Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories

Abstract

Mutations of the hematopoietic master regulator RUNX1 cause acute myeloid leukaemia, familial platelet disorder and other haematological malignancies whose phenotypes and prognoses depend upon the class of 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 mutated 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 that are consistent with the nature of the final disease phenotype. The development of novel treatments for RUNX1-driven diseases will therefore require individual consideration.

A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification

“…We also show that the most enhancer positive ATAC fragments overlap with open chromatin sites found in purified hemogenic endothelium and endothelial cells from day 9.5 and day 13.5 mouse embryos 26,27 indicating that the same elements are active in vivo (Figure S2e). Finally, the comparison with previously collected TF ChIP data 18,20,28,29,30 shows that between 17% (in HB) and 76% (in HP cells) of all enhancer fragments are bound by ubiquitous and differentiation stage-specific TFs, depending on the number of available ChIP experiments for each stage (data not shown).…”

“…We also show that the most enhancer positive ATAC fragments overlap with open chromatin sites found in purified hemogenic endothelium and endothelial cells from day 9.5 and day 13.5 mouse embryos 26,27 indicating that the same elements are active in vivo (Figure S2e). Finally, the comparison with previously collected TF ChIP data 18,20, 28,29,30 shows that between 17% (in HB) and 76% (in HP which identified thousands of elements active in this assay in one cell type. However, it is unclear how many of these elements can function in a chromatin environment and how their cell stage-specific activity is regulated.…”

The transcriptional regulation of normal and malignant blood cell development

“…It should be noted that while cancers come in different forms and can arise from many tissues, the rewiring of normal GRNs into one that sustains a malignant phenotype is a hallmark of all of them. In AML, each mutation shapes the aberrant differentiation process in a different way, and even different mutations in a single TF‐encoding gene such as RUNX1, which give rise to different aberrant version of RUNX1, can lead to completely different disease outcomes and cellular identities with distinct chromatin landscapes [122,123]. Moreover, the inducible expression of different RUNX1 oncoproteins causes an immediate reprogramming of their chromatin and TF‐binding landscape, which is specific for each aberrant protein [123,124].…”

“…In AML, each mutation shapes the aberrant differentiation process in a different way, and even different mutations in a single TF‐encoding gene such as RUNX1, which give rise to different aberrant version of RUNX1, can lead to completely different disease outcomes and cellular identities with distinct chromatin landscapes [122,123]. Moreover, the inducible expression of different RUNX1 oncoproteins causes an immediate reprogramming of their chromatin and TF‐binding landscape, which is specific for each aberrant protein [123,124]. These data suggest that once different epigenetic landscapes have been set up after the first oncogenic hit, cells on their way to malignancy tweak their GRNs to compensate for the weakness of one differentiation process to activate another to maintain a stable state that is compatible with growth.…”

The RARγ Oncogene: An Achilles Heel for Some Cancers

“…Similarly, different mutant RUNX1 oncoproteins, which are drivers of some case of acute myeloid leukemia, were also observed to program distinct HSC lineage trajectories, skewing cells towards either a B cell or megakaryocyte/erythroid identity. The different mutant proteins were also observed to alter lineage-specific chromatin priming [ 64 ]. Another aspect to the importance of epigenetics in leukemia is the role of DNA methytransferases alongside ATRA in the regulation of expression Hox genes, which are critical for the proper maintenance of HSC, as well as proliferation and survival of LSC [ 65 ].…”