Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories

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.

Validation and refinement of a RUNX1 mutation-associated gene expression signature in blast crisis chronic myeloid leukemia

“…2C and Supplementary Table 7 ). This observation supports the notion of functional differences between these 2 types of RUNX1 mutations as recently reported by Kellaway et al [ 9 ].…”

Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells

“…RUNX1–EVI1 expression does not cause the loss or gain of a cell lineage, but lineage priming is disrupted whereby chromatin accessibility sites associated with B-cells and megakaryocytes are gained and ones associated with erythroblasts and monocytes are lost. For cells that express RUNX1–ETO, accessibility sites associated with B-cell development and common myeloid progenitors are, gained and ones associated with megakaryocytes are lost [ 36 ].…”

Hematopoietic and Chronic Myeloid Leukemia Stem Cells: Multi-Stability versus Lineage Restriction

“…Differentiation of myeloid and erythroid cells was reduced by RUNX1-EV11 expression. Expression of the mutant proteins perturbed chromatin priming of lineage-specific sites [ 43 ], and RUNX1 plays a role in the organization of the chromatin landscape at the onset of hematopoiesis in order to maintain accessibility [ 44 , 45 ], and shapes landscapes via a cascade of direct and indirect targets [ 46 ].…”