Present address: Institute of Hematology, Chinese Academy of Medical Sciences and Beking Union of Medical College, Tianjin 300020, P. R. China.
Hydroxyurea exerts bi-modal dose-dependent effects on erythropoiesis in human cultured erythroid cells via distinct pathways
Version of Record online: 11 DEC 2002
British Journal of Haematology
Volume 119, Issue 4, pages 1098–1105, December 2002
How to Cite
Wang, M., Tang, D. C., Liu, W., Chin, K., Zhu, J. G., Fibach, E. and Rodgers, G. P. (2002), Hydroxyurea exerts bi-modal dose-dependent effects on erythropoiesis in human cultured erythroid cells via distinct pathways. British Journal of Haematology, 119: 1098–1105. doi: 10.1046/j.1365-2141.2002.03958.x
- Issue online: 11 DEC 2002
- Version of Record online: 11 DEC 2002
- Received 8 February 2002;accepted for publication 9 July 2002
- human erythroid cells;
- death receptor;
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.