Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma [ATAC-seq]

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that requires long-term intensive multimodal therapies. Despite this, high-risk patients have a poor survival rate, which has prompted extensive studies aimed at identifying more effective therapies against neuroblastomas with MNA. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein can promote a cellular state switch in mesenchymal cells to an adrenergic state. This cellular state transition is accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C), which act in concert to control the expression of MYCN and adrenergic core regulatory transcription factors (CRC TF). Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation, apoptosis, and a type I interferon response. Further, KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA, without overt toxicity in animals. Thus, KDM4 blockade may be a novel and transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.