MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells. 2013

J H Schulte, and S Lindner, and A Bohrer, and J Maurer, and K De Preter, and S Lefever, and L Heukamp, and S Schulte, and J Molenaar, and R Versteeg, and T Thor, and A Künkele, and J Vandesompele, and F Speleman, and H Schorle, and A Eggert, and A Schramm
Department of Pediatric Oncology and Haematology, University Children's Hospital Essen, Essen, Germany. Johannes.schulte@uni-due.de

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.

UI MeSH Term Description Entries
D008819 Mice, Nude Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses. Athymic Mice,Mice, Athymic,Nude Mice,Mouse, Athymic,Mouse, Nude,Athymic Mouse,Nude Mouse
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D009432 Neural Crest The two longitudinal ridges along the PRIMITIVE STREAK appearing near the end of GASTRULATION during development of nervous system (NEURULATION). The ridges are formed by folding of NEURAL PLATE. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the NEURAL TUBE. Neural Crest Cells,Neural Fold,Neural Groove,Cell, Neural Crest,Cells, Neural Crest,Crest, Neural,Crests, Neural,Fold, Neural,Folds, Neural,Groove, Neural,Grooves, Neural,Neural Crest Cell,Neural Crests,Neural Folds,Neural Grooves
D009447 Neuroblastoma A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51) Neuroblastomas
D009687 Nuclear Proteins Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. Nucleolar Protein,Nucleolar Proteins,Nuclear Protein,Protein, Nuclear,Protein, Nucleolar,Proteins, Nuclear,Proteins, Nucleolar
D002471 Cell Transformation, Neoplastic Cell changes manifested by escape from control mechanisms, increased growth potential, alterations in the cell surface, karyotypic abnormalities, morphological and biochemical deviations from the norm, and other attributes conferring the ability to invade, metastasize, and kill. Neoplastic Transformation, Cell,Neoplastic Cell Transformation,Transformation, Neoplastic Cell,Tumorigenic Transformation,Cell Neoplastic Transformation,Cell Neoplastic Transformations,Cell Transformations, Neoplastic,Neoplastic Cell Transformations,Neoplastic Transformations, Cell,Transformation, Cell Neoplastic,Transformation, Tumorigenic,Transformations, Cell Neoplastic,Transformations, Neoplastic Cell,Transformations, Tumorigenic,Tumorigenic Transformations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071447 N-Myc Proto-Oncogene Protein A basic helix-loop-helix leucine zipper (bHLHZ) transcription factor and proto-oncogene protein that functions in cell growth and proliferation. In mammals, it is highly expressed in the brain during embryogenesis and is essential for brain development; it is not expressed in adult tissues. Amplification or overexpression of N-Myc occurs in at least 20% of tumors and is associated with a poor prognosis in cases of NEUROBLASTOMA; ALVEOLAR RHABDOMYOSARCOMA; SMALL CELL LUNG CARCINOMA; and neuroendocrine prostate cancer. BHLHE37 Protein,Class E Basic Helix-Loop-Helix Protein 37,MYCN Protein,N-Myc Protein,NMYC Protein,Class E Basic Helix Loop Helix Protein 37,N Myc Protein,N Myc Proto Oncogene Protein,Proto-Oncogene Protein, N-Myc
D000077548 Anaplastic Lymphoma Kinase A receptor tyrosine kinase that is essential for development and differentiation of the nervous system in response to secreted growth factors. It phosphorylates the first tyrosine of the Y-x-x-x-Y-Y motif of targets that include PROTO-ONCOGENE PROTEINS C-CBL; INSULIN RECEPTOR SUBSTRATE-1; and MITOGEN-ACTIVATED PROTEIN KINASES, leading to activation of the MAPK signaling pathway and cell proliferation. A chromosomal aberration involving the ALK gene results in its constitutive expression in some cases of NON-HODGKIN LYMPHOMA. ALK Kinase,ALK Tyrosine Kinase Receptor,Anaplastic Lymphoma Receptor Tyrosine Kinase,CD246 Antigen,NPM-ALK,Nucleophosmin-Anaplastic Lymphoma Kinase,Nucleophosmin Anaplastic Lymphoma Kinase
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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