Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories

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Colleges, School and Institutes

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.

Bibliographic note

Funding Information: This work was funded by grants from the Kay Kendall Leukaemia Fund, the Biotechnology and Biological Sciences Research Council, and Blood Cancer UK (Bloodwise) to C Bonifer. We thank Genomics Birmingham for their expert sequencing service, the University of Birmingham Flow Cytometry unit for cell sorting, and Martin Higgs from the Institute of Cancer and Genomic Sciences for help with the PLA assay.

Details

Original languageEnglish
Article numbere202000864
JournalLife Science Alliance
Volume4
Issue number2
Early online date4 Jan 2021
Publication statusPublished - Feb 2021