Ribosome profiling analysis of neuroblastoma cells in response to amidino-rocaglate treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261760 | GEO | 2024/06/25
REPOSITORIES: GEO
Similar Datasets
Project description:MYCN-amplified neuroblastoma cells exhibit upregulation of translation initiation factors as a result of MYCN-driven transcriptional amplification, including the RNA helicase eIF4A1. Here, we treated MYCN-amplified patient derived xenograft (PDX) neuroblastoma cells with a novel translation initiation inhibitor, amidino-rocaglate CMLD12824, to analyze the impact on the global pattern of eIF4A1 binding to mRNA compared to the naive condition.
2024-06-25 | GSE261761 | GEO
Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
2023-05-10 | PXD039332 | Pride
Project description:<p>Neuroblastoma is the most common extra-cranial solid tumor in children. It represents 8% to 10% of all childhood cancers. Stage 4 Neuroblastoma is characterized by its clinical heterogeneous outcome. The special category, stage 4S tumors (2-5% of all NB) are chemo-sensitive, and the patients show spontaneous regression. On the other hand, MYCN amplification (25-30% of all NB) is associated with poor outcome of neuroblastoma, thus we further categorize stage 4 neuroblastoma into MYCN non-amplified and MYCN amplified group. Here we use transcriptome sequencing to characterize the transcriptome in 29 stage 4 Neuroblastoma samples.</p>
| phs000868 | dbGaP
Project description:The let-7 microRNA families are tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has been implicated as a critical regulator of MYCN ; however, here we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN amplified neuroblastoma cell lines despite robust de-repression of let-7 . We further report that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-set of self-sponging amplified competing endogenous RNA (aceRNA) and reconciles the dispensability of LIN28B . In addition, we observe frequent genomic loss of let-7 that inversely associates with MYCN- amplification, providing an explanation for common, yet unresolved amplification-independent patterns of chromosome loss. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN amplified tumors marks decreased survival, further underscoring its importance. The inverse relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis.
2016-07-06 | GSE81499 | GEO
Project description:The let-7 microRNA families are tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has been implicated as a critical regulator of MYCN ; however, here we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN amplified neuroblastoma cell lines despite robust de-repression of let-7 . We further report that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-set of self-sponging amplified competing endogenous RNA (aceRNA) and reconciles the dispensability of LIN28B . In addition, we observe frequent genomic loss of let-7 that inversely associates with MYCN- amplification, providing an explanation for common, yet unresolved amplification-independent patterns of chromosome loss. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN amplified tumors marks decreased survival, further underscoring its importance. The inverse relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis.
2016-07-06 | GSE81498 | GEO
Project description:The let-7 microRNA families are tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has been implicated as a critical regulator of MYCN ; however, here we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN amplified neuroblastoma cell lines despite robust de-repression of let-7 . We further report that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-set of self-sponging amplified competing endogenous RNA (aceRNA) and reconciles the dispensability of LIN28B . In addition, we observe frequent genomic loss of let-7 that inversely associates with MYCN- amplification, providing an explanation for common, yet unresolved amplification-independent patterns of chromosome loss. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN amplified tumors marks decreased survival, further underscoring its importance. The inverse relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis.
2016-07-06 | GSE81497 | GEO
Project description:The let-7 microRNA families are tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has been implicated as a critical regulator of MYCN ; however, here we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN amplified neuroblastoma cell lines despite robust de-repression of let-7 . We further report that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-set of self-sponging amplified competing endogenous RNA (aceRNA) and reconciles the dispensability of LIN28B . In addition, we observe frequent genomic loss of let-7 that inversely associates with MYCN- amplification, providing an explanation for common, yet unresolved amplification-independent patterns of chromosome loss. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN amplified tumors marks decreased survival, further underscoring its importance. The inverse relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis. BE(2)C:MYCN-ORF cells transfected with siRNA and miRNA mimics
2016-07-06 | E-GEOD-81497 | biostudies-arrayexpress
Project description:The let-7 microRNA families are tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has been implicated as a critical regulator of MYCN ; however, here we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN amplified neuroblastoma cell lines despite robust de-repression of let-7 . We further report that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-set of self-sponging amplified competing endogenous RNA (aceRNA) and reconciles the dispensability of LIN28B . In addition, we observe frequent genomic loss of let-7 that inversely associates with MYCN- amplification, providing an explanation for common, yet unresolved amplification-independent patterns of chromosome loss. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN amplified tumors marks decreased survival, further underscoring its importance. The inverse relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis. Two cell lines, sampled in triplicate.
2016-07-06 | E-GEOD-81499 | biostudies-arrayexpress
Project description:The let-7 microRNA families are tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has been implicated as a critical regulator of MYCN ; however, here we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN amplified neuroblastoma cell lines despite robust de-repression of let-7 . We further report that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-set of self-sponging amplified competing endogenous RNA (aceRNA) and reconciles the dispensability of LIN28B . In addition, we observe frequent genomic loss of let-7 that inversely associates with MYCN- amplification, providing an explanation for common, yet unresolved amplification-independent patterns of chromosome loss. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN amplified tumors marks decreased survival, further underscoring its importance. The inverse relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis. Three cell lines, sampled in triplicate.
2016-07-06 | E-GEOD-81498 | biostudies-arrayexpress
Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma.
2013-02-25 | GSE43392 | GEO