@article{5cb8de8056b849cd9a36ed5150e26c09,
title = "Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state",
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.",
keywords = "BRD4 inhibitor, Enhancer activation, Epigenomic reprogramming, Malignant peripheral nerve sheath tumor, Neural-crest phenotype, Polycomb repressor complex 2",
author = "Veena Kochat and Raman, {Ayush T.} and Landers, {Sharon M.} and Ming Tang and Jonathan Schulz and Christopher Terranova and Landry, {Jace P.} and Bhalla, {Angela D.} and Beird, {Hannah C.} and Wu, {Chia Chin} and Yingda Jiang and Xizeng Mao and Rossana Lazcano and Swati Gite and Ingram, {Davis R.} and Min Yi and Jianhua Zhang and Keung, {Emily Z.} and Scally, {Christopher P.} and Roland, {Christina L.} and Hunt, {Kelly K.} and Feig, {Barry W.} and Futreal, {P. Andrew} and Patrick Hwu and Wang, {Wei Lien} and Lazar, {Alexander J.} and Slopis, {John M.} and Heather Wilson-Robles and Wiener, {Dominique J.} and McCutcheon, {Ian E.} and Brandan Wustefeld-Janssens and Kunal Rai and Torres, {Keila E.}",
note = "Funding Information: We thank Amy Ninetto for critical input and editing of the manuscript. We thank Erika Thompson, the Advanced Technology Genomics Core Facility (NCI Grant CA016672(ATGC), the Research Animal Support Facility, the Advanced Microscopy Core Facility (funded by NIH S10 RR029552), Functional Genomics Core (NCI Cancer Center Support Grant (P30 CA016672), Cytogenetics and Cell Authentication core, MD Anderson Cancer Center Clinical Core and MD Anderson Cancer Center Science Park Research Histology, Pathology and Imaging Core (supported by P30 CA16672 DHHS/NCI Cancer Center Support Grant). This work was partially supported by Department of Defense CDRMP Grant (NF160026 to K.E.T and NF190074 to K.R.), to K.E.T., The Texas Neurofibromatosis Foundation, The Sally Kingsbury Sarcoma Research Foundation to K.E.T. and DoD New Investigator Award to Kunal Rai (NF190074). V.K and S.M.L were funded by The Jay Vernon Jackson Sarcoma Research Fund and Friends MDA Sarcoma Research. Support for the clinical sample collection was provided by the Ferrin R Zeitlin Foundation, Artz Cure Sarcoma Foundation (K.E.T.) and A Shelter for Cancer Families (formerly Amschwand Sarcoma Cancer Foundation) (K.E.T). Support for the proteomics analysis was from MoJo{\textquoteright}s Miracle (K.E.T.). J.P.L. was funded by National Institutes of Health (T32 CA 009599) and the MD Anderson Cancer Center support grant (P30 CA016672). Funding Information: We thank Amy Ninetto for critical input and editing of the manuscript. We thank Erika Thompson, the Advanced Technology Genomics Core Facility (NCI Grant CA016672(ATGC), the Research Animal Support Facility, the Advanced Microscopy Core Facility (funded by NIH S10 RR029552), Functional Genomics Core (NCI Cancer Center Support Grant (P30 CA016672), Cytogenetics and Cell Authentication core, MD Anderson Cancer Center Clinical Core and MD Anderson Cancer Center Science Park Research Histology, Pathology and Imaging Core (supported by P30 CA16672 DHHS/NCI Cancer Center Support Grant). This work was partially supported by Department of Defense CDRMP Grant (NF160026 to K.E.T and NF190074 to K.R.), to K.E.T., The Texas Neurofibromatosis Foundation, The Sally Kingsbury Sarcoma Research Foundation to K.E.T. and DoD New Investigator Award to Kunal Rai (NF190074). V.K and S.M.L were funded by The Jay Vernon Jackson Sarcoma Research Fund and Friends MDA Sarcoma Research. Support for the clinical sample collection was provided by the Ferrin R Zeitlin Foundation, Artz Cure Sarcoma Foundation (K.E.T.) and A Shelter for Cancer Families (formerly Amschwand Sarcoma Cancer Foundation) (K.E.T). Support for the proteomics analysis was from MoJo?s Miracle (K.E.T.). J.P.L. was funded by National Institutes of Health (T32 CA 009599) and the MD Anderson Cancer Center support grant (P30 CA016672). Publisher Copyright: {\textcopyright} 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
year = "2021",
month = sep,
doi = "10.1007/s00401-021-02341-z",
language = "English (US)",
volume = "142",
pages = "565--590",
journal = "Acta neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "3",
}