Erythropoietic stages and the development of chronic anemia. The erythropoietic stages in the BM begin with the HSCs, which proliferate and differentiate, giving rise to the common myeloid progenitors (CMPs) and burst-forming unit-erythroid (BFU-Es) before reaching the first stage of EPO dependence, the CFU-E. These progenitors are defined by their growth in culture, but their progeny, the proerythroblast (Pro-EB) through orthochromatic erythroblast (Ortho-EB) stages are recognized by their morphological appearance in stained smears of BM aspirates or ultrastructural studies of purified populations, as shown for mouse erythroblasts. The CFU-E and proerythroblasts express large amounts of the proapoptotic receptor Fas, which can be down-regulated by EPO. Fas mediates apoptosis induced by its binding of FasL on other erythroblasts and multiple myeloma cells. Other apoptosis inducers in the BM include TNF-α and TRAIL. After the Pro-EB stage, the basophilic (Baso-EB) and polychromatophilic (Poly-EB) stages are characterized by Hgb production and progressive deceases in cell size. The relative rates of cell division and protein synthesis during these 2 stages determine the size of the erythrocytes that are produced. Impaired DNA synthesis and DNA damage result in apoptosis of erythroblasts and macrocytic erythrocytes. Excess globin chains that are not assembled into Hgb, as in thalassemia or insufficient heme production from iron deficiency, cause oxidative damage that can lead to apoptosis, but their effects are mitigated by a heme-regulated inhibitor that decreases protein synthesis and leads to microcytosis. Enucleation at the Ortho-EB stage results in extruded nuclei (N) that are rapidly phagocytosed in the BM and reticulocytes (R) that egress into the BM venous sinusoids and circulate in the blood. The circulating reticulocytes (Retics.) mature over 1-2 days by shedding and degrading their internal organelles and assuming their biconcave discoid shape (RBCs). Electron micrograph images of erythroblast stages are modified from Koury et al⁴¹  and Kelley et al⁴² ; and differential interference contrast microscopy images of reticulocytes and RBCs are modified from Koury et al.⁴³