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Glioma

Targeting a histone mutant

Nature Reviews Cancer volume 15, page 2 (2015)Cite this article

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Oncogenic mutation of histone H3.3 occurs frequently in paediatric brainstem gliomas. Funato et al. created a model of the aggressive brainstem glioma diffuse intrinsic pontine glioma (DIPG) using human embryonic stem cells (ESCs). Early neural progenitor cells (NPCs) were derived from ESCs and then engineered to express mutant H3.3 (H3.3-K27M), constitutively active platelet-derived growth factor receptor-α (PDGFRA) and a short hairpin RNA against p53, as PDGFRA activation and p53 loss commonly occur with H3.3-K27M mutations. These cells were transformed in vitro and formed tumours resembling low-grade DIPGs when injected into the brainstems of immunocompromised mice. Furthermore, the transformed NPCs seemed to undergo epigenetic changes that reverted them to a more primitive state. The authors also used these cells in vitro for drug discovery and determined that an inhibitor of menin, which is part of a histone methyltransferase complex and involved in transcriptional regulation, could reduce tumour growth in vivo. Hasizume et al. showed that brainstem glioma cells with H3.3-K27M mutations have lower levels of dimethylated and trimethylated H3.3-K27. The Jumonji-domain demethylase JMJD3 demethylates lysine 27, and the authors found that an inhibitor of JMJD3, GSKJ4, had antitumour activity against subcutaneous and orthotopic brainstem glioma xenografts. These papers both suggest possible therapeutics for brainstem gliomas.

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References

  1. Funato, K. et al. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science http://dx.doi.org/10.1126/science.1253799 (2014)

  2. Hasizume, R. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nature Med. 20, 1394–1396 (2014)

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  1. Sarah Seton-Rogers
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Seton-Rogers, S. Targeting a histone mutant. Nat Rev Cancer 15, 2 (2015). https://doi.org/10.1038/nrc3885

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