| Author |
Schulte, J H and Lindner, S and Bohrer, A and Maurer, J and De Preter, K and Lefever, S and Heukamp, L and Schulte, S and Molenaar, J and Versteeg, R and Thor, T and Künkele, A and Vandesompele, J and Speleman, F and Schorle, H and Eggert, A and Schramm, A |
| Abstract |
Neuroblastoma is an embryonal tumor with a heterogeneous clinical course. The tumor is presumed to be derived from the neural crest, but the cells of origin remain to be determined. To date, few recurrent genetic changes contributing to neuroblastoma formation, such as amplification of the {MYCN} oncogene and activating mutations of the {ALK} oncogene, have been identified. The possibility to model neuroblastoma in mice allows investigation of the cell of origin hypothesis in further detail. Here we present the evidence that murine neural crest progenitor cells can give rise to neuroblastoma upon transformation with {MYCN} or {ALK(F1174L).} For this purpose we used {JoMa1}, a multipotent neural crest progenitor cell line, which is kept in a viable and undifferentiated state by a tamoxifen-activated c-Myc transgene (c-{MycER(T)).} Expression of {MYCN} or {ALK(F1174L)}, one of the oncogenic {ALK} variants identified in primary neuroblastomas, enabled these cells to grow independently of c-{MycER(T)} activity in vitro and caused formation of neuroblastoma-like tumors in vivo in contrast to parental {JoMa1} cells and {JoMa1} cells-expressing {TrkA} or {GFP.} Tumorigenicity was enhanced upon serial transplantation of tumor-derived cells, and tumor cells remained susceptible to the {MYC-inhibitor}, {NBT-272}, indicating that cell growth depended on functional {MYCN.} Our findings support neural crest progenitor cells as the precursor cells of neuroblastoma, and indicate that neuroblastomas arise as their malignant progeny.
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