Model of the 2-stage block in erythropoiesis in Eklf^−/− definitive erythroid cells. The first block, as described previously,^16,18,19  occurs during early erythropoiesis and causes an increased proportion of erythroid progenitor cells and inefficient entry into terminal differentiation. This is attributed to premature cell cycle exit due to reduced levels of E2F2. The cells that escape the first block proceed into terminal differentiation, reaching the orthochromatic erythroblast stage where they undergo a second block leading to an absence of enucleation. This latter block is due to impaired cell cycle exit and an increased proportion of orthochromatic erythroblasts in S phase as a result of reduced levels of p18 (Cdkn2c) and p27 (Cdkn1b). Restoring the levels of p18 or p27 in Eklf^−/− cells rescues the cell cycle defects and restores enucleation. A novel aspect that is critical for understanding terminal erythroid differentiation is that the 2-stage block in cell cycle follows from almost diametrically opposed control deficits: the first results in a premature cell cycle exit leading to impaired entry into terminal differentiation, but the second at the orthochromatic erythroblast stage results in impaired cell cycle exit, yielding late-stage erythroblasts still in S phase that are not able to enucleate.