The PU.1 (SPI1) locus in healthy hematopoiesis and the RUNX1-ETO leukemic context. (A) Representation of the PU.1 (SPI1) locus showing the URE regulatory element, the coding promoter (PrPr), the antisense promoter (AsPr), and RNAs originating from each (LOUP [orange] from the URE, PU.1 coding mRNA from PrPr [blue], and asRNA from AsPr [purple]; arrows indicate transcription initiation sites). Both PrPr and AsPr can be regulated by URE. (B-C) PU.1 locus conformation in healthy cells. T-lymphoid context: URE interacts with AsPr (B), and myeloid context: URE interacts with PrPr (C). Loop formation is mediated by RUNX1 (pink) and LOUP. (D) PU.1 locus conformation in RUNX1-ETO AML. RUNX1-ETO (pink/gray) mediates URE interaction with AsPr, leading to reduced PU.1 mRNA expression. Depletion of RUNX1-ETO leads to restoration of LOUP expression, interaction of the URE with PrPr, and increased PU.1 mRNA expression. Arrow thickness in panels B-D indicates relative transcriptional output from URE, PrPr, and AsPr. Professional illustration by Patrick Lane, ScEYEnce Studios.