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Transcriptional changes associated with resistance to JQ1 treatment in MYCN-amplified neuroblastoma

ABSTRACT: Transcriptional changes associated with resistance to JQ1 treatment in MYCN-amplified neuroblastoma

PROVIDER: PRJNA421163 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6348240.fastq.gz	Fastqsanger.gz
	SRR6348250.fastq.gz	Fastqsanger.gz
	SRR6348241.fastq.gz	Fastqsanger.gz
	SRR6348251.fastq.gz	Fastqsanger.gz
	SRR6348242.fastq.gz	Fastqsanger.gz

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

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2023-05-10 | PXD039332 | Pride

Transcriptional changes associated with resistance to JQ1 treatment in MYCN-amplified neuroblastoma

Project description:Drug resistance is a major clinical challenge in achieving durable responses to targeted cancer therapeutics. Resistance mechanisms to new classes of epigenetic-targeted drugs entering the clinic remain largely unexplored. We used BET inhibition in MYCN-amplified neuroblastoma as a prototype to model innate and acquired resistance to chromatin remodeling inhibitors in cancer. Genome-scale, pooled lentiviral ORF and CRISPR knockout rescue screens nominated the PI3K pathway as a key signaling node that mediates resistance to BET inhibition. RNA-seq profiling of BET inhibitor resistant cells revealed that global enhancer and super-enhancer remodeling leads to differential cell state commitment and the upregulation of receptor tyrosine kinases upstream of PI3K signaling, engendering a vulnerability to receptor tyrosine kinase (RTK) and PI3K inhibition. Large-scale, unbiased, chemical combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations with JQ1, a finding validated in vivo. These studies provide a comprehensive roadmap to elucidate resistance to epigenetic-targeted cancer therapeutics and inform efficacious combination therapies for second-generation clinical trials.

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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.

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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.

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Targeting EZH2 in MYCN-amplified Neuroblastoma

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Project description:Genome copy-number status has been profiled on 13 MYCN-amplified Neuroblastoma cell lines

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