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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [RNA-seq]

ABSTRACT: Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [RNA-seq]

PROVIDER: PRJNA1111558 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29025524_1.fastq.gz	Fastqsanger.gz
	SRR29025524_2.fastq.gz	Fastqsanger.gz
	SRR29025525_1.fastq.gz	Fastqsanger.gz
	SRR29025525_2.fastq.gz	Fastqsanger.gz
	SRR29025526_1.fastq.gz	Fastqsanger.gz

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma

Project description:Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [Hi-C]

Project description:Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [Hi-C]

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [CUT&RUN]

Project description:Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [CUT&RUN]

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [CUT&RUN]

Project description:Medulloblastoma is the most common malignant brain tumor of childhood. The highest-risk tumors are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB. Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with the dual CDK9/7 inhibitor zotiraciclib to evaluate effect on Myc-driven programs and tumor growth. Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cells are susceptible to CDK9 inhibition, which is synergistic with concurrent inhibition of CDK7. The dual CDK9/7 inhibitor zotiraciclib disrupts enhancer-promoter activity in Myc-MB and downregulates Myc-driven transcriptional programs, exerting potent anti-tumor effect.

2024-11-14 | GSE267470 | GEO

Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [RNA-seq]

2024-11-14 | GSE267469 | GEO

Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [Hi-C]

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

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Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma

Project description:Tumor recurrence is a slow biological process involving therapy resistance, immune escape and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two thirds of medulloblastoma. To follow relapse at the single cell level we developed an inducible dual Tet Off animal model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells. SOX9 promoted immune escape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.

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An Animal Model of Myc-driven medulloblastoma

Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB, and identify a novel model that can be used to test therapies for this devastating disease. To gain insight into the pathways that control growth of MYC-driven MB, we compared gene expression profiles of murine Myc/DNp53 (MP) tumor cells to those of freshly isolated cerebellar stem cells (Prom1+Lin- cells) and of tumors from Ptch1 mutant mice (a model for Sonic Hedgehog-associated MB). RNA was isolated from stem cells and tumor cells using the RNAqueous kit (Ambion). RNA was labeled and hybridized to Affymetrix Mouse Genome 430 2.0 arrays. 19 mouse cell samples (stem cells and tumor cells) were analyzed. There are four groups of samples, three with five biological replicates and the last with four (one outlier was removed). To gain insight into the mechanisms of transformation into tumors, we compared the gene expression profiles of MP tumor cells derived from stem cells (Myc/DNp53-infected Prom1+Lin- cells, designated MP-pl) or progenitors (Myc/DNp53-infected Prom1+ cells, designated MP-p) to gene expression profiles of uninfected stem cells (designated NSC) and profiles from a distinct model of medulloblastoma, the patched mutant mouse (designated ptch1).

2011-12-05 | E-GEOD-34126 | biostudies-arrayexpress

Myc-driven medulloblastoma cells treated with Panobinostat (LBH589)

Project description:Mouse MycT58A/DNp53 (MP) medulloblastoma cells were treated with DMSO or HDAC inhibitor (HDACi) panobinostat for 6 or 12 hours in vitro. Gene expression profiling was performed to compare cells treated with panobinostat and DMSO.

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