Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state.
Animals
Biomarkers, Tumor
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Differentiation
/ genetics
Cell Line, Tumor
Dogs
Enhancer Elements, Genetic
/ genetics
Epigenesis, Genetic
/ genetics
Homeodomain Proteins
/ genetics
Humans
Mice
Mice, Transgenic
Mutation
Nerve Sheath Neoplasms
/ drug therapy
Neural Crest
/ pathology
Peripheral Nervous System Neoplasms
/ drug therapy
Polycomb Repressive Complex 2
/ genetics
Species Specificity
Transcription Factors
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Zebrafish
BRD4 inhibitor
Enhancer activation
Epigenomic reprogramming
Malignant peripheral nerve sheath tumor
Neural-crest phenotype
Polycomb repressor complex 2
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
10
02
2021
accepted:
22
06
2021
revised:
09
06
2021
pubmed:
21
7
2021
medline:
22
1
2022
entrez:
20
7
2021
Statut:
ppublish
Résumé
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that frequently harbor genetic alterations in polycomb repressor complex 2 (PRC2) components-SUZ12 and EED. Here, we show that PRC2 loss confers a dedifferentiated early neural-crest phenotype which is exclusive to PRC2-mutant MPNSTs and not a feature of neurofibromas. Neural crest phenotype in PRC2 mutant MPNSTs was validated via cross-species comparative analysis using spontaneous and transgenic MPNST models. Systematic chromatin state profiling of the MPNST cells showed extensive epigenomic reprogramming or chromatin states associated with PRC2 loss and identified gains of active enhancer states/super-enhancers on early neural crest regulators in PRC2-mutant conditions around genomic loci that harbored repressed/poised states in PRC2-WT MPNST cells. Consistently, inverse correlation between H3K27me3 loss and H3K27Ac gain was noted in MPNSTs. Epigenetic editing experiments established functional roles for enhancer gains on DLX5-a key regulator of neural crest phenotype. Consistently, blockade of enhancer activity by bromodomain inhibitors specifically suppressed this neural crest phenotype and tumor burden in PRC2-mutant PDXs. Together, these findings reveal accumulation of dedifferentiated neural crest like state in PRC2-mutant MPNSTs that can be targeted by enhancer blockade.
Identifiants
pubmed: 34283254
doi: 10.1007/s00401-021-02341-z
pii: 10.1007/s00401-021-02341-z
doi:
Substances chimiques
BRD4 protein, human
0
Biomarkers, Tumor
0
Cell Cycle Proteins
0
DLX5 protein, human
0
Homeodomain Proteins
0
Transcription Factors
0
Polycomb Repressive Complex 2
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
565-590Subventions
Organisme : NCI NIH HHS
ID : T32 CA009599
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR029552
Pays : United States
Informations de copyright
© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
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