Acyclovir induces fetal hemoglobin via downregulation of γ-globin repressors, BCL11A and SOX6 trans-acting factors

Pharmacological reactivation of developmentally silenced fetal hemoglobin (HbF) is an attractive approach to ameliorate the clinical manifestations of beta-thalassemia and sickle cell anemia. Hydroxyurea, the only HbF inducer, has obtained regulatory approval. However, hydroxyurea non-responders and associated myelosuppression making its widespread use undesirable. A high level of HbF with safe and effective agents remains an elusive therapeutic goal for this global health burden. This study demonstrated the effect of acyclovir on gamma-globin expression and erythropoiesis, associated with increased HbF production. In vitro, human erythroleukemia cells and human CD34(+) erythroid progenitors, and in vivo beta-YAC transgenic mice were used as experimental models. We found that acyclovir significantly induces expression of the gamma-globin gene and HbF synthesis in CD34(+) erythroid progenitors, without affecting terminal erythroid differentiation and erythroid cell proliferation. In contrast to other HbF inducers, no associated cytotoxicity with acyclovir was observed. Further, we reported the effect of acyclovir on gamma-globin gene transcriptional regulators including BCL11A, FOP1, KLF1 SOX6, and GATA-1. Significant downregulation of the gamma-globin repressors BCL11A and SOX6 was observed at both mRNA and protein levels. Whereas, GATA-1, a master erythroid transcription factor, was upregulated in acyclovir treated human CD34(+) erythroid culture. Similarly, the HbF inducing effect of acyclovir in beta-YAC transgenic mice revealed a good in vitro correlation, with a substantial increase in fetal globin mRNA, and F cells population. These findings collectively suggest acyclovir as an effective HbF inducer and pave the way to evaluate its clinical efficacy in treating beta-globin disorders.

Automated summary

The study demonstrated that acyclovir induces the expression of the gamma-globin gene and HbF synthesis, without affecting terminal erythroid differentiation and proliferation. It also downregulated gamma-globin repressors BCL11A and SOX6, while upregulating the master erythroid transcription factor GATA-1, suggesting its potential as an effective HbF inducer for treating beta-globin disorders.