beta-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload

Abstract

beta-thalassemia encompasses a group of monogenic diseases that have in common defective synthesis of beta-globin. The defects involved are extremely heterogeneous and give rise to a large phenotypic spectrum, with patients that are almost asymptomatic to cases in which regular blood transfusions are required to sustain life. As a result of the inefficient synthesis of beta-globin, the patients suffer from chronic anemia due to a process called ineffective erythropoiesis (IE). The sequelae of IE lead to extramedullary hematopoiesis (EMH) with massive splenomegaly and dramatic iron overload, which in turn is responsible for many of the secondary pathologies observed in thalassemic patients. The processes are intimately linked such that an ideal therapeutic approach should address all of the complications. Although beta-thalassemia is one of the first monogenic diseases to be described and represents a global health problem, only recently has the scientific community started to focus on the real molecular mechanisms that underlie this disease, opening new and exciting therapeutic perspectives for thalassemic patients worldwide.

Figure 1

In normal erythropoiesis, physiological levels of EPO induce the phosphorylation of Jak2 in normal erythroid progenitors and sustain the differentiation to mature RBC (top of the figure). In β-thalassemia, the high levels of EPO induce an uncontrolled proliferation of erythroid precursors, with a higher number of cells associated with the phosphorylated form of Jak2. In β-thalassemia intermedia, where a certain amount of β-globin is still synthesized, there is a high production of reticulocytes that eventually mature in RBC. In β-thalassemia major, where there is a complete lack of β-globin, the orythroid progenitors continue to proliferate and fail to mature into reticulocytes and RBC or undergo apoptosis.

Figure 2

Different approaches to target IE in β-thalassemia. The administration of hepcidin would allow to decrease the iron overload in organs such the liver and heart and to redistribute the iron to hematopoietic organs, allowing a more efficient erythropoiesis and therefore a decrease in splenomegaly. The administration of Jak2 inhibitors would induce a decrease in the inefficient erythropoietic rate, therefore decreasing spleen size. The reduced erythropoiesis would have as indirect effect the increase in serum hepcidin, that in turn would decrease the iron absorption from the gut and the amelioration of iron overload.