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Pharmacological inhibition of BMI1 exerts antitumor effect on MYCN-amplified neuroblastoma with activation of the p53 pathway

ABSTRACT: Pharmacological inhibition of BMI1 exerts antitumor effect on MYCN-amplified neuroblastoma with activation of the p53 pathway

PROVIDER: PRJNA1084836 | ENA |

REPOSITORIES: ENA

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Pharmacological inhibition of BMI1 exerts antitumor effect on MYCN-amplified neuroblastoma with activation of the p53 pathway

Project description:BMI1, a constituent of the Polycomb Repressive Complex 1 (PRC1), has been identified as overexpressed in a variety of cancers, including neuroblastoma, highlighting its potential as a viable target for cancer therapeutics. Given its pivotal role, a number of BMI1 inhibitors have been synthesized and assessed for their therapeutic efficacy across a spectrum of cancers in recent years. This investigation demonstrates that the BMI1 inhibitors PTC-028 and PTC-209 exhibit selective antitumor activities against MYCN-amplified neuroblastoma. Notably, PTC-028, which exhibits toxicity at lower concentrations, triggers apoptosis in neuroblastoma cells, promotes G1 phase accumulation, and reduces S phase cell populations, thereby inducing cell cycle arrest. A thorough examination utilizing RNA sequencing has unveiled that treatment with PTC-028 activates the p53 signaling pathway, suggesting its critical involvement in the mechanism of cell death induction. Moreover, PTC-028 treatment leads to a decrease in the protein levels of anti-apoptotic factors, including BCL2 and MCL1. Significantly, PTC-028 has also demonstrated antitumor efficacy in a mouse xenograft model of human neuroblastoma cells. Consequently, BMI1 inhibitors, especially PTC-028, emerge as promising therapeutic agents for the management of aggressive MYCN-amplified neuroblastomas.

2025-07-09 | GSE261020 | GEO

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

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

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

Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: Kelly and LAN-1 neuroblastoma cells were treated in duplicate with 2 uM GSK126 (Excess Biosciences M60071-2) or DMSO for 2 or 5 days. RNA was extracted from cells with the RNeasy Kit (Qiagen). RNA libraries were prepared for sequencing using standard Illumina protocols. The pool of sixteen samples was sequenced on two lanes of an Illumina HiSeq, generating single end reads of 32-76 bp length. Transcript abundance (reads and FPKM scores) at GRCh37/hg19 RefSeq gene level was computed with the Feature Counts method implemented in the Bioconductor v3.2 Rsubread package (Liao et al., 2014). Results: Pharmacological suppression of EZH2 inhibited neuroblastoma growth. Transcriptomic analysis revealed that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neural differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high risk primary tumors. These observations demonstrate that MYCN upregulates EZH2 leading to inactivation of a tumor suppressor program in neuroblastoma. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

2017-12-02 | GSE85431 | 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

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

AhR promotes dedifferentiation in MYCN amplified neuroblastoma [RNA-seq]

Project description:AhR promotes dedifferentiation in MYCN amplified neuroblastoma

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