Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer

• Published in: Nature communications Vol. 11; no. 1; p. 6216
• Main Authors: Pajovic, Sanja, Siddaway, Robert, Bridge, Taylor, Sheth, Javal, Rakopoulos, Patricia, Kim, Byungjin, Ryall, Scott, Agnihotri, Sameer, Phillips, Lauren, Yu, Man, Li, Christopher, Milos, Scott, Patel, Palak, Srikanthan, Dilakshan, Huang, Annie, Hawkins, Cynthia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/51; 38/1; 38/15; 38/88; 38/90; 38/91; 42/44; 45/23; 631/337/176; 631/67/2332; 631/67/70; 631/80/304; 64/60; 692/308/2778; Animals; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cancer; Carcinoma; Cells (biology); Disease Models, Animal; Epigenesis, Genetic; Epigenetics; Epigenomics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Histone H3; Histones; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Humans; Lysine; Lysine - genetics; Lysine - metabolism; Methylation; Mice, Knockout; multidisciplinary; Mutation; Myc protein; Progenitor cells; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Science; Science (multidisciplinary); Sox10 protein; Transgenic mice; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19972-7

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. Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.