PUBLICATION
Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state
- Authors
- Weichert-Leahey, N., Shi, H., Tao, T., Oldridge, D.A., Durbin, A.D., Abraham, B.J., Zimmerman, M.W., Zhu, S., Wood, A.C., Reyon, D., Joung, J.K., Young, R.A., Diskin, S.J., Maris, J.M., Look, A.T.
- ID
- ZDB-PUB-230516-28
- Date
- 2023
- Source
- The Journal of Clinical Investigation 133(10): (Journal)
- Registered Authors
- Tao, Ting, Zhu, Shizhen, Zimmerman, Mark
- Keywords
- Genetic variation, Genetics, Molecular genetics, Oncology
- Datasets
- GEO:GSE224158
- MeSH Terms
-
- Adrenergic Agents
- Animals
- Child
- Genetic Predisposition to Disease*
- Genotype
- Humans
- N-Myc Proto-Oncogene Protein/genetics
- Neuroblastoma*/pathology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 37183825 Full text @ Journal of Clin. Invest.
Citation
Weichert-Leahey, N., Shi, H., Tao, T., Oldridge, D.A., Durbin, A.D., Abraham, B.J., Zimmerman, M.W., Zhu, S., Wood, A.C., Reyon, D., Joung, J.K., Young, R.A., Diskin, S.J., Maris, J.M., Look, A.T. (2023) Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state. The Journal of Clinical Investigation. 133(10):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping