Serum erythropoietin (EPO) levels of Irp1-/- mice were more than seven-fold higher than that in wild type mice maintained on an iron-deficient diet, and animals with these high EPO levels developed splenomegaly and increased splenic erythropoiesis, supporting a model that there is EPO-dependent extracellular erythropoiesis in Irp1-/- mice. This evidence concerns the gene ACO1 and Splenomegaly.