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

Nat Commun. 2021 Jan 11;12(1):241. doi: 10.1038/s41467-020-20378-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Blast Crisis / pathology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Molecular Targeted Therapy*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • tribbles 2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Protein Serine-Threonine Kinases