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

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

PROVIDER: PRJNA1111545 | 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 [Hi-C]

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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.

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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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