Model depicting how PU.1 and LDB1 could support URE contacts with the PU.1 gene in normal and abnormal situations. LDB1 and PU.1 accumulate at the PU.1 promoter and at the URE supporting contacts during myeloid differentiation in parallel with increasing PU.1 expression. In AML, PU.1 expression is low, and these long-range contacts are reduced. One testable explanation is that PU.1 and LDB1 occupancy in the locus is reduced in AML and that this results in loss of contacts between the URE enhancer and PU.1.