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

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.