One of them is located −15 kb upstream of the SPI1 gene (−14 kb in mice) and is necessary to sustain adequate levels of PU.1.224 Accordingly, ablation of this enhancer, termed upstream regulatory element (URE), results in 80% loss of PU.1, with loss in HSC function and failure in terminal myeloid differentiation that give rise to leukemia.225,226 Nonetheless, the fact that loss of the −15 kb enhancer affects all blood lineages indicates it is a general hematopoietic enhancer. The gene discussed is SPI1; the disease is leukemia.