title: Wild-type ALK and activating ALK-R1275Q and ALK-F1174L  mutations upregulate Myc and initiate tumor formation in  murine neural crest progenitor cells.
abstract: The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC- 1 parental cells in nude mice generated various tumor types, such as NB, osteo/ chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Montavon
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jauquier
authors.forename: Aurélie
authors.initials: A
authors.lastname: Coulon
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: Marjorie
authors.initials: M
authors.lastname: Flahaut
authors.forename: Katia Balmas
authors.initials: KB
authors.lastname: Bourloud
authors.forename: Pu
authors.initials: P
authors.lastname: Yan
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Joseph
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Nicole
authors.initials: N
authors.lastname: Gross
authors.forename: Annick
authors.initials: A
authors.lastname: Mühlethaler-Mottet
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002454:Cell Differentiation; D016259:Genes, myc; D006801:Humans; D051379:Mice; D009154:Mutation; D009432:Neural Crest; D009447:Neuroblastoma / Q000378:metabolism*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D013234:Stem Cells; D015854:Up-Regulation
chemical_list: C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases