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Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma

ABSTRACT: Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma

PROVIDER: PRJNA989247 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25076835_1.fastq.gz	Fastqsanger.gz
	SRR25076835_2.fastq.gz	Fastqsanger.gz
	SRR25076836_1.fastq.gz	Fastqsanger.gz
	SRR25076836_2.fastq.gz	Fastqsanger.gz
	SRR25076837_1.fastq.gz	Fastqsanger.gz

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Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma

Project description:Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP‒qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.

2023-07-04 | GSE236205 | GEO

Silencing of the Long Noncoding RNA MYCNOS1 Suppresses Activity of MYCN-Amplified Retinoblastoma Without RB1 Mutation

Project description:MYCNOS (MYCN opposite strand) is co-amplified with MYCN in pediatric cancers including retinoblastoma. MYCNOS encodes several RNA variants whose functions have not been elucidated in retinoblastoma. Here, we attempted to decipher the role of MYCNOS variant 1 (MYCNOS1) on the activity of MYCN-amplified retinoblastoma. We observed that MYCNOS1 supports progression of retinoblastoma. Inhibition of MYCNOS1 expression may be needed to suppress MYCN activity when treating MYCN-amplified cancers without RB1 mutation.

2020-12-15 | GSE161449 | GEO

Differential gene expression analysis of MYCN-amplified neuroblastoma cells after THZ1 and TKI combination therapy.

Project description:The CDK7 inhibitor THZ1 has been shown to suppress MYCN gene transcription but not cause significant cell death as a single agent. The tyrosine kinase inhibitors (TKIs) ponatinib and lapatinib were found to exert synergistic anti-cancer effects in combination with the CDK7 inhibitor THZ1, on MYCN amplified neuroblastoma cell lines.

2020-03-20 | GSE128649 | GEO

Synergistic anti-tumor effect of combining selective CDK7 and BRD4 inhibition in MYCN-amplified neuroblastoma

Project description:Cyclin-dependent kinases (CDKs) that have critical roles in RNA polymerase II (Pol II)-mediated gene transcription are emerging as therapeutic targets in cancer. We have previously shown that THZ1, a covalent inhibitor of CDKs7/12/13, leads to cytotoxicity in MYCN-amplified neuroblastoma through the downregulation of super-enhancer-associated transcriptional upregulation. We sought to dissect the mechanisms of cytotoxicity in NB cells and to identify additional targets that could be inhibited together with CDK7 in combination therapy.

2022-01-27 | GSE183587 | 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

MYCN-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma

Project description:Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from retinoblastomas, we identified a MYCN-driven cluster of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven cluster were characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models caused growth arrest and reactivated a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identified MYCN-driven retinoblastoma than MYCN amplification and could identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology

2024-05-31 | GSE267015 | GEO

MYCN-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma II

Project description:Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from retinoblastomas, we identified a MYCN-driven of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven were characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models caused growth arrest and reactivated a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identified MYCN-driven retinoblastoma than MYCN amplification and could identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology

2024-05-31 | GSE268136 | GEO

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 of Super-Enhancer-Associated Oncogenic Transcription in MYCN-driven tumor cells by CDK7 inhibition [Gene Expression]

Project description:Global gene expression after CDK7 inhibition by THZ1 Global gene expression after genetic knockdown or overexpression of MYCN

2014-11-21 | E-GEOD-62724 | biostudies-arrayexpress