Lyn is involved in Epo-receptor signaling and is important for erythroid homeostasis. However, downstream pathways influenced following Lyn activation and their significance to erythropoiesis remain unclear. To address this, we determined the consequences a gain-of-function Lyn mutation (Lynup/up) on erythropoiesis and Epo-receptor signaling1. Adult Lynup/up mice were anemic, with dysmorphic red cells ( spherocyte-like, acanthocytes) in their circulation, indicative of hemolytic anemia and resembling the human disorder chorea acanthocytosis. Heterozygous Lyn+/up mice became increasingly anemic with age, indicating that the mutation was dominant. In an attempt to overcome this anemia, extramedullary erythropoiesis was activated. As the mice aged the relative levels of different immature erythroid populations changed, indicating compensatory mechanisms to produce more erythrocytes were dynamic. Major changes in Epo signaling were observed in Lyn+/up erythroid cells and primary CD71+ Lynup/up erythroblasts, including significant alterations to the phosphorylation of Lyn, the Epo receptor, JAK2, STAT5, GAB2, Akt and FoxO3. As a consequence of altered Lyn signaling, Lyn+/up cells remained viable in the absence of Epo, but displayed delayed Epo-induced differentiation. These data demonstrate that Lyn gene dosage and activity is critical for normal erythropoiesis; hyper-active Lyn alters Epo signaling which in turn produces erythroid defects.