Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

Publication date: Available online 20 April 2017
Source:Cancer Cell
Author(s): Surya Nagaraja, Nicholas A. Vitanza, Pamelyn J. Woo, Kathryn R. Taylor, Fang Liu, Lei Zhang, Meng Li, Wei Meng, Anitha Ponnuswami, Wenchao Sun, Jie Ma, Esther Hulleman, Tomek Swigut, Joanna Wysocka, Yujie Tang, Michelle Monje
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.

Graphical abstract

Teaser

Nagaraja et al. show that diffuse intrinsic pontine glioma (DIPG), a fatal pediatric tumor, is vulnerable to BRD4 or CDK7 blockade, and inhibition of either synergizes with HDAC inhibition to block growth of DIPG. Super-enhancer analysis of DIPG suggests oligodendroglial precursors as the cell of origin.


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