Disruption of EPOR/JAK2/STAT5 signaling disrupts BM erythropoiesis selectively at an E2-stage of BM proerythroblast development. (A) Diagrammed are the wild-type EPOR (wt-EPOR); the PY-null allele, EPOR-HM; and a related EPOR-H allele in which a PY343 site for STAT5 is selectively restored. (B-C) EPOR-HM mice exhibit a major selective defect in the expansion of BM stage E2 proerythroblasts. In mice harboring wt-EPOR, EPOR-HM, or EPOR-H alleles, frequencies of stage E1, E2, and E3 cells were analyzed at steady state and at day 2.5 after EPO dosing. In EPOR-HM mice, and on EPO challenge, levels of stage E3 erythroblasts unexpectedly were near-normal. Their stage E2 progenitors, however, failed to undergo the more than or equal to 5-fold expansion observed within wt-EPOR and EPOR-H BM. For EPOR-H BM erythroid cells, also note an enhanced expansion of stage E2 proerythroblasts (and a > 2-fold deficit in EPOR-H stage E3 erythroblast formation). (D) Effects of EPOR-HM (and EPOR-H) allele signaling on E1, E2, and E3 BM cell formation are summarized.