In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 8 ( 2023-8-4), p. e0289084-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0289084
DOI:
10.1371/journal.pone.0289084.g001
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10.1371/journal.pone.0289084.g002
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10.1371/journal.pone.0289084.g003
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10.1371/journal.pone.0289084.g004
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10.1371/journal.pone.0289084.g005
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10.1371/journal.pone.0289084.s001
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10.1371/journal.pone.0289084.s002
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10.1371/journal.pone.0289084.s003
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10.1371/journal.pone.0289084.s004
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10.1371/journal.pone.0289084.s005
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10.1371/journal.pone.0289084.s006
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10.1371/journal.pone.0289084.s007
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10.1371/journal.pone.0289084.s008
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10.1371/journal.pone.0289084.s009
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10.1371/journal.pone.0289084.s010
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10.1371/journal.pone.0289084.s011
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10.1371/journal.pone.0289084.s012
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10.1371/journal.pone.0289084.s013
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10.1371/journal.pone.0289084.s014
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10.1371/journal.pone.0289084.s015
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10.1371/journal.pone.0289084.s016
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10.1371/journal.pone.0289084.s017
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10.1371/journal.pone.0289084.s018
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10.1371/journal.pone.0289084.s019
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10.1371/journal.pone.0289084.s020
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10.1371/journal.pone.0289084.s021
DOI:
10.1371/journal.pone.0289084.r001
DOI:
10.1371/journal.pone.0289084.r002
DOI:
10.1371/journal.pone.0289084.r003
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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