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

doi:10.18632/oncotarget.2036

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.

Highlights

Neuroblastoma (NB) is a heterogeneous childhood malignancy from embryonic origin arising from neural crest progenitor cells (NCPC) of the sympathoadrenal lineage [1]
Mice implanted with MONC-1-ALKF1174L cells developed highly aggressive tumors in all mice (10/10, 100%) within three weeks, while mice engrafted with parental MONC-1 cells developed tumors in adrenal glands (AG) with a significantly longer latency (7/9, 78%) (Figure 1B)
The role of anaplastic lymphoma kinase (ALK)-wt, ALK-F1174L and ALKR1245Q in NB tumor initiation was investigated in two NCPC models, MONC-1 and JoMa1

Summary

Introduction

Neuroblastoma (NB) is a heterogeneous childhood malignancy from embryonic origin arising from neural crest progenitor cells (NCPC) of the sympathoadrenal lineage [1]. Neural crest (NC) is a transient highly migratory population of neuroectodermal pluripotent stem cells in vertebrate embryo. NB is believed to originate from a subset of these migratory NC derivatives committed to the sympathoadrenal lineage, which differentiate into adrenal chromaffin cells or sympathetic ganglia [1, 4]. ALK is expressed in the developing central and peripheral nervous system during embryogenesis [5], and in the developing sympathoadrenal lineage of the NC, where its signaling may regulate the balance between cell proliferation and differentiation [1, 6, 7]. ALK physiological role in the normal development of the nervous system is not yet fully understood, but ALK having a role in neurogenesis control was demonstrated in Drosophila, zebrafish, and chicken [6, 8, 9]

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Conclusion