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Hydroxyurea responsiveness in β-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity
- Source :
- Haematologica, Vol 98, Iss 5 (2013)
- Publication Year :
- 2013
- Publisher :
- Ferrata Storti Foundation, 2013.
-
Abstract
- 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.
- Subjects :
- Diseases of the blood and blood-forming organs
RC633-647.5
Subjects
Details
- Language :
- English
- ISSN :
- 03906078 and 15928721
- Volume :
- 98
- Issue :
- 5
- Database :
- Directory of Open Access Journals
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.22bc795077fd40d1b5600237c3737daf
- Document Type :
- article
- Full Text :
- https://doi.org/10.3324/haematol.2012.074492