Abstract
Sympathetic noradrenergic and NCC-like transcriptional networks promote neuroblastoma heterogeneity.
Major finding: Sympathetic noradrenergic and NCC-like transcriptional networks promote neuroblastoma heterogeneity.
Approach: Characterization of the neuroblastoma superenhancer landscape identifies core transcriptional circuitries.
Impact: Elucidation of neuroblastoma cell identities may provide insight into therapy design.
Neuroblastoma is a pediatric cancer that arises in the peripheral sympathetic nervous system, most frequently in the adrenal glands, and exhibits a great clinical heterogeneity; however, mechanisms underlying neuroblastoma heterogeneity have not been fully elucidated because neuroblastoma harbors few somatic mutations. Recent evidence suggests that core transcriptional regulatory circuitries control the gene expression programs that determine cell identity. To identify core transcriptional networks that drive neuroblastoma identity, Boeva and colleagues characterized the superenhancer landscapes of two human neural crest cell and 25 human neuroblastoma cell lines. Group I neuroblastoma cell lines exhibited a superenhancer pattern which was associated with transcription factor loci that control sympathetic noradrenergic cell identity. Group II neuroblastoma cell lines and human neural crest cell lines exhibited highly similar superenhancer patterns, and four cell lines, some of which were phenotypically heterogeneous, exhibited superenhancer features of both Groups I and II. Predictive algorithms demonstrated that Group I neuroblastomas are characterized by a noradrenergic core transcriptional regulatory module, including PHOX2B, HAND2, and GATA3, whereas Group II neuroblastomas are characterized by a neural crest cell–like core transcriptional regulatory module, including FOS and JUN. Similarly, analysis of primary neuroblastoma expression data showed that most neuroblastomas exhibit a heterogenous mixture of both Groups I and II modules. Further, PHOX2B, HAND2, and GATA3 were shown to simultaneously bind the same active superenhancer sites, suggesting that these are master transcription factors that drive noradrenergic neuroblastoma identity, and ablation of PHOX2B reduced noradrenergic neuroblastoma growth in vitro and in vivo. Paired pretreatment and relapsed neuroblastomas exhibited different module patterns, and chemotherapeutic drug treatment of mixed neuroblastoma cells in vitro resulted in the enrichment of cells exhibiting the Group II neural crest cell–like module. These results identify the transcriptional core regulatory circuitries that drive neuroblastoma cell identity, reveal a novel aspect of tumor heterogeneity, and may inform the design of therapeutic strategies.
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