Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

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, Joanna Wysocka, Tomek Swigut, Yujie Tang, Michelle Monje

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)635-652
TijdschriftCancer cell
Volume31
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 8 jun. 2017
Extern gepubliceerdJa

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