Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors

Sci Rep. 2020 Feb 18;10(1):2851. doi: 10.1038/s41598-020-59469-3.

Abstract

Epigenetic reprogramming in Acute Myeloid Leukemia (AML) leads to the aberrant activation of super enhancer (SE) landscapes that drive the expression of key oncogenes, including the oncogenic MYC pathway. These SEs have been identified as promising therapeutic targets, and have given rise to a new class of drugs, including BET protein inhibitors, which center on targeting SE activity. NR4A nuclear receptors are tumor suppressors of AML that function in part through transcriptional repression of the MYC-driven oncogenic program via mechanisms that remain unclear. Here we show that NR4A1, and the NR4A inducing drug dihydroergotamine (DHE), regulate overlapping gene expression programs in AML and repress transcription of a subset of SE-associated leukemic oncogenes, including MYC. NR4As interact with an AML-selective SE cluster that governs MYC transcription and decommissions its activation status by dismissing essential SE-bound coactivators including BRD4, Mediator and p300, leading to loss of p300-dependent H3K27 acetylation and Pol 2-dependent eRNA transcription. DHE shows similar efficacy to the BET inhibitor JQ1 at repressing SE-dependent MYC expression and AML growth in mouse xenografts. Thus, DHE induction of NR4As provides an alternative strategy to BET inhibitors to target MYC dependencies via suppression of the AML-selective SE governing MYC expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cellular Reprogramming / genetics
  • Dihydroergotamine / pharmacology
  • E1A-Associated p300 Protein / genetics
  • Enhancer Elements, Genetic / genetics*
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / agonists
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics*
  • Oncogenes / genetics
  • Proto-Oncogene Proteins c-myc / genetics*
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • Xenograft Model Antitumor Assays

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • MYC protein, human
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Dihydroergotamine
  • E1A-Associated p300 Protein
  • EP300 protein, human