Hydroxyurea Differentially Modulates Activator and Repressors of γ-globin Gene in Erythroblasts of Responsive and Non-Responsive Patients with Sickle Cell Disease in Correlation with Index of Hydroxyurea Responsiveness
Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34+ cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD.
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The work was supported by P20MD003383 from National Institute on Minority Health and Health Disparities.
Zhu et al. Supplementary appendix provided by the authors.
Zhu, Xingguo; Hu, Tianxiang; Ho, Meng Hsuan; Wang, Yongchao; Yu, Miao; Patel, Niren; Pi, Wenhu; Choi, Jeong-Hyeon; Xu, Hongyan; Ganapathy, Vadivel; Kutlar, Ferdane; Kutlar, Abdullah; and Tuan, Dorothy, "Hydroxyurea Differentially Modulates Activator and Repressors of γ-globin Gene in Erythroblasts of Responsive and Non-Responsive Patients with Sickle Cell Disease in Correlation with Index of Hydroxyurea Responsiveness" (2017). Pharmacology and Nutritional Sciences Faculty Publications. 58.