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Treatment of Erythroid Precursor Cells from β-Thalassemia Patients with Cinchona Alkaloids: Induction of Fetal Hemoglobin Production.

ABSTRACT: β-thalassemias are among the most common inherited hemoglobinopathies worldwide and are the result of autosomal mutations in the gene encoding β-globin, causing an absence or low-level production of adult hemoglobin (HbA). Induction of fetal hemoglobin (HbF) is considered to be of key importance for the development of therapeutic protocols for β-thalassemia and novel HbF inducers need to be proposed for pre-clinical development. The main purpose on this study was to analyze Cinchona alkaloids (cinchonidine, quinidine and cinchonine) as natural HbF-inducing agents in human erythroid cells. The analytical methods employed were Reverse Transcription quantitative real-time PCR (RT-qPCR) (for quantification of γ-globin mRNA) and High Performance Liquid Chromatography (HPLC) (for analysis of the hemoglobin pattern). After an initial analysis using the K562 cell line as an experimental model system, showing induction of hemoglobin and γ-globin mRNA, we verified whether the two more active compounds, cinchonidine and quinidine, were able to induce HbF in erythroid progenitor cells isolated from β-thalassemia patients. The data obtained demonstrate that cinchonidine and quinidine are potent inducers of γ-globin mRNA and HbF in erythroid progenitor cells isolated from nine β-thalassemia patients. In addition, both compounds were found to synergize with the HbF inducer sirolimus for maximal production of HbF. The data obtained strongly indicate that these compounds deserve consideration in the development of pre-clinical approaches for therapeutic protocols of β-thalassemia.

SUBMITTER: Zuccato C

PROVIDER: S-EPMC8706579 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increase of the expression of ?-globin gene and high production of fetal hemoglobin (HbF) in ?-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify ?-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea).A?-globin gene sequencing was performed on genomic DNA isolated from a total of 75 ?-thalassemia patients, including 31 ?039/?039, 33 ?039/?+IVSI-110, 9 ?+IVSI-110/?+IVSI-110, one ?0IVSI-1/?+IVSI-6 and one ?039/?+IVSI-6.The results show that the rs368698783 polymorphism is present in ?-thalassemia patients in the 5'UTR sequence (+25) of the A?-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This A?(+25 G->A) polymorphism is associated with the G?-globin-XmnI polymorphism and both are linked with the ?039-globin gene, but not with the ?+IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the A?(+25 G->A) and G?-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from ?039/?039 thalassemia patients.As a potential explanation of our findings, we hypothesize that in ?-thalassemia the G?-globin-XmnI/A?-globin-(G->A) genotype is frequently under genetic linkage with ?0-thalassemia mutations, but not with the ?+-thalassemia mutation here studied (i.e. ?+IVSI-110) and that this genetic combination has been selected within the population of ?0-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the A?-globin gene associated in ?039 thalassemia patients with high HbF in erythroid precursor cells.

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Treatment of Erythroid Precursor Cells from β-Thalassemia Patients with Cinchona Alkaloids: Induction of Fetal Hemoglobin Production.

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