The switch from fetal to adult hemoglobin

Abstract

The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and β-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and β-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.

Figures

Figure 1.

The fetal-to-adult hemoglobin switch. This illustration depicts the normal timing of the developmental hemoglobin switches in humans. In the top panel, the sites and levels of various β-like globin molecules are shown with colors corresponding to the various developmental groups of genes shown below it in a model of the human β-globin locus (embryonic in blue, fetal in green, and adult in red). The bottom illustration also depicts the upstream enhancer of the β-globin locus, known as the locus control region (LCR), with its corresponding DNAse I hypersensitivity sites (HSs) and a downstream HS known as the 3′HS1.

Figure 2.

A model for regulation of γ-globin silencing in the human β-globin locus. This illustration depicts the human β-globin locus as shown in Figure 1 with an ∼3-kb region upstream of the δ-globin gene that was found by comparing the regions removed in various hereditary persistence of fetal hemoglobin (HPFH) deletions with the regions removed by δβ-thalassemia deletions (Sankaran et al. 2011c). Typical deletions are illustrated in the model below the locus. In addition, the Corfu thalassemia deletion is also known to remove this region, as shown by the model below. BCL11A has been shown to bind to chromatin within this 3-kb region, along with its partners GATA1 and HDAC1 (Sankaran et al. 2011c).