https://orcid.org/0000-0003-1021-0549
Key Points
IFN-γ and IFN-β enhance δ-globin expression in erythroid cells, suggesting an approach to treating β-hemoglobinopathies.
Inhibition of JAK/STAT signaling reduces both basal and IFN-γ–mediated δ-globin expression.
Sickle cell disease (SCD) and β-thalassemia, caused by mutations or deletions in the β-globin gene, are among the most prevalent genetic disorders worldwide, significantly impacting global health and mortality. Recently, reactivation of δ-globin gene expression has been proposed as a potential therapeutic strategy for these conditions. In this study, we found that IFN-γ and IFN-β significantly enhance δ-globin expression and activate the JAK/STAT signaling pathway in erythroid cells, with IFN-γ exerting a stronger effect than IFN-β. In erythroid cells derived from CD34⁺ progenitors, IFN-γ not only increased δ-globin expression but also promoted differentiation, as confirmed by quantitative PCR, Western blotting, high-performance liquid chromatography, and flow cytometry. Inhibition of the JAK/STAT pathway, either through a JAK1/2 inhibitor (AZD1840 or ruxolitinib) or via siRNAs targeting JAK1, JAK2, STAT1, and STAT3, significantly decreased both basal and IFN-γ-induced δ-globin expression in HBD-HiBiT knock-in HUDEP2 cells. Mutation or removal of the putative IRF-1/STAT2 binding site (-265 to -242) and the adjacent STAT binding site (-243 to -231) in the δ-globin promoter impaired IFN-γ-induced δ-promoter activity. ChIP assays confirmed enhanced binding of IRF-1 and STAT1 upon IFN-γ treatment. Our elucidation of the mechanism by which a specific molecule induces δ-globin expression suggests that IFN-γ may hold therapeutic potential for patients with SCD, and that screening for compounds that can induce δ-globin could offer a novel pharmaceutical strategy for treating β-hemoglobinopathies.
