Tenofovir disoproxil fumarate-mediated ?-globin induction is correlated with the suppression of trans-acting factors in CD34+ progenitor cells: A role in the reactivation of fetal hemoglobin

Sickle-cell disease (SCD) and beta-thalassemia are public health issues that affect people all over the world. Fetal hemoglobin (HbF) induction is a molecular intervention, including hydroxyurea, which has made an effort to improve current treatment. Tenofovir disoproxil fumarate (TDF) is formerly reported with improving levels of hemoglobin, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV). Hence, in this pre-clinical investigation, human peripheral whole blood-derived CD34(+) progenitor cells were cultured to prove the efficacy of TDF on erythroid proliferation, differentiation, gamma-globin gene expression regulation, and ultimately HbF production. We observed that TDF increased the proliferation of immature erythroid cells, delayed the terminal erythroid maturation without cytotoxicity as correlated with other HbF inducers. Here, the presented data show that TDF can induce HbF expression by up-regulating the gamma-globin gene transcription up to 7.1 +/- 0.46-fold and subsequently increased the F-cells (10.79 +/- 1.9-fold) population in terminally differentiated erythroid cells. Furthermore, our findings demonstrated that TDF-mediated gamma-globin gene induction and HbF production was associated with down-fold regulation of BCL11A and SOX6, and their corresponding trans-acting regulators, FOP, KLF1, and GATA1. Collectively, our findings suggest TDF as an effective inducer of HbF in CD34(+ )cells and pave the way to put forward the assessment of TDF as a new potential therapy in treating beta-hemoglobinopathies.

Automated summary

Sickle-cell disease and beta-thalassemia are global public health issues. This study demonstrates the effectiveness of Tenofovir disoproxil fumarate in promoting erythroid proliferation, differentiation, and HbF expression, providing a potential therapy for beta-hemoglobinopathies.