Therefore, the impact of NOTCH signaling on NB biology needs to be addressed carefully, as the biological outcomes of NOTCH signaling might be different depending on the subtype of NB (MYCN-amplification status), different experimental settings (physiological expression levels vs. overexpression), developmental stage and cell of origin, as well as the contribution of the tumor microenvironment (ligand activation vs. overexpression of NICD). This evidence concerns the gene MYCN and neoplasm.