title: NF1 loss induces senescence during human melanocyte differentiation in an iPSC-based model.
abstract: Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell-derived neurofibromas or melanocytic lesions called café-au-lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1(+/-) -induced pluripotent stem cell (iPSC)-based model. We demonstrate that NF1 patient-derived fibroblasts can be successfully reprogrammed in NF1(+/-) iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's-derived CALMs, revealing a new role for NF1 in the melanocyte lineage.
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Lionel
authors.initials: L
authors.lastname: Larribere
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Huizi
authors.initials: H
authors.lastname: Wu
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Novak
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Galach
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bernhardt
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Elias
authors.initials: E
authors.lastname: Orouji
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Kasia
authors.initials: K
authors.lastname: Weina
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Knappe
authors.affiliation: Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christos
authors.initials: C
authors.lastname: Sachpekidis
authors.affiliation: Division of Translational Immunology, German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT), Heidelberg, Germany.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.affiliation: Division of Translational Immunology, German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT), Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: De Schepper
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kaufmann
authors.affiliation: INSERM U1065 (Team 1), C3M, Biology and Pathologies of melanocytes, Nice, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.affiliation: INSERM U1065 (Team 1), C3M, Biology and Pathologies of melanocytes, Nice, France.
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
mesh_terms: D000328:Adult; D002454:Cell Differentiation; D016922:Cellular Senescence; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D018631:ras Proteins
keywords: café-au-lait macules; induced pluripotent stem cell; melanocyte; neurofibromatosis type 1; oncogene-induced senescence