Model describing how heme and GATA1 might coordinately regulate erythroid differentiation. (A) Normal erythropoiesis and (B) erythropoiesis in Flvcr1-deleted mice, patients with DBA, and patients with del(5q) MDS. When erythropoiesis begins, GATA1 upregulates ALAS2 and heme synthesis intensifies. Heme and GATA1 then coregulate erythroid gene expression and differentiation. During normal erythropoiesis (A), heme accumulates late when FLVCR is low. This excessive heme downregulates GATA1 and mitotic spindle proteins to ensure red cell differentiation terminates appropriately. In the absence of FLVCR (B), the quantity of heme exceeds the capacity of globin and other metabolic needs during the CFU-E/proerythroblast stage. This excessive heme then prematurely downregulates GATA1 and mitotic spindle proteins, prematurely terminating differentiation. Effective erythropoiesis requires the quick and efficient upregulation of heme and the facile coordination of heme with globin. In DBA, del(5q) MDS, and potentially other disorders in which protein synthesis is decreased (also B), heme synthesis likewise exceeds the capacity of globin and other hemoproteins in CFU-E/proerythroblasts. This also leads to the premature termination of erythropoiesis, and a clinical phenotype similar to Flvcr1-deleted mice. EB, erythroblast. This figure was illustrated with the Biology PPT Drawing Toolkit (Motifolio Inc).