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Nat Med. 2017 Apr;23(4):493-500. doi: 10.1038/nm.4296. Epub 2017 Feb 27.

Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas.

Author information

1
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
2
Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
3
Department of Medicine, Division of Pulmonology, and Department of Pediatrics, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
4
Department of Chemistry, Northwestern University, Evanston, Illinois, USA.
5
Department of Hematology, Oncology, Neuro-Oncology &Stem Cell Transplantation, Ann &Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
6
Department of Surgery, Division of Pediatric Neurosurgery, Ann &Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
7
Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments in vivo with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.

PMID:
28263307
PMCID:
PMC5667640
DOI:
10.1038/nm.4296
[Indexed for MEDLINE]
Free PMC Article

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