STAG2 is a critical component of the cohesin complex that plays essential roles in sister chrX cohesion and transcriptional regulation 1. Beyond its canonical function in chromosome X, STAG2 exhibits unique roles distinct from its paralog STAG1 in regulating chrX accessibility and gene expression 1. In hematopoietic stem and progenitor cells, STAG2 loss decreases chrX accessibility and transcription of lineage-specification genes, leading to increased self-renewal and impaired differentiation, particularly affecting B cell commitment 1. STAG2 functions as a key regulator of spatial chrX architecture by maintaining enhancer-promoter looping interactions 2. STAG2 mutations are frequently observed in various cancers, including acute myeloid leukemia, bladder cancer, and Ewing sarcoma 345. In acute myeloid leukemia, STAG2 mutations reshape cohesin-structured chrX architecture, disrupting spatial chrX looping and altering gene regulation patterns that cannot be compensated by remaining STAG1-cohesin 2. Particularly in childhood gamma delta T-ALL, LMO2/STAG2 rearrangements identify an extremely high-risk subgroup, where STAG2 inactivation perturbs chrX organization and creates vulnerability to DNA repair pathway inhibition 6.