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Targeting Transcriptional Addiction in MYCN-amplified Neuroblastoma via Super Elongation Complex Disruption

ABSTRACT: Targeting Transcriptional Addiction in MYCN-amplified Neuroblastoma via Super Elongation Complex Disruption

PROVIDER: PRJNA818315 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18401327_1.fastq.gz	Fastqsanger.gz
	SRR18401327_2.fastq.gz	Fastqsanger.gz
	SRR18401328_1.fastq.gz	Fastqsanger.gz
	SRR18401328_2.fastq.gz	Fastqsanger.gz
	SRR18401329_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

The Super Elongation Complex Drives Transcriptional Addiction in MYCN-amplified Neuroblastoma

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

Targeting Transcriptional Addiction in MYCN-amplified Neuroblastoma via Super Elongation Complex Disruption

Project description:MYCN amplification in neuroblastoma predicts particular poor prognosis and directly targeting of MYCN remains a major challenge. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastoma. Mechanistically, MYCN directly interacts with the SEC subunit EAF1 and recruits the complex to the target gene loci for ensuing processive transcription elongation, rendering MYCN-mediated transcriptional activation highly dependent on SEC. Pharmacological inhibition of SEC by KL-1 or KL-2 elicits selective cell death in MYCN-overexpressing neuroblastoma cells. Furthermore, drug combination screening identifies the BCL-2 inhibitor ABT-199 synergistic with KL-2. Pre-clinical studies manifest that KL-2 and ABT-199 co-treatment significantly suppresses tumorigenesis and shows therapeutic value in multiple neuroblastoma allograft and xenograft models. These findings highlight SEC as a targetable vulnerability, and simultaneous inhibition of SEC and BCL-2 holds great promise for the treatment of MYCN-driven neuroblastoma.

2023-02-27 | GSE199086 | GEO

The super elongation complex drives transcriptional addiction in <i>MYCN</i>-amplified neuroblastoma.

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 BCL-2 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.

| S-EPMC10058231 | biostudies-literature

Neuroblastoma: MYCN normal vs. MYCN amplified

Project description:To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips. Two-condition experiment, MYCN normal vs. MYCN amplified 10 NB patient tissues for each group.

2013-12-17 | E-GEOD-53371 | biostudies-arrayexpress

To identify transcripts that are differentially expressed in the MYCN amplified vs MYCN non-amplified cell lines using Next Generation Sequencing

Project description:The aims of this study are to compare transcripts that are differentially expressed in the MYCN amplified compare to the MYCN non-amplified neuroblastoma cell lines, in particular, long non-coding RNAs. Methods: Ribosomal depleted RNAs from six human neuroblastoma cell lines were subjected to deep sequencing, using Illumina Hiseq. Results: We identified 459 transcripts are differentially expressed betweeen the MYCN amplified and the MYCN non-amplified cell lines. Conclusions: We have identified a novel long noncoding RNA lncNB1 that is highly expressed in the MYCN amplified compared to the MYCN non-amplified cell lines.

2019-10-08 | GSE114053 | GEO

Genome-wide binding of MYCN protein in MYCN-amplified neuroblastoma cell lines

Project description:The MYCN locus is amplified in about half of high-risk neuroblastoma tumors. To identify genomic loci occupied by MYCN protein in the MYCN-amplified neuroblastoma cell lines NGP, Kelly and NB-1643, we performed chromatin immunoprecipitation coupled with Next-Generation Sequencing (ChIP-seq) using an anti-MYCN antibody.

2017-08-02 | GSE94782 | GEO

MYCN mediates cysteine addiction and sensitizes to ferroptosis

Project description:Overexpression of MYC family members is linked to poor clinical outcome in many human cancers. These oncoproteins drive proliferation, alter metabolism, and mediate an antioxidant response to maintain tumor cell redox balance. However, to date, there are no effective inhibitors that specifically target MYC-amplified tumors. We demonstrate that MYCN-amplified, aggressive childhood neuroblastoma cells undergo ferroptotic cell death in vivo in the absence of intracellular cysteine, thus implicating MYCN as a predictive biomarker for ferroptosis sensitivity in neuroblastoma. Although cysteine is provided by both uptake from the microenvironment and MYCN-induced transsulfuration of methionine, glutathione levels remain low in these highly proliferative cancer cells due to concomitant cysteine utilization for protein and nucleotide synthesis. Consequently, MYCN-amplified neuroblastoma cells are highly susceptible to lipid peroxidation and ferroptosis, which must be counteracted by GPX4 activity. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. Our data show that MYCN-amplified neuroblastoma is sensitized to ferroptosis, which can be exploited therapeutically, by depleting the intracellular cysteine pool with concomitant GPX4 inactivation. These findings may help to develop novel clinical strategies to target MYCN-amplified tumors by inducing ferroptotic cell death.

2022-01-18 | GSE189174 | GEO

RNA-sequencing in two MYCN amplified/high-risk and one non-MYCN amplified/low-risk neuroblastoma cell lines

Project description:RNA-sequencing has been used to obtain and observe transcriptome-wide differences that occur in two parasspeckle-deficient, MYCN-amplified/model high-risk and one paraspeckle-abundant, non-MYCN-amplified/low-risk cell lines, to decipher the role of paraspeckles in this cancer type.

2021-09-09 | GSE133552 | GEO

Targeting EZH2 in MYCN-amplified Neuroblastoma

Project description:Targeting EZH2 in MYCN-amplified Neuroblastoma

| PRJNA338446 | ENA

Targeting EZH2 in MYCN-amplified Neuroblastoma [ChIP-seq]

Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: ChIP-Seq experiments were performed on Kelly and LAN-1 neuroblastoma cells by using the following antibodies: anti-EZH2 (Cell Signaling 5246S); anti-H3K27me3 (Millipore 07-449); anti-H3K4me3 (Abcam ab8580). We evaluated the global EZH2 PRC2-dependence by identifiying direct genome-wide target genes for EZH2, H3K27me3 and H3K4me3. Results: We found that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neuronal differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high-risk primary tumors. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

2017-12-02 | GSE85430 | GEO

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