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

Sanja Pajovic, Robert Siddaway, Taylor Bridge, Javal Sheth, Patricia Rakopoulos, Byungjin Kim, Scott Ryall, Sameer Agnihotri, Lauren Phillips, Man Yu, Christopher Li, Scott Milos, Palak Patel, Dilakshan Srikanthan, Annie Huang and Cynthia Hawkins ()
Additional contact information
Sanja Pajovic: The Hospital for Sick Children
Robert Siddaway: The Hospital for Sick Children
Taylor Bridge: The Hospital for Sick Children
Javal Sheth: The Hospital for Sick Children
Patricia Rakopoulos: The Hospital for Sick Children
Byungjin Kim: The Hospital for Sick Children
Scott Ryall: The Hospital for Sick Children
Sameer Agnihotri: Children’s Hospital of Pittsburgh of UPMC
Lauren Phillips: The Hospital for Sick Children
Man Yu: The Hospital for Sick Children
Christopher Li: The Hospital for Sick Children
Scott Milos: The Hospital for Sick Children
Palak Patel: The Hospital for Sick Children
Dilakshan Srikanthan: The Hospital for Sick Children
Annie Huang: The Hospital for Sick Children
Cynthia Hawkins: The Hospital for Sick Children

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19972-7

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