Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma
Copyright policy )Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.
- Amsterdam UMC Netherlands
- Shanghai Jiao Tong University China (People's Republic of)
- Howard Hughes Medical Institute United States
- Institute for Stem Cell Biology and Regenerative Medicine United States
- Stanford University United States
Male, Time Factors, Indoles, Drug Resistance, Cell Cycle Proteins, Phenylenediamines, Hydroxamic Acids, Histones, Mice, Receptors, Antineoplastic Combined Chemotherapy Protocols, Brain Stem Neoplasms, Non-U.S. Gov't, Cultured, Eph Family, Nuclear Proteins, Drug Synergism, Azepines, Glioma, Cyclin-Dependent Kinases, Tumor Cells, Gene Expression Regulation, Neoplastic, RNA Interference, Female, Drug, Transcription, Signal Transduction, Primary Cell Culture, Non-P.H.S., SCID, Transfection, Research Support, N.I.H., Dose-Response Relationship, Genetic, Journal Article, Animals, Humans, Protein Kinase Inhibitors, Cell Proliferation, Neoplastic, Dose-Response Relationship, Drug, Extramural, Triazoles, Chromatin Assembly and Disassembly, Xenograft Model Antitumor Assays, Histone Deacetylase Inhibitors, Pyrimidines, Gene Expression Regulation, Drug Resistance, Neoplasm, Mutation, Neoplasm, Inbred NOD, U.S. Gov't, Transcription Factors
Male, Time Factors, Indoles, Drug Resistance, Cell Cycle Proteins, Phenylenediamines, Hydroxamic Acids, Histones, Mice, Receptors, Antineoplastic Combined Chemotherapy Protocols, Brain Stem Neoplasms, Non-U.S. Gov't, Cultured, Eph Family, Nuclear Proteins, Drug Synergism, Azepines, Glioma, Cyclin-Dependent Kinases, Tumor Cells, Gene Expression Regulation, Neoplastic, RNA Interference, Female, Drug, Transcription, Signal Transduction, Primary Cell Culture, Non-P.H.S., SCID, Transfection, Research Support, N.I.H., Dose-Response Relationship, Genetic, Journal Article, Animals, Humans, Protein Kinase Inhibitors, Cell Proliferation, Neoplastic, Dose-Response Relationship, Drug, Extramural, Triazoles, Chromatin Assembly and Disassembly, Xenograft Model Antitumor Assays, Histone Deacetylase Inhibitors, Pyrimidines, Gene Expression Regulation, Drug Resistance, Neoplasm, Mutation, Neoplasm, Inbred NOD, U.S. Gov't, Transcription Factors
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