Molecular pathogenesis of myelodysplastic syndromes with concurrent mutations in cohesin STAG2 and transcription factor RUNX1

Abstract

STAG2 and other cohesin complex components are mutated in ∼10-15% of myeloid neoplasms, particularly in myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia. STAG2 mutations often coincide with other driver mutations, such as RUNX1, SRSF2, and ASXL1, suggesting a strong functional interaction among these mutations in myeloid neoplasms. To elucidate the mechanism of cohesin-induced leukemogenesis, we generated Stag2 conditional knockout (KO) mice but they only exhibited relatively mild hematopoietic abnormalities and did not develop lethal myeloid neoplasms. In contrast, Stag2/Runx1 double KO mice exhibited marked differentiation abnormalities, expanded hematopoietic stem/progenitor cell pools, and pancytopenia, which led to the development of lethal MDS. Abnormalities in gene expression and transcription factor activities were also more extensive in double KO mice than in single KO mice. Additionally, in situ Hi-C revealed a marked reduction in chromosomal three-dimensional loop formation between enhancer and promoter elements. This was associated with the downregulation of genes with high basal transcriptional pausing that are important for HSPC regulation. Thus, cohesin cooperates with the transcription factor RUNX1 to regulate chromosomal three-dimensional structure and gene expression, and mutational dysfunction of these proteins, along with consequent loss of regulation, is thought to result in the formation of myeloid neoplasms.