title: Runx1 contributes to neurofibromatosis type 1 neurofibroma formation.
abstract: Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas but the driver(s) that contribute to neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human neurofibroma-initiating cells and developed neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human neurofibroma initiation cells, suggesting RUNX1 might relate to neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbfβ interaction inhibitor, Ro5-3335, decreased mouse neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1(+)/Blbp(+) progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for neurofibroma patients.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yan
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Jessen
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH, USA.
authors.forename: M-O
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Dombi
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Huang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D023081:CCAAT-Binding Factor / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000071438:Fatty Acid-Binding Protein 7; D006801:Humans; D051379:Mice; D009455:Neurofibroma / Q000473:pathology*; D018318:Neurofibroma, Plexiform / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000473:pathology*; D025542:Neurofibromin 1 / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012583:Schwann Cells / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D023081:CCAAT-Binding Factor; D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; C107608:FABP7 protein, human; D000071438:Fatty Acid-Binding Protein 7; D025542:Neurofibromin 1; D034741:RNA, Small Interfering; C493726:Runx1 protein, mouse; D025521:Tumor Suppressor Proteins