Similar Datasets
Project description:Chromosome 17q gain is an independent prognostic marker in neuroblastoma, harboring several potential oncogenes including IGF2BP1 and BIRC5. IGF2BP1 was shown to be upregulated in unfavorable neuroblastoma and correlates with poor patient survival. Here, we report that overexpression of IGF2BP1 in a transgenic mouse model induces neuroblastoma with all characteristics known for human neuroblastoma, including MYCN upregulation and genomic aberrations. Furthermore, we demonstrate that genes located at chromosome 17q have an exceptionally high potential as therapeutic targets in addition to a combined inhibition of IGF2BP1 and BIRC5 resulting in additive effects.
2023-05-31 | GSE181581 | GEO
Project description:Chromosome 17q gain is an independent prognostic marker in neuroblastoma, harboring several potential oncogenes including IGF2BP1 and BIRC5. IGF2BP1 was shown to be upregulated in unfavorable neuroblastoma and correlates with poor patient survival. Here, we report that overexpression of IGF2BP1 in a transgenic mouse model induces neuroblastoma with all characteristics known for human neuroblastoma, including MYCN upregulation and genomic aberrations. Furthermore, we demonstrate that genes located at chromosome 17q have an exceptionally high potential as therapeutic targets in addition to a combined inhibition of IGF2BP1 and BIRC5 resulting in additive effects.
2023-05-31 | GSE181579 | GEO
Project description:Chromosome 17q gain is an independent prognostic marker in neuroblastoma, harboring several potential oncogenes including IGF2BP1 and BIRC5. IGF2BP1 was shown to be upregulated in unfavorable neuroblastoma and correlates with poor patient survival. Here, we report that overexpression of IGF2BP1 in a transgenic mouse model induces neuroblastoma with all characteristics known for human neuroblastoma, including MYCN upregulation and genomic aberrations. Furthermore, we demonstrate that genes located at chromosome 17q have an exceptionally high potential as therapeutic targets in addition to a combined inhibition of IGF2BP1 and BIRC5 resulting in additive effects.
2023-05-31 | GSE221848 | GEO
Project description:Chromosome 17q gain is an independent prognostic marker in neuroblastoma, harboring several potential oncogenes including IGF2BP1 and BIRC5. IGF2BP1 was shown to be upregulated in unfavorable neuroblastoma and correlates with poor patient survival. Here, we report that overexpression of IGF2BP1 in a transgenic mouse model induces neuroblastoma with all characteristics known for human neuroblastoma, including MYCN upregulation and genomic aberrations. Furthermore, we demonstrate that genes located at chromosome 17q have an exceptionally high potential as therapeutic targets in addition to a combined inhibition of IGF2BP1 and BIRC5 resulting in additive effects.
2023-05-31 | GSE181580 | GEO
Project description:Chromosome 17q gain is an independent prognostic marker in neuroblastoma, harboring several potential oncogenes including IGF2BP1 and BIRC5. IGF2BP1 was shown to be upregulated in unfavorable neuroblastoma and correlates with poor patient survival. Here, we report that overexpression of IGF2BP1 in a transgenic mouse model induces neuroblastoma with all characteristics known for human neuroblastoma, including MYCN upregulation and genomic aberrations. Furthermore, we demonstrate that genes located at chromosome 17q have an exceptionally high potential as therapeutic targets in addition to a combined inhibition of IGF2BP1 and BIRC5 resulting in additive effects.
2023-05-31 | GSE181559 | GEO
Project description:Neuroblastoma (NBL) is an embryonal cancer of the sympathetic nervous system (SNS), which causes 15% of pediatric cancer deaths. High-risk NBL is characterized by N-Myc amplification and segmental chromosomal gains and losses. Owing to limited disease models, the etiology of NBL is largely unknown, including both the cell of origin and the majority of oncogenic drivers. We have established a novel system for studying NBL based on the transformation of neural crest cells (NCCs), the progenitor cells of the SNS, isolated from mouse embryonic day 9.5 trunk neural tube explants. Based on pathology and gene expression analysis, we report the first successful transformation of wild-type NCCs into NBL by enforced expression of N-Myc, to generate phenotypically and molecularly accurate tumors that closely model human MYCN-amplified NBL. Using comparative genomic hybridization, we found that NCC-derived NBL tumors acquired copy number gains and losses that are syntenic to those observed in human MYCN-amplified NBL including 17q gain, 2p gain and loss of 1p36. When p53-compromised NCCs were transformed with N-Myc, we generated primitive neuroectodermal tumors with divergent differentiation including osteosarcoma. These subcutaneous tumors were metastatic to regional lymph nodes, liver and lung. Our novel experimental approach accurately models human NBL and establishes a new system with potential to study early stages of NBL oncogenesis, to functionally assess NBL oncogenic drivers and to characterize NBL metastasis.
| S-EPMC5582212 | biostudies-literature
Project description:BackgroundAmplification of the MYCN oncogene is a molecular hallmark of aggressive neuroblastoma (NB), a childhood cancer of the sympathetic nervous system. There is evidence that MYCN promotes a non-inflamed and T-cell infiltration-poor ('cold') tumor microenvironment (TME) by suppressing interferon signaling. This may explain, at least in part, why patients with NB seem to have little benefit from single-agent immune checkpoint blockade (ICB) therapy. Targeting MYCN or its effectors could be a strategy to convert a cold TME into a 'hot' (inflamed) TME and improve the efficacy of ICB therapy.MethodsNB transcriptome analyses were used to identify epigenetic drivers of a T-cell infiltration-poor TME. Biological and molecular responses of NB cells to epigenetic drugs and interferon (IFN)-γ exposure were assessed by proliferation assays, immunoblotting, ELISA, qRT-PCR, RNA-seq and ChIP-qPCR as well as co-culture assays with T cells.ResultsWe identified H3K9 euchromatic histone-lysine methyltransferases EHMT2 and EHMT1, also known as G9a and GLP, as epigenetic effectors of the MYCN-driven malignant phenotype and repressors of IFN-γ transcriptional responses in NB cells. EHMT inhibitors enhanced IFN-γ-induced expression of the Th1-type chemokines CXCL9 and CXCL10, key factors of T-cell recruitment into the TME. In MYCN-amplified NB cells, co-inhibition of EZH2 (enhancer of zeste homologue 2), a H3K27 histone methyltransferase cooperating with EHMTs, was needed for strong transcriptional responses to IFN-γ, in line with histone mark changes at CXCL9 and CXCL10 chemokine gene loci. EHMT and EZH2 inhibitor response gene signatures from NB cells were established as surrogate measures and revealed high EHMT and EZH2 activity in MYCN-amplified high-risk NBs with a cold immune phenotype.ConclusionOur results delineate a strategy for targeted epigenetic immunomodulation of high-risk NBs, whereby EHMT inhibitors alone or in combination with EZH2 inhibitors (in particular, MYCN-amplified NBs) could promote a T-cell-infiltrated TME via enhanced Th1-type chemokine expression.
| S-EPMC8141444 | biostudies-literature
Project description:Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.
| S-EPMC1940236 | biostudies-literature
Project description:BackgroundMicroRNAs (miRNAs) regulate expression of many cancer-related genes through posttranscriptional repression of their mRNAs. In this study we investigate the proto-oncogene MYCN as a target for miRNA regulation.MethodsA luciferase reporter assay was used to investigate software-predicted miRNA target sites in the 3'-untranslated region (3'UTR) of MYCN. The miRNAs were overexpressed in cell lines by transfection of miRNA mimics or miRNA-expressing plasmids. Mutation of the target sites was used to validate MYCN 3'UTR as a direct target of several miRNAs. To measure miRNA-mediated suppression of endogenous N-myc protein, inhibition of proliferation and inhibition of clonogenic growth, miRNAs were overexpressed in a MYCN-amplified neuroblastoma cell line.ResultsThe results from this study show that MYCN is targeted by several miRNAs. In addition to the previously shown mir-34a/c, we experimentally validate mir-449, mir-19a/b, mir-29a/b/c, mir-101 and let-7e/mir-202 as direct MYCN-targeting miRNAs. These miRNAs were able to suppress endogenous N-myc protein in a MYCN-amplified neuroblastoma cell line. The let-7e and mir-202 were strong negative regulators of MYCN expression. The mir-101 and the let-7 family miRNAs let-7e and mir-202 inhibited proliferation and clonogenic growth when overexpressed in Kelly cells.ConclusionThe tumour-suppressor miRNAs let-7 and mir-101 target MYCN and inhibit proliferation and clonogenic growth of MYCN-amplified neuroblastoma cells.
| S-EPMC3142803 | biostudies-literature
Project description:This study investigates the influence expression of the MYCN oncogene has on the DNA damage response, replication fork progression and sensitivity to PARP inhibition in neuroblastoma. In a panel of neuroblastoma cell lines, MYCN amplification or MYCN expression resulted in increased cell death in response to a range of PARP inhibitors (niraparib, veliparib, talazoparib and olaparib) compared to the response seen in non-expressing/amplified cells. MYCN expression slowed replication fork speed and increased replication fork stalling, an effect that was amplified by PARP inhibition or PARP1 depletion. Increased DNA damage seen was specifically induced in S-phase cells. Importantly, PARP inhibition caused a significant increase in the survival of mice bearing MYCN expressing tumours in a transgenic murine model of MYCN expressing neuroblastoma. Olaparib also sensitized MYCN expressing cells to camptothecin- and temozolomide-induced cell death to a greater degree than non-expressing cells. In summary, MYCN expression leads to increased replication stress in neuroblastoma cells. This effect is exaggerated by inhibition of PARP, resulting in S-phase specific DNA damage and ultimately increased tumour cell death. PARP inhibition alone or in combination with classical chemotherapeutics is therefore a potential therapeutic strategy for neuroblastoma and may be more effective in MYCN expressing tumours.
| S-EPMC7289530 | biostudies-literature