α-Globin as a molecular target in the treatment of β-thalassemia

Abstract

The thalassemias, together with sickle cell anemia and its variants, are the world's most common form of inherited anemia, and in economically undeveloped countries, they still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is also still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the course of the last 50 years have demonstrated how coinheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion-dependent thalassemia into relatively mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression, and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.

Figure 1

Schematic diagram of α- and β-globin gene clusters and the types of hemoglobin produced at each developmental stage. Genes are arranged along the chromosome in the order in which they are expressed during development; (A) in the α-cluster ζ (embryonic) and α (fetal and adult); (B) in the β-cluster ε (embryonic), γ (fetal), and δ and β (adult). The 4 upstream regulatory elements of the α-locus are known as MCSR1 to MCSR4, whereas the 5 regulatory elements of the β-locus are collectively referred to as locus control region (LCR). The hemoglobin types expressed during different stages of development are embryonic (Hb Gower-I [ζ₂ε₂], Hb Gower-II [α₂ε₂], and Hb Portland [ζ₂γ₂]), fetal (HbF [α₂γ₂]), and adult (HbA [α₂β₂] and HbA₂[α₂δ₂]).

Figure 2

Pathophysiology of β-thalassemia. Absent or reduced β-globin production leads to an unbalanced excess of α-globin chains, which then trigger cascade of events through the generation of ROS, resulting in hemolysis of mature red blood cells and destruction of immature erythroid precursors in the bone marrow (ineffective erythropoiesis). AHSP, α hemoglobin stabilizing protein; HSP70, heat shock protein 70.

Figure 3

Contrasting epigenetic landscape of α- and β- globin loci. In the silent, nonexpressed state (nonerythroid cells), the α-globin locus (red dot) is in open chromatin environment, whereas the β-globin locus (yellow dot) is in a closed chromatin conformation incorporated into heterochromatin (dark blue circle within the nucleus). The promoter of α-globin is unmethylated, bound by PRC2, and the associated histone has the H3K27me3 modification. In contrast, the β-globin locus is heavily methylated and does not show binding of PRC2 or the H3K27me3 chromatin modification. In the active state (erythroid cells), both loci are located away from heterochromatin and form loop structures to facilitate respective enhancer–promoter interactions, and both promoters show H3K4me3 active chromatin modification. However, only in the α-globin locus, PRC2 is detached and JMJD3 is recruited to facilitate removal of the H3K27me3 repressive chromatin modification.