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

Sclafani, Serena; Pecoraro, A.; Agrigento,; Troia, Antonio; R, Di Maggio; Sacco, Massimiliano; Maggio, Aurelio; D’Alcamo, Elena

doi:10.4081/hr.2016.6678

Cited by 9 publications

(10 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has recently been reported that, in erythroblasts cultured from peripheral blood CD34 + cells of a group of SCD and β-thalassemia patients who were initially not on HU therapy but were subsequently put on prospective HU therapy, HU-induced changes in HbF levels either before or after HU therapy are similar. 42 This finding, together with our results, indicates that HU and blood exchange therapies did not exert lasting genetic effects on bone marrow CD34 + cells of the patients to significantly change HU-induced HbF levels in patient erythroblasts cultured from the CD34 + cells.…”

Section: Discussionsupporting

confidence: 77%

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness

Zhu

et al. 2017

Haematologica

View full text Add to dashboard Cite

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34+ cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD.

show abstract

Section: Discussionsupporting

confidence: 77%

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness

Zhu

et al. 2017

Haematologica

View full text Add to dashboard Cite

show abstract

“…Even if predicting sickle cell severity is complex, stroke appears to be the most devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of this risk have been described [38][39][40]. Thus our severity classification based on the "existence or not of the risk of cerebral vasculopathy" enabled us to better characterize the role of genetic modifiers of SCA.…”

Section: Hbf Is Associated With a High Risk Of Cerebra Vasculopathymentioning

confidence: 99%

“…On the contrary, low HbF was associated with vaso-occlusive complications, requiring treatment with hydroxycarbamide. HU or hydroxycarbamide is the only HbF inducer approved for the treatment of SCD [39]. As reported in several studies, HbF levels have a clinically beneficial effect on SCD [40,41].…”

Section: Hbf Is Associated With a High Risk Of Cerebra Vasculopathymentioning

confidence: 99%

High fetal hemoglobin level is associated with increased risk of cerebral vasculopathy in children with sickle cell disease in Mayotte.

Elenga

CHAMOUINE²,

SAANDI³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia, specific to each population, would be prognostically useful and could inform personalized therapeutics. The objective of this study was to describe the genetic modulators of sickle cell disease in a cohort of pediatric patients followed up in Mayotte. Methods: In this retrospective cohort study, clinical and biological data, collected between 1 January 2007 and 31 December 2017, in children younger than 18 years, were considered for the analysis. Results: We included 185 children with 72 % SS, 16 % Sβ0-thalassemia and 12 % Sβ+ thalassemia. The mean age was 9.5 years; 10 % of patients were lost to follow up. The Bantu haplotype was associated with an increase in hospitalizations and transfusions. The alpha-thalassemic mutation was associated with a decrease of hemolysis biological parameters (anemia, reticulocytes), and less cerebral vasculopathy. The Single Nucleotide Polymorphisms BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were associated with the group of children with HbF> 10%. The survival analysis without occurrence of cerebral vasculopathy showed that the group of patients with HbF> 10% presented a significant risk of early onset of cerebral vasculopathy. Conclusions: The most remarkable result of our study was the association of SNPs with the phenotypic groups that we aimed to determine. BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were correlated with the HbF group> 10%, which presents a higher risk of cerebral vasculopathy and would be oriented towards the hemolytic sub-phenotype.

show abstract

“…Hydroxyurea (HYD), is an antimetabolite and antineoplastic agent that is used alone or in combination with itraconazole, clotrimazole, and terbinafine for the treatment of several kinds of cancer and fungal infections [10,11]. It increases fetal hemoglobin concentration and thus decreases the prevalence of severe health crises and urgent blood transmissions in sickle cell anemia patients.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of hydroxyurea and eflornithine against most blood parasites Babesia and Theileria

et al. 2020

View full text Add to dashboard Cite

Background The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis. Methods In this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin-Darby bovine kidney (MDBK) cells. Findings HYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 μM, while HYD affected the MDBK cell viability at EC 50 value of 887.5±14.4 μM. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species.

show abstract

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

Cited by 9 publications

References 28 publications

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness

High fetal hemoglobin level is associated with increased risk of cerebral vasculopathy in children with sickle cell disease in Mayotte.

Safety and efficacy of hydroxyurea and eflornithine against most blood parasites Babesia and Theileria

Contact Info

Product

Resources

About