Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

Chondrou, Vasiliki; Kolovos, Petros; Sgourou, Argyro; Kourakli, Alexandra; Pavlidaki, Alexia; Kastrinou, Vlasia; John, Anne; Symeonidis, Argiris; Ali, Bassam R.; Papachatzopoulou, Adamantia; Κάτσιλα, Θεοδώρα; Patrinos, George P.

doi:10.1186/s40246-017-0120-8

Cited by 12 publications

(10 citation statements)

References 45 publications

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“…Another study suggests that the vascular endothelial growth factor (VEGFA) gene is a biomarker in β-type hemoglobinopathies severity and efficacy of HU therapy (Chondrou et al, 2017). These findings are in agreement with a study included in this systematic review that found SNPs in the FLT1 gene, encoding VEGF receptor 1, associated with HbF changes by HU therapy in Hb SS patients (Ma et al, 2007).…”

Section: Signaling Pathways Underlying Hbf Changes In Response To Hu Therapysupporting

confidence: 75%

“…Three studies did not assess whether the SNPs affected HbF levels (Italia et al, 2010;Zhu et al, 2017;Yahouedehou et al, 2020). Four studies did not differentiate patients with SCA from patients with SCD (Borg et al, 2012;Gravia et al, 2016;Chondrou et al, 2017;Elalfy et al, 2017). One study was part of an oral session and their results were later published in an original article already included in this systematic review (Wyszynski et al, 2004).…”

Section: Study Selectionmentioning

confidence: 99%

“…This evidence is of huge importance to assess the cost-effectiveness of the use of pharmacogenetic tests for these SNPs in the SCA management. Some studies do not meet the inclusion criteria of this review due to the different genotypes of the study subjects (Borg et al, 2012;Chondrou et al, 2017;Elalfy et al, 2017). They involve other β-type hemoglobinopathies, and known differences in their hematological parameter could bias the review.…”

Section: Signaling Pathways Underlying Hbf Changes In Response To Hu Therapymentioning

confidence: 99%

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Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis

et al. 2022

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Hydroxyurea has long been used for the treatment of sickle cell anemia (SCA), and its clinical effectiveness is related to the induction of fetal hemoglobin (HbF), a major modifier of SCA phenotypes. However, there is substantial variability in response to hydroxyurea among patients with SCA. While some patients show an increase in HbF levels and an ameliorated clinical condition under low doses of hydroxyurea, other patients present a poor effect or even develop toxicity. However, the effects of genetic polymorphisms on increasing HbF levels in response to hydroxyurea in patients with SCA (Hb SS) have been less explored. Therefore, we performed a systematic review to assess whether single-nucleotide polymorphisms (SNPs) affect HbF levels in patients with SCA treated with hydroxyurea. Moreover, we performed pathway analysis using the set of genes with SNPs found to be associated with changes in HbF levels in response to hydroxyurea among the included studies. The systematic literature search was conducted on Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Web of Science. Seven cohort studies were included following our inclusion and exclusion criteria. From the 728 genetic polymorphisms examined in the included studies, 50 different SNPs of 17 genes were found to be associated with HbF changes in patients with SCA treated with hydroxyurea, which are known to affect baseline HbF but are not restricted to them. Enrichment analysis of this gene set revealed reactome pathways with the lowest adjusted p-values and highest combined scores related to VEGF ligand–receptor interactions (R-HSA-194313; R-HSA-195399) and the urea cycle (R-HSA-70635). Pharmacogenetic studies of response to hydroxyurea therapy in patients with SCA are still scarce and markedly heterogeneous regarding candidate genes and SNPs examined for association with HbF changes and outcomes, suggesting that further studies are needed. The reviewed findings highlighted that similar to baseline HbF, changes in HbF levels upon hydroxyurea therapy are likely to be regulated by multiple loci. There is evidence that SNPs in intron 2 of BCL11A affect HbF changes in response to hydroxyurea therapy, a potential application that might improve the clinical management of SCA.Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=208790).

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Section: Signaling Pathways Underlying Hbf Changes In Response To Hu Therapysupporting

confidence: 75%

Section: Study Selectionmentioning

confidence: 99%

Section: Signaling Pathways Underlying Hbf Changes In Response To Hu Therapymentioning

confidence: 99%

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Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis

et al. 2022

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“…HU treatment is up-to-date the only approved FDA-treatment for SCD and beta-thalassemia (Chondrou V. et al (2017) 62 . The mechanisms of its HbF induction and its effects on the global transcriptome are not yet fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic gene profiles in anex vivomodel of erythropoiesis to unravel molecular pathomechanisms of Sickle Cell Disease

Tinguely,

Opitz,

Schaer

et al. 2023

Preprint

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Sickle cell disease (SCD) is an autosomal recessive, single gene disorder caused by a point mutation in the beta globin(HBB)gene. The single amino acid substitution of the haemoglobin molecule leads to aberrant β-chain formation, polymerizing sickled haemoglobin (HbS) molecules together during episodes of deoxygenation and therefore causing intracellular sickling. Hydroxyurea (HU) is still the most indicated drug inducing fetal hemoglobin (HbF) production for SCD treatment, especially for the SCD patients with a severe clinical profile. In this study we could identify transcriptional profiles in erythroid cells of SCD patients, which have been treated with HU in comparison to untreated SCD patients and healthy controls.Our present transcriptomic profile analysis contained a new subset of genes identified for the first time as associated with SCD. In SCD non-treated-derived erythroid cells compared to controls, 398 differentially expressed genes (DEGs) were identified, of which 100 genes were upregulated and 298 genes were downregulated in the SCD patient cells. 65 DEGs were identified in SCD HU-treated patient-derived erythroid cells compared to controls, of which 37 genes were upregulated and 28 genes were downregulated. 212 DEGs were identified in SCD HU-treated patient-derived compared to SCD non-treated derived erythroid cells, of which 113 genes were upregulated and 99 genes were downregulated. 141 DEGs were identified in SCD derived erythroid cells compared to controls, of which 58 genes were upregulated and 83 genes were downregulated. We found biological processes such as oxidative phosphorylation pathway, Fanconi anaemia pathway, adaptive immune response or inflammatory response to be part of our significantly enriched Gene Ontology (GO) terms. Further genes encoding significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for proteasome, autophagy, immune response, platelet activation, as well as for natural killer cell (NK) cytotoxicity, oxidative phosphorylation, Fanconi anaemia pathway, ribosome biogenesis were upregulated in both SCD non treated and SCD HU-treated patient-derived erythroid cells in comparison to healthy controls. Our findings collectively suggest different as well as common molecular signatures between SCD non-treated, SCD HU-treated compared to HC. We could validate 12 of our top significant genes by qRT-PCR (calneuron 1 (CALN1), nucleoporin 85 (NUP85), tumor protein 63 (TP63), ras and rab interactor 2 (RIN2), solute carrier family 44 member 5 (SLC44A5), phenylethanolamine N-methyltransferase (PNMT), stabilin 1/ clever-1 (STAB1), SLX1 Homolog A, Structure-Specific Endonuclease Subunit (SLX1A), ATPase phospholipid transporting 9A (ATP9A), MSH5-SAPCD1, G protein subunit gamma 4 (GNG4) and glutathione S-transferase theta 2B (GSTT2B)) and compare their mRNA levels in bone marrow and spleen tissue from the Berkely SCD mouse model.In short, our study could identify new genes and pathways that may be involved in the SCD disease pathogenesis and that may be influenced by the HU treatment. The findings encourage future characterization of their roles in SCD to establish these findings as basis for new therapeutic targets.

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“…1,2 The molecular machinery involved in human Hb switching has been extensively studied, leading to identification of genetic modifier genes and the defining of the contribution of modifier variants in modulating the phenotypic diversity of b-thalassemia and sickle cell disease by regulating HbF levels. [3][4][5] Two transcription factors (TFs), BCL11A and ZBTB7A/LRF, have been identified as major erythroid-specific HbF repressors, [6][7][8][9] and both have recently been shown to bind cis-acting elements in the g-globin promoter. 10,11 A domainfocused CRISPR screen has identified heme-regulated inhibitor 12 as a potentially druggable target involved in HbF silencing through the regulation of BCL11A.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia

Bao

Zhang

Wang

et al. 2021

The American Journal of Human Genetics

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The fetal-to-adult hemoglobin switch is regulated in a developmental stage-specific manner and reactivation of fetal hemoglobin (HbF) has therapeutic implications for treatment of b-thalassemia and sickle cell anemia, two major global health problems. Although significant progress has been made in our understanding of the molecular mechanism of the fetal-to-adult hemoglobin switch, the mechanism of epigenetic regulation of HbF silencing remains to be fully defined. Here, we performed whole-genome bisulfite sequencing and RNA sequencing analysis of the bone marrow-derived GYPA þ erythroid cells from b-thalassemia-affected individuals with widely varying levels of HbF groups (HbF R 95th percentile or HbF % 5th percentile) to screen epigenetic modulators of HbF and phenotypic diversity of b-thalassemia. We identified an ETS2 repressor factor encoded by ERF, whose promoter hypermethylation and mRNA downregulation are associated with high HbF levels in b-thalassemia. We further observed that hypermethylation of the ERF promoter mediated by enrichment of DNMT3A leads to demethylation of g-globin genes and attenuation of binding of ERF on the HBG promoter and eventually re-activation of HbF in b-thalassemia. We demonstrated that ERF depletion markedly increased HbF production in human CD34 þ erythroid progenitor cells, HUDEP-2 cell lines, and transplanted NCG-Kit-V831M mice. ERF represses g-globin expression by directly binding to two consensus motifs regulating g-globin gene expression. Importantly, ERF depletion did not affect maturation of erythroid cells. Identification of alterations in DNA methylation of ERF as a modulator of HbF synthesis opens up therapeutic targets for b-hemoglobinopathies.

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Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

Cited by 12 publications

References 45 publications

Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis

Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis

Transcriptomic gene profiles in anex vivomodel of erythropoiesis to unravel molecular pathomechanisms of Sickle Cell Disease

Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia

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