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

ABSTRACT: Neuroblastoma is a pediatric solid tumor originating from neural crest cells, which are precursors of the sympathetic nervous system. Amplification of MYCN proto-oncogene is a key factor contributing to poor prognosis of neuroblastoma and is strongly associated with aggressive disease progression. Additionally, the anaplastic lymphoma kinase plays an important role in the pathogenesis of neuroblastoma. Mutation or amplification of anaplastic lymphoma kinase drives oncogenic signaling pathways, such as the MAPK and Ras pathways, which together with MYCN amplification exacerbate tumor malignancy. The use of human induced pluripotent stem cell-derived cranial neural crest cells to establish a neuroblastoma model is expected to be of great significance in studying the pathogenesis of this disease. In this study, we sought to mimic the tumorigenic process of neuroblastoma by overexpressing MYCN and anaplastic lymphoma kinase in cranial neural crest cells derived from human induced pluripotent stem cells. These modified cells when subcutaneously transplanted into immunodeficient mice induced neuroblastoma-like tumors, and could thus be used an in vitro model to study this cancer. Through extensive gene expression profiling and whole exome sequencing of MYCN/anaplastic lymphoma kinase-induced clones, we identified key features of neuroblastoma, including activation of the MAPK signaling 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 anaplastic lymphoma kinase mutations and MYCN amplification in neuroblastoma derived from cranial neural crest cells as well as for exploring potential therapeutic approaches against these targets to improve patient prognosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287422 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates. As a proto-oncogene, targeted MYCN overexpression in peripheral neural crest is sufficient to initiate disease in mouse models. In MYCN amplified neuroblastoma, elevated expression of the factor is crucial to maintain tumor stemness and is associated with increased proliferation and aberrant cell cycle progression, as these tumors lack the ability to arrest in G1 in response to irradiation. MYCN down-regulation broadly reverses these oncogenic phenotypes in a variety of neuroblastoma models and recent thereapeutic strategies to indirectly target MYCN production or protein stability have reduced tumor growth in vivo. These observations motivate an investigation of MYCN binding in MYCN amplified tumors as it remains fundamentally unclear how elevated levels of the factor occupy the genome and alter transcriptional programs in neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of direct MYCN perturbation in neuroblastoma. We find that at oncogenic levels, MYCN associates with E-box (CANNTG) binding motifs in an affinity dependent manner across most active cis-regulatory promoters and enhancers. MYCN shutdown globally reduces histone acetylation and transcription, consistent with prior descriptions of MYC proteins as non-linear amplifiers of gene expression. We establish that MYCN load at the promoter and proximal enhancers predicts transcriptional responsiveness to MYCN shutdown and that MYCN enhancer binding occurs prominently at the most strongly occupied and down-regulated genes, suggesting a role for these tissue specific elements in predicating MYCN responsive âtargetâ genes. At these invaded enhancers, we identify the lineage specific bHLH TWIST1 as a key collaborator and dependency of oncogenic MYCN. These data suggest that MYCN enhancer invasion helps shape transcriptional amplification of the neuroblastoma gene expression program to promote tumorigenesis. ChIP-Seq in SHEP21, BE2C, KELLY, and NGP neuroblastoma cell lines for H3K27ac, H3K4me3, RNA PolII, MYCN, BRD4, or TWIST1

Project description:In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates1,2. As a proto-oncogene, targeted MYCN overexpression in peripheral neural crest is sufficient to initiate disease in mouse models3. In MYCN amplified neuroblastoma, elevated expression of the factor is crucial to maintain tumor stemness4,5 and is associated with increased proliferation and aberrant cell cycle progression, as these tumors lack the ability to arrest in G1 in response to irradiation6-9. MYCN down-regulation broadly reverses these oncogenic phenotypes in a variety of neuroblastoma models10-12 and recent thereapeutic strategies to indirectly target MYCN production or protein stability have reduced tumor growth in vivo13-15. These observations motivate an investigation of MYCN binding in MYCN amplified tumors as it remains fundamentally unclear how elevated levels of the factor occupy the genome and alter transcriptional programs in neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of direct MYCN perturbation in neuroblastoma. We find that at oncogenic levels, MYCN associates with E-box (CANNTG) binding motifs in an affinity dependent manner across most active cis-regulatory promoters and enhancers. MYCN shutdown globally reduces histone acetylation and transcription, consistent with prior descriptions of MYC proteins as non-linear amplifiers of gene expression. We establish that MYCN load at the promoter and proximal enhancers predicts transcriptional responsiveness to MYCN shutdown and that MYCN enhancer binding occurs prominently at the most strongly occupied and down-regulated genes, suggesting a role for these tissue specific elements in predicating MYCN responsive â??targetâ?? genes. At these invaded enhancers, we identify the lineage specific bHLH TWIST1 as a key collaborator and dependency of oncogenic MYCN. These data suggest that MYCN enhancer invasion helps shape transcriptional amplification of the neuroblastoma gene expression program to promote tumorigenesis. ATAC-Seq in SHEP21, BE2C, KELLY, NGP, and MM1S cell lines

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

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