Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN

Abstract

Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation. Here we show that when MYCN-amplified neuroblastomas cells are treated with retinoic acid, histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1 and SOX4 expression. These findings indicate that treatment with retinoids can reprogram the enhancer landscape, resulting in downregulation of MYCN expression, while establishing a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids in high-risk neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of amplification of this gene.