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In the context of NF1, MPNSTs develop from benign premalignant precursors and the transition to malignancy is typically accompanied by loss of the polycomb repressive complex 2 (PRC2), which results in aberrant upregulation of over 1200 genes due to global depletion of histone H3 lysine 27 trimethylation (H3K27me3). Previous studies suggest cells compensate for the loss of this repressive histone mark via hypermethylation of the genome. Here we analyzed genome\u2010wide DNA methylation and the transcriptome in MPNST cell lines and isogenic PRC2\u2010deficient and \u2010proficient CRISPR\u2010engineered immortalized human Schwann cells. In addition to effects of PRC2 status, we also measured the effects of two DNA methyltransferase inhibitors (DNMTi), decitabine and azacitidine. We found that PRC2 status does not affect global DNA methylation or average methylation levels across specific genomic features. Furthermore, decitabine and azacitidine have differential effects on MPNSTs. While both DNMTis hypomethylate the genome, they upregulate different targets. Azacitidine upregulates genes involved in RNA processing pathways and exhibits direct tumor cell cytotoxicity, while decitabine upregulates genes involved in the immune response, has no direct\u2010cell killing effects, and likely suppresses tumor growth in\u00a0vivo by altering the tumor microenvironment. We show that DNA hypomethylation alone is insufficient to kill MPNST cells, regardless of PRC2 status. Consequently, these findings suggest that DNMT inhibitors should be utilized in combination with other targeted therapies for MPNST patients.<\/jats:p>","DOI":"10.1002\/gcc.70156","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:37:07Z","timestamp":1785904627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>DNA<\/scp>\n                    Hypomethylation Is Not Cell Intrinsically Toxic to Polycomb Repressive Complex 2 Deficient Malignant Peripheral Nerve Sheath Tumors"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0855-671X","authenticated-orcid":false,"given":"Madilyn R.","family":"Stahl","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Masonic Cancer Center University of Minnesota  Minneapolis Minnesota USA"},{"name":"Department of Genetics, Cell Biology and Development University of Minnesota, Twin Cities  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-1954","authenticated-orcid":false,"given":"Christopher M.","family":"Stehn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Masonic Cancer Center University of Minnesota  Minneapolis Minnesota USA"},{"name":"Department of Genetics, Cell Biology and Development University of Minnesota, Twin Cities  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0285-3624","authenticated-orcid":false,"given":"Zachary J.","family":"Seeman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Masonic Cancer Center University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-9658","authenticated-orcid":false,"given":"Christopher","family":"Faulk","sequence":"additional","affiliation":[{"name":"Department of Animal Science, College of Food, Agricultural and Natural Resource Sciences University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3183-0491","authenticated-orcid":false,"given":"David A.","family":"Largaespada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Masonic Cancer Center University of Minnesota  Minneapolis Minnesota USA"},{"name":"Department of Genetics, Cell Biology and Development University of Minnesota, Twin Cities  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.113"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15041077"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.12.027"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23552"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2017.05.010"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201022\u20100786"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2641"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3095"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09784"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.83"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdae188"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201018\u20103704"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201021\u20101671"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nly076"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.109678.110"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.056"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2007.06.016"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2012.07.025"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2012\u20100465"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010021\u201001218\u20100"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201009\u20100458"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20102952(76)90407\u2010X"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201014121\u20100"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.7543"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18112341"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.277743.123"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201024\u20101053"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111363"},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","unstructured":"K. B.Williams A. T.Larsson B. J.Keller et\u00a0al. \u201cPharmacogenomic Synthetic Lethal Screens Reveal Hidden Vulnerabilities and New Therapeutic Approaches for Treatment of NF1\u2010Associated Tumors \u201dpreprint bioRxiv March 25 2024 https:\/\/www.biorxiv.org\/content\/10.1101\/2024.03.25.585959.","DOI":"10.1101\/2024.03.25.585959"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010118"},{"issue":"3","key":"e_1_2_10_32_1","first-page":"795","article-title":"Antiproliferative and Antitumor Effects of Azacitidine Against the Human Myelodysplastic Syndrome Cell Line SKM\u20101","volume":"32","author":"Kimura S.","year":"2012","journal-title":"Anticancer Research"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97924"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1145\/3332186.3333156"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010014\u20100550\u20108"},{"key":"e_1_2_10_36_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2024"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv422"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2007.07.015"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24783"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300038"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.566511"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010012\u20101056\u20107"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201024\u20101454"}],"container-title":["Genes, Chromosomes and Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gcc.70156","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/gcc.70156","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gcc.70156","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:25:52Z","timestamp":1787837152000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/gcc.70156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":45,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/gcc.70156"],"URL":"https:\/\/doi.org\/10.1002\/gcc.70156","archive":["Portico"],"relation":{},"ISSN":["1045-2257","1098-2264"],"issn-type":[{"value":"1045-2257","type":"print"},{"value":"1098-2264","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-04-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70156"}}