid, Acute
- Molecular Targeted Therapy
- Transcription Factors
- Tumor Suppressor Protein p53