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Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β-Thalassemia.

ABSTRACT: Thalassemia, an inherited quantitative globin disorder, consists of two types, α- and β-thalassemia. β-thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the β-globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases β-globin expression. Down-regulation of γ-globin suppressor genes, i.e., BCL11A, KLF1, HBG-XMN1, HBS1L-MYB, and SOX6, elevates the HbF level. β-thalassemia severity is predictable through FLT1, ARG2, NOS2A, and MAP3K5 gene expression. NOS2A and MAP3K5 may predict the β-thalassemia patient's response to hydroxyurea, a HbF-inducing drug. The transcription factors NRF2 and BACH1 work with antioxidant enzymes, i.e., PRDX1, PRDX2, TRX1, and SOD1, to protect erythrocytes from oxidative damage, thus increasing their lifespan. A single β-thalassemia-causing mutation can result in different phenotypes, and these are predictable by IGSF4 and LARP2 methylation as well as long non-coding RNA expression levels. Finally, the coinheritance of β-thalassemia with α-thalassemia ameliorates the β-thalassemia clinical presentation. In conclusion, the management of β-thalassemia is currently limited to genetic and epigenetic approaches, and numerous factors should be further explored in the future.

SUBMITTER: Zakaria NA

PROVIDER: S-EPMC8158146 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β-Thalassemia.

Zakaria Nur Atikah NA Islam Md Asiful MA Abdullah Wan Zaidah WZ Bahar Rosnah R Mohamed Yusoff Abdul Aziz AA Abdul Wahab Ridhwan R Shamsuddin Shaharum S Johan Muhammad Farid MF

Biomolecules 20210518 5

Thalassemia, an inherited quantitative globin disorder, consists of two types, α- and β-thalassemia. β-thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the β-globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases β- ...[more]

PMID: 34070036

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Project description:β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin-heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described. Clinically, β-thalassemias can be classified as transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) according to the severity of the phenotype, which is caused by a wide spectrum of mutations in a homozygous or compound heterozygous state. Current treatment of TDT consists of regular transfusions that lead to iron overload, requiring iron chelation to prevent iron-related organ toxicity. NTDT patients do not require transfusions or only occasionally require them; however, they develop iron overload as well because of increased intestinal iron absorption caused by chronic anemia. Hematopoietic stem cell allogenic transplant is the only approved cure for β-thalassemia; however, it is still limited by clinical conditions and the availability of matched donors as well as by potential graft-versus-host disease (GVHD). Gene therapy could avoid the GVHD risk, although hematopoietic stem cells must be genetically modified ex vivo. Epigenetic manipulation and genomic editing are novel experimental approaches. An increased understanding of the pathophysiology that controls the disease process prompted us to explore alternative therapeutic approaches that address the underlying chain unbalance, ineffective erythropoiesis, and iron dysregulation. Molecules, such as JAK2 inhibitors and the activin-receptor ligand trap that target ineffective erythropoiesis, are already in clinical trials with promising results. Other agents aimed to generate iron-restricted erythropoiesis are also under experimental evaluation.

Dataset Information

Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β-Thalassemia.

Publications

Epigenetic Insights and Potential Modifiers as Therapeutic Targets in <i>β</i>-Thalassemia.

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