Insight of fetal to adult hemoglobin switch: Genetic modulators and therapeutic targets

Hariharan, Priya; Nadkarni, Anita

doi:10.1016/j.blre.2021.100823

Cited by 13 publications

(5 citation statements)

References 76 publications

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“…β-Thalassemia is a heterogeneous disease, and the clinical manifestations of β-thalassemia in pediatric and adult patients may be different. 65,66 Because of the high hematopoietic stem cell repopulating capacity in children and the impaired functions of the bone marrow niche during aging, pediatric patients with β-thalassemia have a superior therapeutic response to hematopoietic stem cell gene therapy than adult patients with β-thalassemia. 67 Therefore, pediatric and adult β-thalassemia may have different molecular characteristics.…”

Section: Discussionmentioning

confidence: 99%

Abnormal regulation of microRNAs and related genes in pediatric β‐thalassemia

Wang

Chen

et al. 2021

Clinical Laboratory Analysis

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Background MicroRNAs (miRNAs) participate in the reactivation of γ‐globin expression in β‐thalassemia. However, the miRNA transcriptional profiles of pediatric β‐thalassemia remain unclear. Accordingly, in this study, we assessed miRNA expression in pediatric patients with β‐thalassemia. Methods Differentially expressed miRNAs in pediatric patients with β‐thalassemia were determined using microRNA sequencing. Results Hsa‐miR‐483‐3p, hsa‐let‐7f‐1‐3p, hsa‐let‐7a‐3p, hsa‐miR‐543, hsa‐miR‐433‐3p, hsa‐miR‐4435, hsa‐miR‐329‐3p, hsa‐miR‐92b‐5p, hsa‐miR‐6747‐3p and hsa‐miR‐495‐3p were significantly upregulated, whereas hsa‐miR‐4508, hsa‐miR‐20a‐5p, hsa‐let‐7b‐5p, hsa‐miR‐93‐5p, hsa‐let‐7i‐5p, hsa‐miR‐6501‐5p, hsa‐miR‐221‐3p, hsa‐let‐7g‐5p, hsa‐miR‐106a‐5p, and hsa‐miR‐17‐5p were significantly downregulated in pediatric patients with β‐thalassemia. After integrating our data with a previously published dataset, we found that hsa‐let‐7b‐5p and hsa‐let‐7i‐5p expression levels were also lower in adolescent or adult patients with β‐thalassemia. The predicted target genes of hsa‐let‐7b‐5p and hsa‐let‐7i‐5p were associated with the transforming growth factor β receptor, phosphatidylinositol 3‐kinase/AKT, FoxO, Hippo, and mitogen‐activated protein kinase signaling pathways. We also identified 12 target genes of hsa‐let‐7a‐3p and hsa‐let‐7f‐1‐3p and 21 target genes of hsa‐let‐7a‐3p and hsa‐let‐7f‐1‐3p, which were differentially expressed in patients with β‐thalassemia. Finally, we found that hsa‐miR‐190‐5p and hsa‐miR‐1278‐5p may regulate hemoglobin switching by modulation of the B‐cell lymphoma/leukemia 11A gene. Conclusion The results of the study show that several microRNAs are dysregulated in pediatric β‐thalassemia. Further, the results also indicate toward a critical role of let7 miRNAs in the pathogenesis of pediatric β‐thalassemia, which needs to be investigated further.

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Section: Discussionmentioning

confidence: 99%

Abnormal regulation of microRNAs and related genes in pediatric β‐thalassemia

Wang

Chen

et al. 2021

Clinical Laboratory Analysis

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“…In our study, it has been found in combination with other KLF1 sequence variations in a β-thalassemia heterozygous ( Table 3 , subjects 3) and in two subjects with normal α- and β-globin genotypes. The p.M39L (c.115A > C) variation falls in the transactivation domain encoded by exon 1 and involves a methionine for leucine substitution at codon 39 (ATG > CTG) [ 41 ]. It is currently classified as probably benign (rs112631212) and, in our study, it has been found in cis with S102P in two related subjects both heterozygous for a β-thalassemia mutation ( Table 3 , subjects 12 and 15).…”

Section: Resultsmentioning

confidence: 99%

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Catapano

Sessa

Trombetti

et al. 2023

Biology

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The erythroid transcriptional factor Krüppel-like factor 1 (KLF1) is a master regulator of erythropoiesis. Mutations that cause KLF1 haploinsufficiency have been linked to increased fetal hemoglobin (HbF) and hemoglobin A2 (HbA2) levels with ameliorative effects on the severity of β-thalassemia. With the aim of determining if KLF1 gene variations might play a role in the modulation of β-thalassemia, in this study we screened 17 subjects showing a β-thalassemia-like phenotype with a slight or marked increase in HbA2 and HbF levels. Overall, seven KLF1 gene variants were identified, of which two were novel. Functional studies were performed in K562 cells to clarify the pathogenic significance of these mutations. Our study confirmed the ameliorative effect on the thalassemia phenotype for some of these variants but also raised the notion that certain mutations may have deteriorating effects by increasing KLF1 expression levels or enhancing its transcriptional activity. Our results indicate that functional studies are required to evaluate the possible effects of KLF1 mutations, particularly in the case of the co-existence of two or more mutations that could differently contribute to KLF1 expression or transcriptional activity and consequently to the thalassemia phenotype.

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“…Initially, embryonic erythropoietin ( HBE1 ) is replaced by foetal erythropoietin ( HBG1 , HBG2 ) expression in primitive erythroid cells, correlating with the beginning of erythropoiesis. Shortly after birth, adult EPO progressively replaces foetal EPO in the last erythrocytes 25 . Patients with SCA typically have a mutation in the adult β‐globin gene ( HBB ) that results in abnormal haemoglobin synthesis.…”

Section: Erythroid Disordersmentioning

confidence: 99%

“…Shortly after birth, adult EPO progressively replaces foetal EPO in the last erythrocytes. 25 Patients with SCA typically have a mutation in the adult β-globin gene (HBB) that results in abnormal haemoglobin synthesis. During deoxygenation, they produce haemoglobin tetramers that are inadequately soluble.…”

Section: Genetic Factorsmentioning

confidence: 99%

Molecular regulatory mechanisms of erythropoiesis and related diseases

Zhu

Guo³

et al. 2023

European J of Haematology

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The metabolism of cells and blood circulation allow for the constant production and destruction of red blood cells. Erythrocyte formation allows red blood cells to regenerate, which is crucial for maintaining the equilibrium of the organism. Erythrocyte formation is a multi‐step, intricate process with distinct structural and functional characteristics at each stage. Erythropoiesis is regulated by a number of signaling pathways; malfunctional regulatory mechanisms may result in disease and aberrant erythropoiesis. Therefore, this article focuses on a review of the erythroid formation process, related signaling pathways, and red blood cell lineage diseases.

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Insight of fetal to adult hemoglobin switch: Genetic modulators and therapeutic targets

Cited by 13 publications

References 76 publications

Abnormal regulation of microRNAs and related genes in pediatric β‐thalassemia

Abnormal regulation of microRNAs and related genes in pediatric β‐thalassemia

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Molecular regulatory mechanisms of erythropoiesis and related diseases

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