While complete genetic ablation of PU.1 can yield a profound differentiation block that graduates to an AML-like phenotype (Steidl et al., 2006), early stages of myeloid oncogenesis are typically characterized by graded reductions in PU.1 activity due to the action of oncogenic mutations, rather than complete ablation of expression (Will et al., 2015). The gene discussed is SPI1; the disease is acute myeloid leukemia.