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Review
.2015 Apr;100(4):418-30.
doi: 10.3324/haematol.2014.114827.

β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

Affiliations
Review

β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

Stefano Rivella. Haematologica.2015 Apr.

Abstract

β-thalassemias are monogenic disorders characterized by defective synthesis of the β-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the β-globin gene or its regulatory elements have been associated with β-thalassemias. Due to the complexity of the regulation of the β-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of β-globin and abnormal erythropoiesis, as well as current and novel therapies.

Copyright© Ferrata Storti Foundation.

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Figures

Figure 1.
Figure 1.
Representation of the genomic structure of the α- and β-globin loci. (A) Genes are indicated. LCR: locus control region (not to scale). (B) Relative expression of the globin genes during development. (C) Graphic representation of some of the candidate proteins involved in the regulation of the switching between to fetal to adult hemoglobin.
Figure 2.
Figure 2.
Illustration of the looping model and mechanism of HbF reactivation mediated by ZF-Ldb1. (A) In erythroid cell, the chromatin at the LCR is composed of arrays of multiple ubiquitous and lineage-specific transcription factor-binding sites, forming a holocomplex. This holocomplex loops on promoters at the β-globin locus determining the activation of the corresponding γ or β-globin gene. (A) ZF-Ldb1 is made by fusing Ldb1 to a specific zinc finger protein that recognizes a sequence in the γ-globin promoter. When ZF-Ldb1 is expressed in erythroid cells, this forces the holocomplex to move from the β-globin promoter and loop on the γ-globin promoter, determining the reactivation of HbF in adult cells.
Figure 3.
Figure 3.
Representation of some of the pathways regulating steady state and stress erythropoiesis and their relationship to ineffective erythropoiesis in β-thalassemia. In this disorder, the imbalanced synthesis between α- and β-globin chains leads to formation of hemichromes, ROS formation and apoptosis of the late stage erythroid progenitors. This leads to anemia and hypoxia. As a consequence, Epo and Gdf1 synthesis are increased, leading to activation of the Jak2/Stat5 and R-Smad pathways respectively, thus altering the proliferation and differentiation of the erythroid progenitors. Furthermore, increased iron absorption and stress erythropoiesis macrophage activity (SEMA) also negatively influence ineffective erythropoiesis by supporting the proliferation of erythroid progenitors. Altogether, activation of these pathways leads to increased proliferation and reduced maturation of the erythroid progenitors, exacerbating the ineffective erythropoiesis. The question mark indicates molecules and related pathways that have not yet been identified.
Figure 4.
Figure 4.
Illustration of the relationship between anemia, hypoxia, Epo, erythropoiesis and iron metabolism in β-tha-lassemia. Hypoxia, through HIF2a, contributes to augmented iron absorption by increasing expression of Fpn, Dmt1 and DcytB in the duodenum. Epo, ROS and Growth differentiation factor 11 (Gdf11) alter erythropoiesis, increasing cell proliferation and decreasing cell maturation, contributing to the extramedullary hematopoiesis. As the number of erythroid progenitors increases, more ERFE and less hepcidin are produced, leading to increased iron absorption and increased Tf-sat. Altogether, these modifications contribute to the pathophysiology of ß-thalassemia, and exacerbate the ineffective erythropoiesis and iron overload over time. The diagram also shows potential targets and therapeutics that might benefit β-thalassemia, as discussed in the text.
Figure 5.
Figure 5.
Potential use of JAK2 inhbitors in β-thalassemia. (A) In NTDT, the underlining chronic stress erythropoiesis exacerbates the anemia and the hepatosplenomegaly over time. This leads to increased sequestration of RBCs and further worsening of the ineffective erythropoiesis and iron overload. (B) Administration of a JAK2 inhibitor for a short period of time might decrease the number of erythroid progenitors, reversing the hepatosplenomegaly and decreasing iron absorption, with no or limited side effects. If administration of the JAK2 inhbitor is associated with reduced production of RBC, some blood transfusion could be provided to NTDT patients during administration of the drug. (C) In β-thalassemia major, splenomegaly might ensue over time, limiting the number of RBC transfused in circulation. (D) Administration of a JAK2 inhibitor might decrease the number of erythroid progenitors and reverse the hepatosplenomegaly. In turn, this might reduce the number of RBC sequestered by the spleen and, in turn, the requirement for blood transfusion, and ameliorate the management of iron overload.
Figure 6.
Figure 6.
Schematic representation of gene therapy/gene editing approach for the cure of hemoglobinopathies. In this approach, HSC are harvested form the patient and modified by transduction (gene addition) or homologous DNA recombination (HDR). Following partial or full myeloablation, the genetically modified HSC are then re-infused in the bone marrow of the patient.
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References

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