Next Article in Journal
Targeting Acute Myeloid Leukemia Using the RevCAR Platform: A Programmable, Switchable and Combinatorial Strategy
Previous Article in Journal
Microbe-Mediated Activation of Toll-like Receptor 2 Drives PDL1 Expression in HNSCC
Article

MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation

1
Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
3
Lowy Cancer Research Centre, Children’s Cancer Institute Australia for Medical Research, UNSW Sydney, Randwick, NSW 2031, Australia
4
School of Women’s and Children’s Health, UNSW Sydney, Randwick, NSW 2031, Australia
5
Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA
6
School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW 2007, Australia
7
Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, Australia
8
Department of Oncology, Division of Molecular Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA
*
Author to whom correspondence should be addressed.
These authors share the last authorship.
Academic Editor: Francisco M. Vega
Cancers 2021, 13(19), 4783; https://doi.org/10.3390/cancers13194783
Received: 2 September 2021 / Accepted: 20 September 2021 / Published: 24 September 2021
Neuroblastoma is a pediatric tumor originating from the sympathetic nervous system responsible for 10–15% of all childhood cancer deaths. Half of all neuroblastoma patients present with high-risk disease, of which nearly 50% relapse and die of their disease. In addition, standard therapies cause serious lifelong side effects and increased risk for secondary tumors. Further research is crucial to better understand the molecular basis of neuroblastomas and to identify novel druggable targets. Neuroblastoma tumorigenesis has to this end been modeled in both mice and zebrafish. Here, we present a detailed dissection of the gene expression patterns that underlie tumor formation in the murine TH-MYCN-driven neuroblastoma model. We identified key factors that are putatively important for neuroblastoma tumor initiation versus tumor progression, pinpointed crucial regulators of the observed expression patterns during neuroblastoma development and scrutinized which factors could be innovative and vulnerable nodes for therapeutic intervention.
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. View Full-Text
Keywords: neuroblastoma; mouse model; MYCN; transcriptome analysis neuroblastoma; mouse model; MYCN; transcriptome analysis
Show Figures

Graphical abstract

MDPI and ACS Style

De Wyn, J.; Zimmerman, M.W.; Weichert-Leahey, N.; Nunes, C.; Cheung, B.B.; Abraham, B.J.; Beckers, A.; Volders, P.-J.; Decaesteker, B.; Carter, D.R.; Look, A.T.; De Preter, K.; Van Loocke, W.; Marshall, G.M.; Durbin, A.D.; Speleman, F.; Durinck, K. MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation. Cancers 2021, 13, 4783. https://doi.org/10.3390/cancers13194783

AMA Style

De Wyn J, Zimmerman MW, Weichert-Leahey N, Nunes C, Cheung BB, Abraham BJ, Beckers A, Volders P-J, Decaesteker B, Carter DR, Look AT, De Preter K, Van Loocke W, Marshall GM, Durbin AD, Speleman F, Durinck K. MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation. Cancers. 2021; 13(19):4783. https://doi.org/10.3390/cancers13194783

Chicago/Turabian Style

De Wyn, Jolien, 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 T. Look, Katleen De Preter, Wouter Van Loocke, Glenn M. Marshall, Adam D. Durbin, Frank Speleman, and Kaat Durinck. 2021. "MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation" Cancers 13, no. 19: 4783. https://doi.org/10.3390/cancers13194783

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop