Exploitation Of A Newly Characterized Metabolic-Cytoskeletal Axis For Effective Combination Therapy Of Iron Restricted Anemia

The erythroid iron restriction response suppresses erythropoiesis in a lineage-selective manner. This response underlies two common types of anemia: anemia of chronic disease and inflammation (ACDI) and iron deficiency anemia (IDA). These anemias confer a major global disease burden, with no optimal therapies available for ACDI. An early step in this cellular response consists of inactivation of the iron-dependent aconitase enzymes. Supplying cells with the downstream product isocitrate abrogates the erythropoietic blockade caused by iron restriction. In several rodent anemia models isocitrate treatment has shown promise, but high intraperitoneal doses were needed, and benefits were transient. A critical aspect of the erythroid iron restriction response comprises progenitor resistance to erythropoietin (Epo), clinically reflected in poor patient responses to Epo treatment. Mechanistically, we have shown that iron deprivation decreases cell surface delivery of the Epo receptor (EpoR) and associated chaperones (Scribble and TfR2), in a manner reversible by isocitrate.