title: Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation.
abstract: To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b to increase β-catenin. Knockdown of Arid1b or Gsk3β in Stat3(fl/fl);Nf1(fl/fl);DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Keng
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Patmore
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jed J
authors.initials: JJ
authors.lastname: Kendall
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Ami V
authors.initials: AV
authors.lastname: Patel
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Jousma
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Jessen
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Choi
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Tschida
authors.affiliation: Biostatistics and Informatics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Kevin A T
authors.initials: KA
authors.lastname: Silverstein
authors.affiliation: Biostatistics and Informatics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Danhua
authors.initials: D
authors.lastname: Fan
authors.affiliation: Ohio State University, College of Pharmacy, Columbus, OH 43210, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Schwartz
authors.affiliation: Ohio State University, College of Pharmacy, Columbus, OH 43210, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Fuchs
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Yuanshu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.affiliation: Department of Pathology and New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA; Hoxworth Blood Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Spinner
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH 45229, USA. Electronic address: nancy.ratner@cchmc.org.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016254:Mutagenesis, Insertional; D063209:N-Terminal Acetyltransferase A / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010524:Peripheral Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; D025542:Neurofibromin 1; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; D063209:N-Terminal Acetyltransferase A; C545086:Naa11 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C513194:Smarca4 protein, mouse; D004265:DNA Helicases