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Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2 , but not its paralog STAG1 , are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression, and local chromatin activation, which were not compensated by the remaining STAG1-cohesin. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. Complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs) revealed effects resembling STAG2 -mutant AML-specific changes following STAG2 knockdown, not invoked by the depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression, and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis. [Display omitted] • AMLs with mutant STAG2 display similar transcriptional and chromatin patterns • Loss of STAG2 but not STAG1 alters gene regulation and differentiation capacity • Loss of STAG2 induces changes in cohesin binding and regulatory chromatin looping • Differentially expressed genes are connected to spatial chromatin changes Fischer et al. explore genetic, transcriptional, and chromatin conformational changes in patients with cohesin-mutated acute myeloid leukemia and cohesin subunit depleted primary hematopoietic cells. They observe specific effects upon loss of cohesin subunit STAG2, including cohesin loss, reduced short-range chromatin looping, and correlating changes in gene expression. [ABSTRACT FROM AUTHOR]