Tenofovir disoproxil fumarate stimulates HbF production in K562 cells
and β-YAC transgenic mice: A therapeutic approach for γ-globin induction
Abstract
Pharmacologic induction of fetal hemoglobin (HbF) is an effective
strategy for treating β-hemoglobinopathies like β-thalassemia and sickle
cell anemia by ameliorating disease severity. Hydroxyurea is the only
FDA-approved agent that induces HbF, but significant non-responders and
requirement for frequent monitoring of blood counts for drug toxicity
limit clinical usefulness. Therefore, this study relates preclinical
investigation of Tenofovir disoproxil fumarate (TDF) as a potential HbF
inducing agent, using human erythroid cell line and a β-YAC mouse model.
Erythroid induction of K562 cells was studied by the benzidine/H2O2
reaction, total hemoglobin production was estimated by plasma hemoglobin
assay kit, and γ-globin gene expression by RT-qPCR, whereas, fetal
hemoglobin production was estimated by flow cytometry and
immunofluorescence microscopy. We observed significantly increased
γ-globin gene transcription and HbF expression mediated by TDF in K562
cells. Subsequent treatment of β-YAC transgenic mice with TDF confirmed
HbF induction in vivo through an increase in γ-globin gene expression
and in the percentage of HbF positive red blood cells. Moreover, TDF
showed no cytotoxic effect at HbF inducing concentrations. These data
support the potential development of TDF for the treatment of
hematological disorders, including β-thalassemia and sickle cell anemia.