Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Parisi, Sarah; Finelli, Carlo; Fazio, Alessia; Stefano, Alessia De; Mongiorgi, Sara; Ratti, Stefano; Cappellini, Alessandra; Billi, Anna Maria; Cocco, Lucio; Follo, Matilde Y.

doi:10.3390/ijms22020827

Cited by 15 publications

(14 citation statements)

References 62 publications

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“…The targets of hsa‐let‐7b‐5p and hsa‐let‐7i‐5p were involved in the negative regulation of translation, positive regulation of cell migration, regulation of cytokine biosynthesis, transforming growth factor (TGF) β receptor signaling pathway, and somatic stem cell population maintenance (Figure 5C). TGFβ is an important cytokine involved in cell migration 56,57 and negatively regulates erythrocyte differentiation and maturation in the early stages of erythropoiesis 58 . In addition, somatic stem cell population maintenance is associated with changes in genes in adult β‐thalassemia 46 …”

Section: Resultsmentioning

confidence: 99%

“…TGFβ is an important cytokine involved in cell migration 56,57 and negatively regulates erythrocyte differentiation and maturation in the early stages of erythropoiesis. 58 In addition, somatic stem cell population maintenance is associated with changes in genes in adult β-thalassemia. 46 The targets of hsa-let-7b-5p and hsa-let-7i-5p were associated (Figure 5D).…”

Section: Biological Processes and Signaling Pathways Associated With The Target Genes Of Let7 Mirnasmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Biological Processes and Signaling Pathways Associated With The Target Genes Of Let7 Mirnasmentioning

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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“…As a likely consequence, roxadustat is effective in some individuals who are relatively resistant to ESAs. Consistent with this view, there is evidence that roxadustat prevents ESA-hyporesponsiveness and anemia in patients with myelodysplastic syndrome (Yu et al, 2020;Parisi et al, 2021). In addition, Li et al (2021a) showed that roxadustat significantly increased the Hb level in patients with renal transplantation anemia without affecting renal function or increasing rejection.…”

Section: Effect Of Roxadustat On Anemiamentioning

confidence: 86%

Roxadustat: Not just for anemia

Zhu

Jiang²,

Wei³

et al. 2022

Front. Pharmacol.

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Roxadustat is a recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. Recent studies found it also has potential for the treatment of other hypoxia-related diseases. Although clinical studies have not yet found significant adverse or off-target effects of roxadustat, clinicians must be vigilant about these possible effects. Hypoxia-inducible factor regulates the expression of many genes and physiological processes in response to a decreased level of oxygen, but its role in the pathogenesis of different diseases is complex and controversial. In addition to increasing the expression of hypoxia-inducible factor, roxadustat also has some effects that may be HIF-independent, indicating some potential off-target effects. This article reviews the pharmacological characteristics of roxadustat, its current status in the treatment of renal anemia, and its possible effects on other pathological mechanisms.

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“…The potential new candidate that may contribute to the development of erythrocytosis are therefore hormones and their receptors that influence proliferation, survival and differentiation of erythrocytes, including macrophage colony-stimulating factor 1 (CSF1/CSF1R), Granulocyte-Macrophage Colony-Stimulating Factor 2 (CSF2/CSF2R) and interleukin 3 (IL3/IL3R). Several transcription factors in which dysregulation may also contribute to disease development are reviewed by Parisi et al (2021) [138]. The Growth Factor Independent 1B Transcriptional Repressor (GFI1B) was confirmed as a novel candidate gene involved in the development of erythrocytosis in one of the previous studies [14].…”

Section: Regulation Of Red Blood Cells Production and Degradationmentioning

confidence: 99%

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Tomc

Debeljak

2021

Genes

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Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

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Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Cited by 15 publications

References 62 publications

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

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

Roxadustat: Not just for anemia

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

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