Model for the role of PU.1 as a suppressor of myeloid leukemia. (A) In normal hematopoiesis, a low level of PU.1 is sufficient for the generation of a pool of myeloid progenitor cells (MP), ¹⁷  but a high level is needed for terminal maturation.⁴¹  (B) In mice with an engineered deletion of a PU.1 enhancer element, up-regulation above the basal level is precluded, so myeloid progenitors accumulate, providing the pool from which leukemia develops.¹⁷  (C) In cells that lack wt PU.1 but express PU.1 with a mutated DNA binding domain (eg, altered Arg235), residual activity of the mutant PU.1 is proposed to allow accumulation of myeloid progenitors but to prevent terminal differentiation, thereby stimulating leukemogenesis.