In our previous studies with mice lacking a key Spi1 (encoding PU.1) cis-enhancer termed upstream regulatory element (URE), we found that UREΔ animals, which harbor downregulated PU.1 expression, eventually succumb to lethal acute myeloid leukemia (AML) (Rosenbauer et al, 2004). Here, SPI1 is linked to acute myeloid leukemia.