News on sickle cell disease: Heme‐driven disordered erythropoiesis

Abstract

Free heme disrupts erythropoiesis in sickle cell disease (SCD) by driving interferon-α (IFNα) production. Polymerization of deoxygenated sickle hemoglobin (HbS) in red blood cells (RBCs) leads to erythrocyte sickling in SCD and increases cell fragility leading to extra-and intra-vascular hemolysis and anemia. In this condition, anemia increases hypoxia-induced erythropoietin (EPO) production by the kidney, which ultimately stimulates erythropoiesis and de novo RBC production in the bone marrow. Upon sickle RBC hemolysis, the release of free heme in the circulation, coupled with the exhaustion of heme scavenging plasma proteins, promotes the production of IFN-α, which in turn increases the expression of the suppressor of cytokine signaling family member, CISH, in erythroid progenitors. CISH decreases erythropoietin signaling in erythroid cells, resulting in impaired bone marrow erythropoiesis.