Neuroblastoma epigenetic landscape: drugging opportunities

The epigenetic machinery interprets cell intrinsic and extrinsic signals in a dynamic yet reversible process and is recruited to specific genes to implement an ordered lineage-specifying program when a stem cell develops to a differentiated cell. Alterations in this epigenetic machinery (mutations or overexpression of many chromatin remodelers, DNA hypermethylation) lead to disruptions in normal development resulting in many pathologies, including cancer. Epigenetics and differentiation are intimately related in neuroblastoma (NB), the most common extracranial solid tumor of childhood. Based on its histology, transcriptome analysis and its propensity to differentiate, NB has been considered a failure of the sympathoadrenal progenitors to differentiate. High-risk NB is one of the most aggressive pediatric tumors accounting for 15% of all pediatric oncology deaths, and less than 50% of patients experience long-term survival, despite intense multimodal treatment. Recently, the epigenome of NB tumors has been explored in order to identify critical enzymes as novel therapeutic targets for differentiation reprogramming. In this chapter, we will focus on the recently discovered epigenetic alterations in enzymes responsible for both DNA methylation and histone modifications in NB.