Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories

Kellaway, Sophie G; Keane, Peter; Edginton-White, Benjamin; Regha, Kakkad; Kennett, Ella; Bonifer, Constanze

Abstract

Mutations of the haematopoietic master regulator RUNX1 are associated with acute myeloid leukaemia, familial platelet disorder and other haematological malignancies whose phenotypes and prognoses depend upon the class of the RUNX1 mutation. The biochemical behaviour of these oncoproteins and their ability to cause unique diseases has been well studied, but the genomic basis of their differential action is unknown. To address this question we compared integrated phenotypic, transcriptomic, and genomic data from cells expressing four types of RUNX1 oncoproteins in an inducible fashion during blood development from embryonic stem cells. We show that each class of mutant RUNX1 deregulates endogenous RUNX1 function by a different mechanism, leading to specific alterations in developmentally controlled transcription factor binding and chromatin programming. The result is distinct perturbations in the trajectories of gene regulatory network changes underlying blood cell development which are consistent with the nature of the final disease phenotype. The development of novel treatments for RUNX1-driven diseases will therefore require individual consideration.

Citation

Kellaway, S. G., Keane, P., Edginton-White, B., Regha, K., Kennett, E., & Bonifer, C. (2021). Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories. Life Science Alliance, 4(2), Article e202000864. https://doi.org/10.26508/lsa.202000864

• Journal Article Type: Article
• Acceptance Date: Dec 7, 2020
• Online Publication Date: Jan 4, 2021
• Publication Date: 2021-02
• Deposit Date: May 14, 2025
• Publicly Available Date: May 15, 2025
• Journal: Life Science Alliance
• Print ISSN: 2575-1077
• Electronic ISSN: 2575-1077
• Publisher: Life Science Alliance
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 2
• Article Number: e202000864
• DOI: https://doi.org/10.26508/lsa.202000864
• Keywords: Health, Toxicology and Mutagenesis; Plant Science; Biochemistry, Genetics and Molecular Biology (miscellaneous); Ecology
• Public URL: https://nottingham-repository.worktribe.com/output/32179644
• Publisher URL: https://www.life-science-alliance.org/content/4/2/e202000864