Fetal hemoglobin in sickle cell anemia

Abstract

Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.

Graphical abstract

Figure 1.

HbF distribution in sickle erythrocytes from 3 patients with 20% HbF. An example of 3 possible distributions of HbF/F-cell in 1000 cells from 3 individuals with mean HbF levels of 20%. The y axis represents numbers of cells, and the x axis represents HbF concentration in 5-pg increments. In red are cells likely to be least protected from HbS polymer damage. These cells have HbF < 6 pg and are not visible by FACS. In yellow are cells visible by FACS but not fully protected from HbS polymerization. They have HbF concentrations of 6 to 10 pg. In green, are cells with HbF concentrations >10 pg. These cells should be fully protected from HbS polymerization. Many other distributions are possible with the same mean HbF accounting for the varied phenotypes associated with the same HbF concentration. Data are derived from Steinberg et al.

Figure 2.

Genome editing to increase HbF production. Only HBG2 and its upstream binding sites for BCL11A and ZBTB7A are depicted. The expression of BCL11A, 1 of 2 major repressors of HbF gene expression, is controlled by an erythroid-specific enhancer. BCL11A binds to a TGACCA motif centered at position −115 in the promoters of both HBG2 and HBG1. ZBTB7A, the other major HbF gene repressor, not shown, binds at positions −195 to −197 and −201 to −202 upstream of both γ-globin genes. A still unknown transcription factor(s) is likely to bind the −158 site. The −158 polymorphism is found only in HBG2. CRISPR-Cas9 editing of either the BCL11A erythroid-specific enhancer, shown as a double-strand break, or its binding sites in the HbF gene promoters, shown before editing, reverses the repression of these genes increasing HbF.