The molecular mechanism of fetal hemoglobin reactivation.

Increased levels of fetal hemoglobin (HbF) are clinically beneficial in patients with sickle cell disease. Hydroxurea fails to increase HbF in at least 25% of patients, and therefore, better drugs are needed. Recent clinical studies have shown that the DNA methyltransferase (DNMT) inhibitor decitabine effectively increased HbF in hydroxyurea-refractory patients. The rational use of DNMT inhibitors as therapeutic agents to reactivate HbF expression in patients with sickle cell disease is based on nearly 25 years of experimental evidence, reviewed in this article, that supports a fundamental role of DNA methylation in the silencing of gamma-globin gene expression in adults.