ArticleThe Journal of clinical investigation2023
Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 12 citations in OpenAlex.
- Molecular Pathogenesis, Tumor Microenvironment and Health Disparities in Select Pediatric Solid Tumors: An Integrative Narrative Review.Diseases (Basel, Switzerland) · 2026Review
- TCF4 Promotes Neuroblastoma Proliferation and Inhibits Ferroptosis by Transactivating GPX4 Expression.Applied biochemistry and biotechnology · 2025Article
- Development of a prognostic model for overall survival in neuroblastoma based on Schwann cell-specific genes, clinical predictors, and MYCN amplification.Translational cancer research · 2025Article
- Lineage-Selective Dependencies in Pediatric Cancers.Cold Spring Harbor perspectives in medicine · 2025Review
- IRF1 is a core transcriptional regulatory circuitry member promoting AML progression by regulating lipid metabolism.Experimental hematology & oncology · 2025Article
- Cell state plasticity in neuroblastoma.EJC paediatric oncology · 2024Article
- BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.Journal of the National Cancer Institute · 2024Article
- Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis.The Journal of clinical investigation · 2023Article
- Two bullets in the gun: combining immunotherapy with chemotherapy to defeat neuroblastoma by targeting adrenergic-mesenchymal plasticity.Frontiers in immunology · 2023Review
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15 authors at 7 institutions in 3 countries.
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Abstract
Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like mesenchymal cell state and a more differentiated sympathetic adrenergic cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional cofactor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism, G/T, that affects a GATA motif in the first intron of LMO1. Here, we showed that WT zebrafish with the GATA genotype developed adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduced the penetrance of MYCN-driven tumors, which were restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrated that TATA/TATA tumors also exhibited a mesenchymal cell state and were low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduced the neuroblastoma-initiation rate by preventing formation of the adrenergic cell state. This mechanism was conserved over 400 million years of evolution, separating zebrafish and humans.
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