{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:05:19Z","timestamp":1792785919205,"version":"4.5.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T00:00:00Z","timestamp":1557878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["K12-HD000850"],"award-info":[{"award-number":["K12-HD000850"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54-CA196519-04"],"award-info":[{"award-number":["U54-CA196519-04"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U54-CA196519-04"],"award-info":[{"award-number":["U54-CA196519-04"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pediatric Scientist Development Program","award":["K12-HD000850"],"award-info":[{"award-number":["K12-HD000850"]}]},{"DOI":"10.13039\/100006733","name":"Indiana University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006733","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and\/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1\u2212\/\u2212 SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.<\/jats:p>","DOI":"10.1093\/hmg\/ddz095","type":"journal-article","created":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T07:35:53Z","timestamp":1557819353000},"page":"2752-2762","source":"Crossref","is-referenced-by-count":91,"title":["Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation"],"prefix":"10.1093","volume":"28","author":[{"given":"Steven D","family":"Rhodes","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"},{"name":"Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzheng","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbi","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingbo","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Mund","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waylan","family":"Bessler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaomin","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Dyer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George E","family":"Sandusky","sequence":"additional","affiliation":[{"name":"Department of Pathology, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew E","family":"Horvai","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, San Francisco, 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"},{"name":"Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Wade","family":"Clapp","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,5,15]]},"reference":[{"key":"2019080902044723400_ref1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1749-6632.1986.tb48061.x","article-title":"The genetic aspects of neurofibromatosis","volume":"486","author":"Carey","year":"1986","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2019080902044723400_ref2","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.ccell.2014.09.009","article-title":"Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma","volume":"26","author":"Chen","year":"2014","journal-title":"Cancer Cell"},{"key":"2019080902044723400_ref3","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1126\/science.1068452","article-title":"Neurofibromas in NF1: Schwann cell origin and role of tumor environment","volume":"296","author":"Zhu","year":"2002","journal-title":"Science"},{"key":"2019080902044723400_ref4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1136\/jmg.39.5.311","article-title":"Malignant peripheral nerve sheath tumours in neurofibromatosis 1","volume":"39","author":"Evans","year":"2002","journal-title":"J. Med. 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Rare Dis."},{"key":"2019080902044723400_ref6","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/emboj\/18.1.22","article-title":"Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53","volume":"18","author":"Honda","year":"1999","journal-title":"EMBO J."},{"key":"2019080902044723400_ref7","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1038\/onc.2010.614","article-title":"p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors","volume":"30","author":"Romagosa","year":"2011","journal-title":"Oncogene"},{"key":"2019080902044723400_ref8","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ccr.2010.06.013","article-title":"Ink4a\/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis","volume":"18","author":"Bennecke","year":"2010","journal-title":"Cancer Cell"},{"key":"2019080902044723400_ref9","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1093\/neuonc\/noy013","article-title":"The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors","volume":"20","author":"Higham","year":"2018","journal-title":"Neuro Oncol."},{"key":"2019080902044723400_ref10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.humpath.2017.05.010","article-title":"Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview","volume":"67","author":"Miettinen","year":"2017","journal-title":"Hum. Pathol."},{"key":"2019080902044723400_ref11","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1002\/gcc.20921","article-title":"Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors","volume":"50","author":"Beert","year":"2011","journal-title":"Genes Chromosomes Cancer"},{"key":"2019080902044723400_ref12","doi-asserted-by":"crossref","first-page":"14992","DOI":"10.1038\/s41598-017-15183-1","article-title":"The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation","volume":"7","author":"Brohl","year":"2017","journal-title":"Sci. Rep."},{"key":"2019080902044723400_ref13","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/ng.3095","article-title":"PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors","volume":"46","author":"Lee","year":"2014","journal-title":"Nat. Genet."},{"key":"2019080902044723400_ref14","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1126\/science.286.5447.2176","article-title":"Mouse tumor model for neurofibromatosis type 1","volume":"286","author":"Vogel","year":"1999","journal-title":"Science"},{"key":"2019080902044723400_ref15","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ccr.2011.12.027","article-title":"Tumorigenic cells are common in mouse MPNSTs but their frequency depends upon tumor genotype and assay conditions","volume":"21","author":"Buchstaller","year":"2012","journal-title":"Cancer Cell"},{"key":"2019080902044723400_ref16","doi-asserted-by":"crossref","first-page":"4978","DOI":"10.1038\/sj.onc.1205632","article-title":"Loss of neurofibromatosis-1 and p19(ARF) cooperate to induce a multiple tumor phenotype","volume":"21","author":"King","year":"2002","journal-title":"Oncogene"},{"key":"2019080902044723400_ref17","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.ydbio.2007.04.041","article-title":"Identification and characterization of a novel Schwann and outflow tract endocardial cushion lineage-restricted periostin enhancer","volume":"307","author":"Lindsley","year":"2007","journal-title":"Dev. 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Mutat."},{"key":"2019080902044723400_ref23","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1172\/JCI66167","article-title":"Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk","volume":"123","author":"Staser","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2019080902044723400_ref24","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1172\/JCI63193","article-title":"Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice","volume":"123","author":"Chang","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2019080902044723400_ref25","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1172\/JCI60578","article-title":"MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors","volume":"123","author":"Jessen","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2019080902044723400_ref26","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.cell.2008.08.041","article-title":"Nf1-dependent tumors require a microenvironment containing Nf1+\/\u2212\u2212 and c-kit-dependent bone marrow","volume":"135","author":"Yang","year":"2008","journal-title":"Cell"},{"key":"2019080902044723400_ref27","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1056\/NEJMoa1605943","article-title":"Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas","volume":"375","author":"Dombi","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"2019080902044723400_ref28","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1016\/S1470-2045(12)70414-X","article-title":"Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial","volume":"13","author":"Robertson","year":"2012","journal-title":"Lancet Oncol."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddz095\/28855743\/ddz095.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/16\/2752\/29111702\/ddz095.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T14:38:11Z","timestamp":1568903891000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/28\/16\/2752\/5489753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,15]]},"references-count":28,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2019,5,15]]},"published-print":{"date-parts":[[2019,8,15]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddz095","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,8,15]]},"published":{"date-parts":[[2019,5,15]]}}}