TY - JOUR
T1 - Two opposing gene expression patterns within ATRX aberrant neuroblastoma
AU - van Gerven, Michael R.
AU - Schild, Linda
AU - van Arkel, Jennemiek
AU - Koopmans, Bianca
AU - Broeils, Luuk A.
AU - Meijs, Loes A. M.
AU - van Oosterhout, Romy
AU - van Noesel, Max M.
AU - Koster, Jan
AU - van Hooff, Sander R.
AU - Molenaar, Jan J.
AU - van den Boogaard, Marlinde L.
N1 - Publisher Copyright: © 2023 van Gerven et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2023/8
Y1 - 2023/8
N2 - Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. 75% of these MEDs are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and the patient-derived models. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic processes in our isogenic ATRX exon 2-10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2-10 MED. In sharp contrast, these same processes showed an increased expression in our isogenic ATRX knock-out and exon 2-13 MED models. Our validations confirmed a role of ATRX in the regulation of ribosome homeostasis. The two distinct molecular expression patterns within ATRX aberrant neuroblastomas that we identified imply that there might be a need for distinct treatment regimens.
AB - Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. 75% of these MEDs are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and the patient-derived models. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic processes in our isogenic ATRX exon 2-10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2-10 MED. In sharp contrast, these same processes showed an increased expression in our isogenic ATRX knock-out and exon 2-13 MED models. Our validations confirmed a role of ATRX in the regulation of ribosome homeostasis. The two distinct molecular expression patterns within ATRX aberrant neuroblastomas that we identified imply that there might be a need for distinct treatment regimens.
UR - http://www.scopus.com/inward/record.url?scp=85166598998&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.pone.0289084
DO - https://doi.org/10.1371/journal.pone.0289084
M3 - Article
C2 - 37540673
SN - 1932-6203
VL - 18
SP - e0289084
JO - PLOS ONE
JF - PLOS ONE
IS - 8 AUGUST
M1 - e0289084
ER -