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

Author

Listed:
  • 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
    University of Toronto)

  • Byungjin Kim

    (The Hospital for Sick Children
    University of Toronto)

  • Scott Ryall

    (The Hospital for Sick Children
    University of Toronto)

  • Sameer Agnihotri

    (Children’s Hospital of Pittsburgh of UPMC)

  • Lauren Phillips

    (The Hospital for Sick Children
    University of Toronto)

  • Man Yu

    (The Hospital for Sick Children)

  • Christopher Li

    (The Hospital for Sick Children
    University of Toronto)

  • Scott Milos

    (The Hospital for Sick Children)

  • Palak Patel

    (The Hospital for Sick Children)

  • Dilakshan Srikanthan

    (The Hospital for Sick Children
    University of Toronto)

  • Annie Huang

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Cynthia Hawkins

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

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.

Suggested Citation

  • 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 Pa, 2020. "Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19972-7
    DOI: 10.1038/s41467-020-19972-7
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    Cited by:

    1. Adrian B. Levine & Liana Nobre & Anirban Das & Scott Milos & Vanessa Bianchi & Monique Johnson & Nicholas R. Fernandez & Lucie Stengs & Scott Ryall & Michelle Ku & Mansuba Rana & Benjamin Laxer & Java, 2024. "Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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