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Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer.
- Source :
-
Nature communications [Nat Commun] 2020 Dec 04; Vol. 11 (1), pp. 6216. Date of Electronic Publication: 2020 Dec 04. - Publication Year :
- 2020
-
Abstract
- Histone H3 lysine 27 (H3K27M) mutations represent the canonical oncohistone, occurring frequently in midline gliomas but also identified in haematopoietic malignancies and carcinomas. H3K27M functions, at least in part, through widespread changes in H3K27 trimethylation but its role in tumour initiation remains obscure. To address this, we created a transgenic mouse expressing H3.3K27M in diverse progenitor cell populations. H3.3K27M expression drives tumorigenesis in multiple tissues, which is further enhanced by Trp53 deletion. We find that H3.3K27M epigenetically activates a transcriptome, enriched for PRC2 and SOX10 targets, that overrides developmental and tissue specificity and is conserved between H3.3K27M-mutant mouse and human tumours. A key feature of the H3K27M transcriptome is activation of a RAS/MYC axis, which we find can be targeted therapeutically in isogenic and primary DIPG cell lines with H3.3K27M mutations, providing an explanation for the common co-occurrence of alterations in these pathways in human H3.3K27M-driven cancer. Taken together, these results show how H3.3K27M-driven transcriptome remodelling promotes tumorigenesis and will be critical for targeting cancers with these mutations.
- Subjects :
- Animals
Brain Neoplasms metabolism
Brain Neoplasms pathology
Disease Models, Animal
Epigenomics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glioma metabolism
Glioma pathology
Histones metabolism
Humans
Lysine genetics
Lysine metabolism
Methylation
Mice, Knockout
Proto-Oncogene Proteins c-myc metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
ras Proteins metabolism
Brain Neoplasms genetics
Epigenesis, Genetic
Glioma genetics
Histones genetics
Proto-Oncogene Proteins c-myc genetics
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33277484
- Full Text :
- https://doi.org/10.1038/s41467-020-19972-7