MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation
Year: 2021
Type: article
Abstract: Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma.
Source: Cancers
Authors: Jolien De Wyn, Mark W. Zimmerman, Nina Weichert-Leahey, Carolina Nunes, Belamy B. Cheung, Brian J. Abraham, Anneleen Beckers, Pieter-Jan Volders, Bieke Decaesteker, Daniel R. Carter, Alfred Thomas Look, Katleen De Preter, Wouter Van Loocke, Glenn M. Marshall, Adam D. Durbin, Frank Speleman, Kaat Durinck
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,376
Funders: Damon Runyon Cancer Research Foundation, Alex's Lemonade Stand Foundation for Childhood Cancer, Rally Foundation, CureSearch for Children's Cancer, Fonds Wetenschappelijk Onderzoek, Kom op tegen Kanker, Vlaamse regering, Stichting Villa Joep, National Institutes of Health, National Cancer Institute
Awards: G1623983230, G1678280148, Targeting EP300, a selective dependency in neuroblastoma, The first genome-wide maps of the micropeptidome validated through large-scale reprocessing of public proteomics data, G3703537882, G4681055516, SOX11 as mediator of the adrenergic cell state in neuroblastoma: towards cell precision medicine, G7842338753, RRM2 controlled replicative stress resistance as a druggable DNA copy number driven cell state in MYC(N) driven cancers
OpenAlex ID: W3202693025