<i>KLF10</i>
            Gene Expression is Associated with High Fetal Hemoglobin Levels and with Response to Hydroxyurea Treatment in β-Hemoglobinopathy Patients

Borg, Joseph; Phylactides, Marios; Bartsakoulia, Marina; Tafrali, Christina; Lederer, Carsten W.; Felice, Alex E.; Papachatzopoulou, Adamantia; Kourakli, Alexandra; Stavrou, Eleana F.; Christou, Soteroula; Hou, Jun; Karkabouna, Sophia; Lappa-Manakou, Christina; Özgür, Zeliha; IJcken, Wilfred F. J. van; Lindern, Marieke von; Grosveld, Frank; Georgitsi, Marianthi; Kleanthous, Marina; Philipsen, Sjaak; Patrinos, George P.

doi:10.2217/pgs.12.125

Cited by 39 publications

(25 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In our study, while the proportion of patients reported to be on hydroxyurea was not different between the groups, the patients with infrequent hospitalizations overall had significantly higher fetal hemoglobin levels. We are unable to comment on the reasons for differences in hemoglobin F levels between the groups which may reflect noncompliance with hydroxyurea; however, pharmacogenetic differences cannot be ruled out 5, 40 . Interestingly high fetal hemoglobin levels, which have been associated with lower pain rates in SCD patients, were also negatively correlated with connectivity between the secondary somatosensory (SII) cortex and left precuneus and positively correlated with connectivity between SLN to pgACC.…”

Section: Discussionmentioning

confidence: 79%

Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease

Darbari

Hampson

Ichesco

et al. 2015

The Journal of Pain

View full text Add to dashboard Cite

Sickle cell disease (SCD) is a hemoglobinopathy affecting more than 100,000 individuals in United States. The disease is characterized by presence of sickle hemoglobin and recurrent episodes of pain. Some individuals with SCD experience frequent hospitalizations and high burden of pain. The role of central mechanisms in SCD pain has not been explored. Twenty-five adolescents and young adults with SCD underwent functional MRI (fMRI). Participants were stratified into high or low pain groups based on the number of hospitalizations for pain in preceding 12 months. Resting state functional connectivity was analyzed using seed based and dual-regression independent component analysis. Intrinsic brain connectivity was compared between high and low pain groups and association with fetal hemoglobin, a known modifier of SCD, was explored. Patients in the high pain group displayed an excess of pro-nociceptive connectivity such as anterior cingulate to default-mode-network structures such as the precuneus, whereas patients in low pain group showed more connectivity to anti-nociceptive structures such as the peri- and sub-genual cingulate. Although a similar proportion of patients in both groups reported to be on hydroxyurea, the fetal hemoglobin levels were significantly higher in the low pain group and were associated with greater connectivity to anti-nociceptive structures. These findings support the role of central mechanisms in SCD pain. Intrinsic brain connectivity should be explored as a complementary and objective outcome measure in SCD pain research.

show abstract

Section: Discussionmentioning

confidence: 79%

Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease

Darbari

Hampson

Ichesco

et al. 2015

The Journal of Pain

View full text Add to dashboard Cite

show abstract

“…Statistically significant associations of HbF response to HU with multiple SNPs in several genes (ARG2, FLT1, HAO2, NOS1, KLF10, SALL2) have been reported. 29,30 To date the use of genetic determinants to predict the effect of HU is still not possible. For this reason human liquid erythroid culture system, an efficacious but complex and time consuming approach, at the moment remains the only method able to predict patients’ response to HU.…”

Section: Discussionmentioning

confidence: 99%

Study on Hydroxyurea Response in Hemoglobinopathies Patients Using Genetic Markers and Liquid Erythroid Cultures

et al. 2016

View full text Add to dashboard Cite

Increased expression of fetal hemoglobin (HbF) may ameliorate the clinical course of hemoglobinopathies. Hydroxyurea (HU) is the only inducer approved for the treatment of these diseases able to stimulate HbF production but patients’ response is highly variable indicating the utility of the identification of pharmacogenomic biomarkers in order to predict pharmacological treatment efficacy. To date few studies to evaluate the role of genetic determinants in HU response have been conducted showing contradictory results. In this study we analyzed BCL11A, GATA-1, KLF-1 genes and γ-globin promoter in 60 alleles from 30 hemoglobinopathies patients under HU treatment to assess the role of these markers in HU response. We did not find any association between these genetic determinants and HU response. Before treatment started, the same patients were analyzed in vitro using liquid erythroid cultures in a test able to predict their response to HU. The results of our analysis confirm the absence of pharmacogenomic biomarker associated to HU response indicating that, the quantification of γ-globin mRNA fold increase remains the only method able to predict in vivo patients response to the drug.

show abstract

“…We have previously shown that genomic variants in the MAP3K5 , KLF10 , SIN3A , NOS1 , ARG1 , and ARG2 genes are associated with elevated HbF levels and, hence, milder disease severity in β-type hemoglobinopathy patients and HU treatment response rate in SCD/β-thalassemia compound heterozygous patients [ 4 , 7 , 17 , 40 ]. Herein, we adopted a whole transcriptome analysis of erythroid cells derived from human hematopoietic tissues of various developmental stages to identify candidate genes that are differentially expressed at various developmental stages.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

BackgroundHuman erythropoiesis is characterized by distinct gene expression profiles at various developmental stages. Previous studies suggest that fetal-to-adult hemoglobin switch is regulated by a complex mechanism, in which many key players still remain unknown. Here, we report our findings from whole transcriptome analysis of erythroid cells, isolated from erythroid tissues at various developmental stages in an effort to identify distinct molecular signatures of each erythroid tissue.ResultsFrom our in-depth data analysis, pathway analysis, and text mining, we opted to focus on the VEGFA gene, given its gene expression characteristics. Selected VEGFA genomic variants, identified through linkage disequilibrium analysis, were explored further for their association with elevated fetal hemoglobin levels in β-type hemoglobinopathy patients. Our downstream analysis of non-transfusion-dependent β-thalassemia patients, β-thalassemia major patients, compound heterozygous sickle cell disease/β-thalassemia patients receiving hydroxyurea as fetal hemoglobin augmentation treatment, and non-thalassemic individuals indicated that VEGFA genomic variants were associated with disease severity in β-thalassemia patients and hydroxyurea treatment efficacy in SCD/β-thalassemia compound heterozygous patients.ConclusionsOur findings suggest that VEGFA may act as a modifier gene of human globin gene expression and, at the same time, serve as a genomic biomarker in β-type hemoglobinopathy disease severity and hydroxyurea treatment efficacy.Electronic supplementary materialThe online version of this article (10.1186/s40246-017-0120-8) contains supplementary material, which is available to authorized users.

show abstract

KLF10 Gene Expression is Associated with High Fetal Hemoglobin Levels and with Response to Hydroxyurea Treatment in β-Hemoglobinopathy Patients

Abstract: These data suggest that KLF10 may constitute a pharmacogenomic marker to discriminate between response and nonresponse to HU treatment.

Cited by 39 publications

References 39 publications

Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease

Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease

Study on Hydroxyurea Response in Hemoglobinopathies Patients Using Genetic Markers and Liquid Erythroid Cultures

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

Contact Info

Product

Resources

About