Iron metabolism under conditions of ineffective erythropoiesis in β-thalassemia

Abstract

β-Thalassemia (BT) is an inherited genetic disorder that is characterized by ineffective erythropoiesis (IE), leading to anemia and abnormal iron metabolism. IE is an abnormal expansion of the number of erythroid progenitor cells with unproductive synthesis of enucleated erythrocytes, leading to anemia and hypoxia. Anemic patients affected by BT suffer from iron overload, even in the absence of chronic blood transfusion, suggesting the presence of ≥1 erythroid factor with the ability to modulate iron metabolism and dietary iron absorption. Recent studies suggest that decreased erythroid cell differentiation and survival also contribute to IE, aggravating the anemia in BT. Furthermore, hypoxia can also affect and increase iron absorption. Understanding the relationship between iron metabolism and IE could provide important insights into the BT condition and help to develop novel treatments. In fact, genetic or pharmacological manipulations of iron metabolism or erythroid cell differentiation and survival have been shown to improve IE, iron overload, and anemia in animal models of BT. Based on those findings, new therapeutic approaches and drugs have been proposed; clinical trials are underway that have the potential to improve erythrocyte production, as well as to reduce the iron overload and organ toxicity in BT and in other disorders characterized by IE.

Figure 1.

Iron metabolism and erythropoiesis. (A) Hepcidin is a master regulator of iron metabolism. It is produced in the liver in response to iron demand, iron storage, anemia, and inflammation. Once secreted, it targets and degrades the iron exporter ferroportin. (B) EPO is the main hormone controlling erythropoiesis. It works by modulating or interacting with a variety of proteins that control iron intake, cell replication, cell survival, and sensitivity to EPO itself. (C) Erythroferrone is secreted by erythroid progenitor cells and suppresses hepcidin in the liver. Another factor, PDGF-BB, suppresses hepcidin under hypoxic conditions.

Figure 2.

Causes and consequences of β-thalassemia. (A) During the early stages of BT, as well as in the absence of transfusion or when transfusion is inadequate, IE and erythroid expansion are responsible for hepcidin suppression, likely through erythroferrone. (B) This leads to increased iron absorption and iron overload. (C) Over time, splenomegaly occurs, exacerbating extramedullary erythropoiesis, RBC sequestration, anemia, and hypoxia. In particular, hypoxia stabilizes a transcription factor called HIF2α in enterocytes (D), which increases expression of ferroportin, among other iron-related molecules, in the duodenum (E). Therefore, the relative balance of hepcidin vs ferroportin is such that iron absorption is still increased, despite the fact that iron overload is promoting hepcidin expression.

Figure 3.

Targeting iron metabolism or IE to improve anemia and iron overload in BT. (A) Iron restriction can be achieved by using hepcidin agonists or activators or inhibitors of ferroportin, HIF2α, and erythroferrone to reduce iron intake and increase iron sequestration into macrophages, decreasing TSat. This limits hemichrome formation, ROS, and, potentially, free α-globin chain accumulation, resulting in improvements to RBC lifespan, anemia, extramedullary erythropoiesis and also iron overload. (B) Improvement of IE with drugs that inhibit JAK2 or modulate TGFβ/SMAD (eg, luspatercept) and GATA-1 activity. Use of JAK2 inhibitors will only decrease the number of erythroid progenitors and improve splenomegaly. In the event of the use of TGFβ/SMAD and GATA-1 modulators, it is expected that, as the differentiation of erythroid progenitors increases and the relative number of RBC increases, iron consumption improves and, as a consequence, hemichrome formation is reduced. In this last case, the end points are similar to those observed with the use of iron-restrictive agents, although the extent of each improvement can vary based on the activity and characteristics of each drug. Of note, the challenge in the development of GATA-1 modulators would require identifying compounds that protect GATA-1 in cells in which HSP70 is sequestered by the excess of α-globin chains, but not in cells in which GATA-1 is fully active, to prevent undesirable effects.