Oncotarget

Research Papers:

Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells

Gisèle Montavon _, Nicolas Jauquier, Aurélie Coulon, Michel Peuchmaur, Marjorie Flahaut, Katia Balmas Bourloud, Pu Yan, Olivier Delattre, Lukas Sommer, Jean-Marc Joseph, Isabelle Janoueix-Lerosey, Nicole Gross and Annick Mühlethaler-Mottet

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2014; 5:4452-4466. https://doi.org/10.18632/oncotarget.2036

Metrics: PDF 1943 views  |   HTML 2295 views  |   ?  


Abstract

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

Correspondence:

Annick Mühlethaler-Mottet, email:

Keywords: ALK, neuroblastoma, Myc, tumorigenesis, differentiation

Received: April 24, 2014 Accepted: May 27, 2014 Published: May 27, 2014

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 2036