Although induction of differentiation represents an effective strategy for
neuroblastoma treatment, the mechanisms underlying
neuroblastoma differentiation are poorly understood. We generated a computational model of
neuroblastoma differentiation consisting of interconnected gene clusters identified based on symmetric and asymmetric gene expression relationships. We identified a differentiation signature consisting of series of gene clusters comprised of 1251 independent genes that predicted
neuroblastoma differentiation in independent datasets and in
neuroblastoma cell lines treated with agents known to induce differentiation. This differentiation signature was associated with patient outcomes in multiple independent patient cohorts and validated the role of MYCN expression as a marker of
neuroblastoma differentiation. Our results further identified novel genes associated with MYCN via asymmetric Boolean implication relationships that would not have been identified using symmetric computational approaches and that were associated with both
neuroblastoma differentiation and patient outcomes. Our differentiation signature included a cluster of genes involved in intracellular signaling and
growth factor receptor trafficking pathways that is strongly associated with
neuroblastoma differentiation, and we validated the associations of UBE4B, a gene within this cluster, with
neuroblastoma cell and
tumor differentiation. Our findings demonstrate that Boolean network analyses of symmetric and asymmetric gene expression relationships can identify novel genes and pathways relevant for
neuroblastoma tumor differentiation that could represent potential therapeutic targets.