Fetal hemoglobin induction pathway (HbF induction)

The fetal hemoglobin (HbF) induction pathway is a complex regulatory network responsible for the production of γ-globin, which combines with α-globin to form HbF (α2γ2). In humans, a developmental switch occurs shortly after birth where γ-globin expression is silenced and replaced by adult β-globin, a process primarily mediated by transcriptional repressors like BCL11A and ZBTB7A (Source: Sankaran et al., Science, 2008; Masuda et al., Science, 2016). In patients with β-hemoglobinopathies such as sickle cell disease and β-thalassemia, reactivating this pathway is a major therapeutic goal because HbF can functionally replace defective adult hemoglobin and inhibit the polymerization of sickle hemoglobin (Source: NIH, 2024). Pharmacological agents like hydroxyurea increase HbF levels through multiple mechanisms, including the alteration of erythroid kinetics and signaling (Source: Platt et al., NEJM, 1995). More recently, gene-editing therapies like exagamglogene autotemcel have been developed to disrupt the BCL11A erythroid-specific enhancer, providing a durable method for γ-globin reactivation (Source: FDA, 2023). Successful induction of HbF significantly improves clinical outcomes by reducing vaso-occlusive crises and the need for chronic blood transfusions.

Other names

Gamma-globin gene expressionHbF reactivationγ-globin induction pathwayHemoglobin F inductionHBG1/HBG2 induction

Reactivation of γ-globin gene expression by inhibiting transcriptional repressors such as BCL11A or ZBTB7A (LRF), or by modulating epigenetic states through HDAC or DNMT inhibition to favor the transition from adult to fetal hemoglobin production.