Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation

Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease. [Display omitted] •Cohesin mutants impair differentiation and enforce stem cell programs in human HSPCs•Effects are cell context dependent, restricted to immature HSC and MPP populations•Mutants showed increased chromatin accessibility and binding of ERG, GATA2, and RUNX1•Cohesin-mutant-induced stem cell programs are dependent on ERG, GATA2, and RUNX1 Mazumdar et al. investigate the effects of leukemia-associated cohesin complex mutations on human hematopoietic stem and progenitor cells. Cohesin mutants are found to impair differentiation and enforce stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity, suggesting a mechanism contributing to leukemogenesis.