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Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis

While MYCN expression is an important contributing factor to heterogeneity in the natural history of neuroblastoma (NBL), a mechanistic understanding of this often mutationally quiet tumor has remained elusive. In this issue of the JCI, Weichert-Leahey and authors focused on the adrenergic and mesen...

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Detalles Bibliográficos
Autores principales: Wertman, Jaime N., Berman, Jason N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178827/
https://www.ncbi.nlm.nih.gov/pubmed/37183823
http://dx.doi.org/10.1172/JCI167824
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author Wertman, Jaime N.
Berman, Jason N.
author_facet Wertman, Jaime N.
Berman, Jason N.
author_sort Wertman, Jaime N.
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description While MYCN expression is an important contributing factor to heterogeneity in the natural history of neuroblastoma (NBL), a mechanistic understanding of this often mutationally quiet tumor has remained elusive. In this issue of the JCI, Weichert-Leahey and authors focused on the adrenergic and mesenchymal core regulatory circuitries (CRC) as NBL transcriptional programs. The authors previously showed that overexpression of LIM-domain-only 1 (LMO1), a transcriptional coregulator, synergizes with MYCN to accelerate tumor formation and metastasis in an NBL-zebrafish model. They now demonstrate experimentally, using genome-edited zebrafish, that a polymorphism in the human rs2168101 locus of the LMO1 gene determines which CRC is active in a tumor. In some cases, LMO3 compensated for LMO1 loss and drove the adrenergic CRC in MYCN-positive NBL. This study exemplifies the value of evolutionary relationships and zebrafish models in the investigation of human disease and reveals pathways of NBL development that may affect prevention or intervention strategies.
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spelling pubmed-101788272023-05-15 Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis Wertman, Jaime N. Berman, Jason N. J Clin Invest Commentary While MYCN expression is an important contributing factor to heterogeneity in the natural history of neuroblastoma (NBL), a mechanistic understanding of this often mutationally quiet tumor has remained elusive. In this issue of the JCI, Weichert-Leahey and authors focused on the adrenergic and mesenchymal core regulatory circuitries (CRC) as NBL transcriptional programs. The authors previously showed that overexpression of LIM-domain-only 1 (LMO1), a transcriptional coregulator, synergizes with MYCN to accelerate tumor formation and metastasis in an NBL-zebrafish model. They now demonstrate experimentally, using genome-edited zebrafish, that a polymorphism in the human rs2168101 locus of the LMO1 gene determines which CRC is active in a tumor. In some cases, LMO3 compensated for LMO1 loss and drove the adrenergic CRC in MYCN-positive NBL. This study exemplifies the value of evolutionary relationships and zebrafish models in the investigation of human disease and reveals pathways of NBL development that may affect prevention or intervention strategies. American Society for Clinical Investigation 2023-05-15 /pmc/articles/PMC10178827/ /pubmed/37183823 http://dx.doi.org/10.1172/JCI167824 Text en © 2023 Wertman et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Commentary
Wertman, Jaime N.
Berman, Jason N.
Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
title Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
title_full Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
title_fullStr Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
title_full_unstemmed Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
title_short Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
title_sort back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178827/
https://www.ncbi.nlm.nih.gov/pubmed/37183823
http://dx.doi.org/10.1172/JCI167824
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