title: Clonogenic cell subpopulations maintain congenital melanocytic nevi.
abstract: Large congenital melanocytic nevi (lCMN) are benign melanocytic tumors associated with an increased risk of melanoma transformation. They result predominantly from a post-zygotic somatic NRAS mutation. These lesions persist and even increase after birth proportionally to the child's growth. Therefore, we asked here whether cells with clonogenic and tumorigenic properties persisted postnatally in lCMN. Subpopulations of lCMN cells expressed stem cell/progenitor lineage markers such as Sox10, Nestin, Oct4, and ABCB5. In vitro, 1 in 250 cells from fresh lCMN formed colonies that could be passaged and harbored the same NRAS mutation as the original nevus. In vivo, lCMN specimens xenografted in immunocompromised mice expanded 4-fold. BrdU(+)-proliferating and label-retaining melanocytes were found within the outgrowth skin tissue of these xenografts, which displayed the same benign nested architecture as the original nevus. lCMN cell suspensions were not able to expand when xenografted alone in Rag 2-/- mice. Conversely, when mixed with keratinocytes, these cells reconstituted the architecture of the human nevus with its characteristic melanocyte layout, lentiginous hyperplasia, and nested architecture. Overall, our data demonstrate that, after birth, certain lCMN cell subtypes still display features such as clonogenic potential and expand into nevus-like structures when cooperating with adjacent keratinocytes.
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Charbel
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France.
authors.forename: Romain H
authors.initials: RH
authors.lastname: Fontaine
authors.affiliation: Université René Descartes-Paris V, Paris, France; Department of Maxillofacial and Plastic Surgery, Hôpital Necker, Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Kadlub
authors.affiliation: Université Pierre et Marie Curie-Paris VI, Paris, France; Department of Pathology, Hôpital Trousseau, Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Coulomb-L'Hermine
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rouillé
authors.affiliation: Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: How-Kit
authors.affiliation: Department of Pathology, Hôpital Tenon, Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moguelet
authors.affiliation: Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France; Laboratory for Epigenetics & Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France.
authors.forename: Jorg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Université René Descartes-Paris V, Paris, France; Department of Maxillofacial and Plastic Surgery, Hôpital Necker, Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Picard
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université René Descartes-Paris V, Paris, France; Department of Dermatology, Hôpital Cochin, Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Selim
authors.initials: S
authors.lastname: Aractingi
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France; Department of Dermatology, Hôpital Tenon, Publique-Hôpitaux de Paris, Paris, France. Electronic address: sarah.guegan.bart@gmail.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Guégan
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002675:Child, Preschool; D020558:GTP Phosphohydrolases / Q000235:genetics; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D015603:Keratinocytes / Q000473:pathology; D008544:Melanocytes / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009508:Nevus, Pigmented / Q000151:congenital* / Q000235:genetics / Q000473:pathology*; D012878:Skin Neoplasms / Q000151:congenital* / Q000235:genetics / Q000473:pathology*; D014410:Tumor Stem Cell Assay
chemical_list: D018398:Homeodomain Proteins; D008565:Membrane Proteins; C064658:RAG-1 protein; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human