title: MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells.
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.
authors.affiliation: Department of Pediatric Oncology and Haematology, University Children's Hospital Essen, Essen, Germany. Johannes.schulte@uni-due.de
authors.forename: J H
authors.initials: JH
authors.lastname: Schulte
authors.forename: S
authors.initials: S
authors.lastname: Lindner
authors.forename: A
authors.initials: A
authors.lastname: Bohrer
authors.forename: J
authors.initials: J
authors.lastname: Maurer
authors.forename: K
authors.initials: K
authors.lastname: De Preter
authors.forename: S
authors.initials: S
authors.lastname: Lefever
authors.forename: L
authors.initials: L
authors.lastname: Heukamp
authors.forename: S
authors.initials: S
authors.lastname: Schulte
authors.forename: J
authors.initials: J
authors.lastname: Molenaar
authors.forename: R
authors.initials: R
authors.lastname: Versteeg
authors.forename: T
authors.initials: T
authors.lastname: Thor
authors.forename: A
authors.initials: A
authors.lastname: Künkele
authors.forename: J
authors.initials: J
authors.lastname: Vandesompele
authors.forename: F
authors.initials: F
authors.lastname: Speleman
authors.forename: H
authors.initials: H
authors.lastname: Schorle
authors.forename: A
authors.initials: A
authors.lastname: Eggert
authors.forename: A
authors.initials: A
authors.lastname: Schramm
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009432:Neural Crest / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases