The Runx1-Gata2 axis: epigenetic architecture of lineage fate

Cellular identity is established through the precise coordination of transcription factors (TFs) and chromatin remodeling complexes that shape the epigenetic landscape. In hematopoiesis, the interaction between Runx1 and Gata2 transcription factors exemplifies the role of master TFs in direct lineage specification and self-renewal. In this review, we have consolidated recent findings on the epigenetic regulation of the master TFs of the Runx1-Gata2 axis, highlighting roles beyond their classical functions as chromatin architects. Gata2 functions as a pioneer factor that accesses closed chromatin, while Runx1 participates in reshaping topologically associating domains (TADs) and enhancer-promoter interactions, recruiting effectors such as chromodomain helicase DNA-binding protein 7 (CHD7) and ten-eleven translocation (TET) enzymes. Disruptions to this axis, including hypermethylation, enhancer hijacking, or haploinsufficiency, lead to an "epigenetic addiction" in myeloid malignancies, promoting the development of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We have discussed the recent research on emerging therapeutic strategies, such as epigenetic editing and super-enhancer targeting, which aim to restore proper chromatin architecture in malignant clones.