Control of fetal globin expression in man: new opportunities to challenge past discoveries

Decades-old findings supporting origin of F cells in adult life from adult-type progenitors and the in vitro and in vivo enhancement of fetal globin under stress conditions have been juxtaposed against recent mechanistic underpinnings. An updated molecular interrogation did not debunk prior conclusions on the origin of F cells. Although fetal globin reactivation by widely diverse approaches in vitro and in response to anemic stresses in vivo is a work in progress, accumulating evidence converges toward an integrated stress response pathway. The newly uncovered developmental regulators of globin gene switching not only have provided answers to the long-awaited quest of transregulation of switching, they are also reaching a clinical threshold. Although the effect of fetal globin silencers has been robustly validated in adult cells, the response of cells at earlier developmental stages has been unclear and inadequately studied.