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Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells [RNA-seq]

ABSTRACT: Neuroblastoma (NB) is a pediatric solid tumor originating from neural crest cells (NCCs), which are precursors of the sympathetic nervous system. MYCN amplification is a key factor contributing to poor prognosis of NB. Additionally, anaplastic lymphoma kinase (ALK) mutation or amplification drives oncogenic signaling pathways, such as MAPK signaling, which together with MYCN amplification exacerbate NB malignancy. NCCs are mainly classified into cranial NCCs (cNCCs) and trunk NCCs (tNCCs), and recent studies have reported NB development from tNCCs. However, the potential for NB development from cNCCs remains unexplored. In this study, we sought to mimic the tumorigenic process of NB by overexpressing MYCN and ALK in cNCCs derived from human induced pluripotent stem cells. These modified cells when subcutaneously transplanted into immunodeficient mice induced NB -like tumors, and could thus be used an in vitro model to study this tumor. Through extensive gene expression profiling and whole exome sequencing of MYCN/ALK-induced clones, we identified key features of NB, including activation of the MAPK pathway and gain of 17q chromosome, which is critical for malignant tumor development. This model provides a valuable platform for studying the biological mechanisms driving ALK and MYCN amplification in NB derived from cNCCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294865 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:Less than 30% of children with high-risk (HR) metastatic neuroblastoma (NB) show a long survival (Pearson 2000). In order to identify novel molecular prognostic markers useful to better predict patientsM-bM-^@M-^Y relapse risk estimation, we performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR-NBs. This is the largest study for this NB subtype. Children older than 1 year of age at diagnosis were categorized as M-bM-^@M-^\short-survivorsM-bM-^@M-^] (dead of disease within 5 years from diagnosis) and M-bM-^@M-^\long-survivorsM-bM-^@M-^] (alive with an overall survival time > 5 years). A significant correlation of patient survival with the presence of small number of segmental copy number aberrations (CNA < 3) was observed. Thus, within the group of stage 4 HR-NBs, we identified a specific subgroup of patients (those with highest number of CNA) that have a higher risk of progression/recurrence. The complex genomic pattern is an independent prognostic marker, since MYCN oncogene amplification only affects the predictive value of single CNA (i.e., 1p loss, 17q gain). Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is associated with loss of cell cycle control and with progression of tumor due to deregulation of Rho GTPase signaling and genes related to cell motility. Tumors with MYCN amplification showed a lower chromosome instability compared to MYCN-single copy NBs (P=0.0008), dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives the disruption of neuronal differentiation and the reduction of cell adhesion process involved in tumor invasion and metastasis. For array-CGH profiling, we analyzed 91 samples of metastatic neuroblastomas. All patients were classified as stage 4 and they were older than 1 year of age at time of diagnosis. Regarding the clinical course, 46 were short-survivors (dead of disease within 60 months from diagnosis. Deaths due to toxicity were censored) and 45 were long-survivors (alive with an overall survival time > 60 months). This submission consists of 22 new samples and 69 other cases previously deposited in GEO under Series accessions GSE14109 and GSE25771.

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Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells [RNA-seq]

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