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- Title
Hydroxyurea exerts bi-modal dose-dependent effects on erythropoiesis in human cultured erythroid cells via distinct pathways.
- Authors
Wang, Min; Tang, Delia C.; Liu, Wenli; Chin, Kyung; Zhu, Jianqion G.; Fibach, Eitan; Rodgers, Griffin P.
- Abstract
Summary. Hydroxyurea (HU) has been shown to increase the proportion of fetal haemoglobin (HbF) in most sickle cell patients. A low-dosage regimen increased total haemoglobin (Hb) levels in some thalassaemia intermedia patients by preferentially increasing β-globin biosynthesis. To further characterize these apparent dose-dependent effects of HU, we examined erythroid cells exposed to HU (5–100 µmol/l) in two-phase liquid culture. Low doses (from 5 to 25 µmol/l) increased Hb levels by up to 2·7-fold, and a high dose (100 µmol/l) increased Hb levels when added at d 3–6 of phase II, with no significant changes in response to HU during the late stage of phase II culture (≥ 9 d). HU exposure during d 0–3 of phase II culture increased the number of erythroid colonies to a maximum of fivefold at 5 µmol/l HU. GATA-1 mRNA was downregulated at a high dose and GATA-2 was dose dependently upregulated over a lower dosage range. Treatment with 100 µmol/l HU dramatically upregulated the death receptor DR-5, caspase 3, as determined by cDNA microarray analysis. In contrast, 10 µmol/l HU modestly upregulated mRNA levels of the early growth response gene. Our results suggest that HU exerts concentration-dependent effects on HbF production and erythropoiesis and that these two effects are mediated by distinct molecular mechanisms.
- Subjects
HYDROXY acids; ERYTHROPOIESIS; ERYTHROCYTE membranes
- Publication
British Journal of Haematology, 2002, Vol 119, Issue 4, p1098
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1046/j.1365-2141.2002.03958.x