Pharmacologic induction of fetal hemoglobin synthesis: cellular and molecular mechanisms.

The switch from embryonic to fetal then to adult hemoglobin synthesis is a unique phenomenon during early human development. Fetal hemoglobin (Hb F) is known to interfere with polymerization of Hb S in erythrocytes. Several pharmacologic agents such as 5-azacytidine, myleran, hydroxyurea, erthropoietin, and butyrates enhance fetal hemoglobin production and have been used in hemoglobinopathy patients to ameliorate severe pain episodes and reduce severe anemia. Among these, hydroxyurea is the agent of choice because of its safety and ease of administration. One of the primary cellular mechanisms involved in pharmacologic induction of Hb F synthesis is rapid regeneration of erythroid precursors following the cytoreduction phase of certain pharmacologic agents. Molecular mechanisms involving changes in chromatin structure and/or transcription factor binding have been demonstrated for gamma gene induction by butyrate. Identifying the proteins involved in gamma gene activation by various compounds may offer a new strategy for gene therapy to cure hemoglobinopathy disorders.