Although the Sfpi1 mutations are often accompanied by additional genetic alterations, such as amplification of Myc (Rosenbauer et al, 2004; Hirouchi et al, 2008), studies with genetically engineered mice show that downregulation or inactivation of PU.1 is sufficient to induce AML (Rosenbauer et al, 2004; Metcalf et al, 2006). This evidence concerns the gene SPI1 and acute myeloid leukemia.