Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells
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Gisèle Montavon1, Nicolas Jauquier2, Aurélie Coulon3, Michel Peuchmaur4, Marjorie Flahaut3, Katia Balmas Bourloud3, Pu Yan5, Olivier Delattre6, Lukas Sommer7, Jean-Marc Joseph2, Isabelle Janoueix-Lerosey6, Nicole Gross3, and Annick Mühlethaler-Mottet3
1 Pediatric Department, HFR Hospital Fribourg, Villars-sur-Glâne, Switzerland
2 Pediatric Surgery, Pediatric Department, University Hospital CHUV, Lausanne, Switzerland
3 Pediatric Oncology Research, Pediatric Department, University Hospital CHUV, Lausanne, Switzerland
4 Service d’anatomie pathologique, Hôpital Robert Debré, Paris, France
5 Pediatric Pathology, Pathology Department, University Hospital CHUV, Lausanne, Switzerland
6 INSERM U830, Institut Curie, Centre de Recherche, Paris, France
7 Cell and Developmental Biology, Institute of Anatomy, University of Zürich, Zürich, Switzerland
Annick Mühlethaler-Mottet, email:
Keywords: ALK, neuroblastoma, Myc, tumorigenesis, differentiation
Received: April 24, 2014 Accepted: May 27, 2014 Published: May 27, 2014
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.
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