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

S. Greg Call,Sandra L. Grimm,Orla M. Conneely,Loc Nguyen,Ryan P. Duren,Cristian Coarfa,Pablo R. Freire,Anil K. Panigrahi

doi:10.1038/s41598-020-59469-3

S. Greg Call, Sandra L. Grimm + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-59469-3

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Journal: Scientific Reports	Publication Date: Feb 18, 2020
Citations: 20	License type: open-access

Affiliation: Baylor College of Medicine

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.

Highlights

The c-MYC proto-oncogene is a common driver of leukemogenicity and Acute Myeloid Leukemia (AML) progression[21]
We show that NR4A1 binds directly to the MYC super enhancer (SE) where it dismisses essential coactivators, leading to loss of SE functional activity by eliminating Pol II-dependent Enhancer RNA (eRNA) transcription and enhancer-promoter looping
Using a chemical genomics screening approach, we recently identified an FDA-approved drug, dihydroergotamine (DHE), that relieves NR4A silencing in AML cells by promoting transcription elongation of silenced NR4As

Summary

Introduction

The c-MYC proto-oncogene (hereafter referred to as MYC) is a common driver of leukemogenicity and AML progression[21]. Using in silico chemical genomics screening, we recently identified the FDA-approved drug dihydroergotamine (DHE) as a small molecule inducer of silenced NR4As, which promotes NR4A-dependent suppression of AML cell proliferation and exhibits antileukemic activity across a subset of cytogenetically distinct human AML cells both in vitro and in xenograft models of human AML33. We show that the efficacy of DHE in suppressing SE-dependent expression of MYC in vitro, and MYC-dependent AML maintenance in vivo, is similar to that of BET bromodomain inhibitor JQ1 These data predict that DHE reactivation of NR4A nuclear receptors provides an alternative strategy to BET inhibitors to target MYC dependencies in AML cells via suppression of the AML-selective SE governing MYC expression

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