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Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state.
- Source :
-
Acta neuropathologica [Acta Neuropathol] 2021 Sep; Vol. 142 (3), pp. 565-590. Date of Electronic Publication: 2021 Jul 20. - Publication Year :
- 2021
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Abstract
- 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.<br /> (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
- Subjects :
- 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 pathology
Neural Crest pathology
Peripheral Nervous System Neoplasms pathology
Species Specificity
Transcription Factors antagonists & inhibitors
Transcription Factors genetics
Xenograft Model Antitumor Assays
Zebrafish
Nerve Sheath Neoplasms drug therapy
Nerve Sheath Neoplasms genetics
Peripheral Nervous System Neoplasms drug therapy
Peripheral Nervous System Neoplasms genetics
Polycomb Repressive Complex 2 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0533
- Volume :
- 142
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Acta neuropathologica
- Publication Type :
- Academic Journal
- Accession number :
- 34283254
- Full Text :
- https://doi.org/10.1007/s00401-021-02341-z