Pharmacoproteomics Profiling of Plasma From beta-Thalassemia Patients in Response to Hydroxyurea Treatment

摘要

beta-Thalassemia is a genetic disorder caused by defects in the beta-globin gene resulting in the absence or reduced synthesis of adult hemoglobin (HbA). Hydroxyurea is an effective drug to increase fetal gamma-globin (HbF) expression, replacing the missing adult beta-globin. The mechanism of HbF induction by hydroxyurea and improvement in clinical symptoms are still poorly understood. In the present study we performed comparative analysis of plasma proteome in pre- and post-hydroxyurea-treated beta-thalassemia major transfusion-dependent children (n = 10, mean age = 3.2 years) as well as responders versus nonresponders to hydroxyurea treatment. Plasma was collected before and after 6 months of hydroxyurea treatment, with patients subcategorized on the basis of their response to hydroxyurea. Among 400 identified proteins using a label-free quantitative proteomics approach, 28 proteins were found to be significantly different in pre- versus post-hydroxyurea-treated groups, with transferrin receptor protein-1 being most downregulated and hemopexin and haptoglobin the most upregulated proteins after treatment. In responder versus nonresponder comparison, 26 proteins were found to be differentially expressed, with carbonic anhydrase 1, hemoglobin subunit gamma-1, and peroxiredoxin-2 showing the significant changes. The mechanism of hydroxyurea treatment in beta-thalassemia patients appears to be complex, requiring a large sample size and a longer period of treatment to reveal its details.