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Cancer Cell. 2017 May 8;31(5):635-652.e6. doi: 10.1016/j.ccell.2017.03.011. Epub 2017 Apr 20.

Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma.

Author information

1
Department of Neurology, Stanford University, Palo Alto, CA 94305, USA.
2
Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, P.R. China.
3
Department of Pediatric Neurosurgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
4
Department of Pediatric Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands.
5
Department of Chemical and Systems Biology, Stanford University, Palo Alto, CA 94305, USA.
6
Department of Chemical and Systems Biology, Stanford University, Palo Alto, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, California 94305, USA; Department of Developmental Biology, Stanford University, Palo Alto, California 94305, USA; Howard Hughes Medical Institute, Stanford School of Medicine, Stanford University, Palo Alto, California 94305, USA.
7
Department of Neurology, Stanford University, Palo Alto, CA 94305, USA; Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, P.R. China; Department of Pediatric Neurosurgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China. Electronic address: yujietang@shsmu.edu.cn.
8
Department of Neurology, Stanford University, Palo Alto, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, California 94305, USA. Electronic address: mmonje@stanford.edu.

Abstract

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.

KEYWORDS:

BRD4; CDK7; DIPG; EPH; oligodendrocyte precursor cell; potassium channel; super-enhancer

PMID:
28434841
PMCID:
PMC5462626
DOI:
10.1016/j.ccell.2017.03.011
[Indexed for MEDLINE]
Free PMC Article

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