Cell Reports
Volume 31, Issue 1, 7 April 2020, 107485
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Article
Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma

https://doi.org/10.1016/j.celrep.2020.03.049Get rights and content
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Highlights

  • RNAi screen identifies SEC as a molecular dependency in diffuse midline glioma

  • H3K27M mutation alters epigenetic regulation at SEC member AFF4 promoter

  • CDK9 inhibition promotes RNA Pol II pausing and neuroglial differentiation programs

  • CDK9 inhibitors demonstrate anti-tumor effect in xenograft models of DMG

Summary

Histone 3 gene mutations are the eponymous drivers in diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. These recurrent oncohistones induce a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify therapeutically targetable dependencies within this disease context, we performed an RNAi screen targeting epigenetic/chromatin-associated genes in patient-derived DMG cultures. This identified AFF4, the scaffold protein of the super elongation complex (SEC), as a molecular dependency in DMG. Interrogation of SEC function demonstrates a key role for maintaining clonogenic potential while promoting self-renewal of tumor stem cells. Small-molecule inhibition of SEC using clinically relevant CDK9 inhibitors restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a rationale for further exploration of SEC inhibition as a promising therapeutic approach to this intractable disease.

Keywords

diffuse intrinsic pontine glioma
DIPG
diffuse midline glioma
DMG
super elongation complex
SEC
AFF4
CDK9
atuveciclib
AZD4573

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