Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2017 Apr 25

PMID 28434841

Citations 197

Authors

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

Affiliations

Soon will be listed here.

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.

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