Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis
Jaime N. Wertman, Jason N. Berman
Jaime N. Wertman, Jason N. Berman
Published May 15, 2023
Citation Information: J Clin Invest. 2023;133(10):e167824. https://doi.org/10.1172/JCI167824.
View: Text | PDF
Commentary Article has an altmetric score of 3

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

Abstract

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.

Authors

Jaime N. Wertman, Jason N. Berman

×

Figure 1

The rs2168101 G → T transversion in LMO1 reduces GATA3 binding, resulting in lower LMO1 levels and reliance on the mesenchymal CRC.

Options: View larger image (or click on image) Download as PowerPoint
The rs2168101 G → T transversion in LMO1 reduces GATA3 binding, resultin...
NBL cells arise from neural crest cells during development. The adrenergic and mesenchymal CRCs are the main autoregulatory transcriptional loops involved in NBL. LMO1 is a coregulator in the adrenergic CRC. The presence of a G allele at the rs2168101 SNP results in a GATA-binding motif in this intron, promoting GATA3 binding and creating a super enhancer that drives high levels of LMO1 expression. When replaced by a T, this TATA sequence prevents GATA3 binding, resulting in lower LMO1 levels and lower NBL risk. Transgenic zebrafish lines harboring this SNP replicate findings in humans.