Hydroxyurea responsiveness in β-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

• Published in: Haematologica (Roma) 2013-05, Vol.98 (5), p.696-704
• Main Authors: Pourfarzad, Farzin, von Lindern, Marieke, Azarkeivan, Azita, Hou, Jun, Kia, Sima Kheradmand, Esteghamat, Fatemehsadat, van Ijcken, Wilfred, Philipsen, Sjaak, Najmabadi, Hossein, Grosveld, Frank
• Format: Article
• Language: English
• Subjects: Adaptation, Biological - genetics; ADP-Ribosylation Factors - genetics; Apoptosis - genetics; beta-Thalassemia - drug therapy; beta-Thalassemia - genetics; beta-Thalassemia - metabolism; Cell Differentiation; Cluster Analysis; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - metabolism; Fetal Hemoglobin - genetics; Fetal Hemoglobin - metabolism; gamma-Globins - genetics; Gene Expression Profiling; Gene Expression Regulation; Genetic Loci; Hemoglobin A - metabolism; Humans; Hydroxyurea - therapeutic use; Original and Brief Reports; Stress, Physiological - genetics; Treatment Outcome
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2012.074492

β-thalassemia is caused by mutations in the β-globin locus resulting in loss of, or reduced, hemoglobin A (adult hemoglobin, HbA, α2β2) production. Hydroxyurea treatment increases fetal γ-globin (fetal hemoglobin, HbF, α2γ2) expression in postnatal life substituting for the missing adult β-globin and is, therefore, an attractive therapeutic approach. Patients treated with hydroxyurea fall into three categories: i) 'responders' who increase hemoglobin to therapeutic levels; (ii) 'moderate-responders' who increase hemoglobin levels but still need transfusions at longer intervals; and (iii) 'non-responders' who do not reach adequate hemoglobin levels and remain transfusion-dependent. The mechanisms underlying these differential responses remain largely unclear. We generated RNA expression profiles from erythroblast progenitors of 8 responder and 8 non-responder β-thalassemia patients. These profiles revealed that hydroxyurea treatment induced differential expression of many genes in cells from non-responders while it had little impact on cells from responders. Part of the gene program up-regulated by hydroxyurea in non-responders was already highly expressed in responders before hydroxyurea treatment. Baseline HbF expression was low in non-responders, and hydroxyurea treatment induced significant cell death. We conclude that cells from responders have adapted well to constitutive stress conditions and display a propensity to proceed to the erythroid differentiation program.