Aryl hydrocarbon receptor is a tumor promoter in -amplified neuroblastoma cells through suppression of differentiation.

Neuroblastoma is the most common extracranial solid tumor in children. amplification is detected in almost half of high-risk cases and is associated with poorly differentiated tumors, poor patient prognosis and poor response to therapy, including retinoids. We identify the aryl hydrocarbon receptor (AhR) as a transcription factor promoting the growth and suppressing the differentiation of -amplified neuroblastoma. A neuroblastoma specific AhR transcriptional signature reveals an inverse correlation of AhR activity with patients' outcome, suggesting AhR activity is critical for disease progression. AhR modulates chromatin structures, reducing accessibility to regions responsive to retinoic acid. Genetic and pharmacological inhibition of AhR results in induction of differentiation. Importantly, AhR antagonism with clofazimine synergizes with retinoic acid in inducing differentiation both and . Thus, we propose AhR as a target for -amplified neuroblastoma and that its antagonism, combined with current standard-of-care, may result in a more durable response in patients.