11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma.
Adrenergic Agents
/ metabolism
Anaplastic Lymphoma Kinase
/ genetics
Animals
Carcinogenesis
/ drug effects
Cell Differentiation
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Chromaffin Cells
/ drug effects
Chromosome Deletion
Chromosomes, Human, Pair 11
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Guanylate Kinases
/ genetics
Humans
MAP Kinase Signaling System
/ drug effects
Mice, Inbred BALB C
Nerve Growth Factor
/ pharmacology
Neuroblastoma
/ genetics
Neurons
/ metabolism
Phenotype
Prognosis
Schwann Cells
/ drug effects
Sp1 Transcription Factor
/ metabolism
Transcription, Genetic
/ drug effects
Treatment Outcome
Tretinoin
/ pharmacology
Tumor Suppressor Proteins
/ genetics
Up-Regulation
/ drug effects
ALK
DLG2
ERK
NGF
SNP
TRK
genomic profiles
neuroblastoma
retinoic acid
tumor suppressor
whole-genome sequencing
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
22 09 2020
22 09 2020
Historique:
received:
30
03
2020
revised:
09
07
2020
accepted:
27
08
2020
entrez:
23
9
2020
pubmed:
24
9
2020
medline:
6
5
2021
Statut:
ppublish
Résumé
High-risk neuroblastomas typically display an undifferentiated or poorly differentiated morphology. It is therefore vital to understand molecular mechanisms that block the differentiation process. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in the maintenance of undifferentiated neural crest-derived progenitors through the repression of DLG2, a candidate tumor suppressor gene in neuroblastoma. DLG2 is expressed in the murine "bridge signature" that represents the transcriptional transition state when neural crest cells or Schwann cell precursors differentiate to chromaffin cells of the adrenal gland. We show that the restoration of DLG2 expression spontaneously drives neuroblastoma cell differentiation, highlighting the importance of DLG2 in this process. These findings are supported by genetic analyses of high-risk 11q deletion neuroblastomas, which identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other bridge genes may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastomas.
Identifiants
pubmed: 32966799
pii: S2211-1247(20)31160-8
doi: 10.1016/j.celrep.2020.108171
pii:
doi:
Substances chimiques
Adrenergic Agents
0
Sp1 Transcription Factor
0
Tumor Suppressor Proteins
0
Tretinoin
5688UTC01R
Nerve Growth Factor
9061-61-4
ALK protein, human
EC 2.7.10.1
Anaplastic Lymphoma Kinase
EC 2.7.10.1
DLG2 protein, human
EC 2.7.4.8
Guanylate Kinases
EC 2.7.4.8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108171Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.