Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders

Abstract

The level of fetal hemoglobin (HbF) modifies the severity of the common β-globin disorders. Knowledge of the normal mechanisms that repress HbF in the adult stage has remained limited until recently despite nearly 3 decades of molecular investigation, in part because of imperfect model systems. Recent studies have provided new insights into the developmental regulation of globin genes and identified specific transcription factors and epigenetic regulators responsible for physiologic silencing of HbF. Most prominent among these regulators is BCL11A, a transcriptional repressor that inhibits adult-stage HbF expression. KLF1 and c-Myb are additional critical HbF-regulating erythroid transcription factors more broadly involved in erythroid gene expression programs. Chromatin modifiers, including histone deacetylases and DNA methyltransferases, also play key roles in orchestrating appropriate globin gene expression. Taken together, these discoveries present novel therapeutic targets for further consideration. Although substantial hurdles remain, opportunities are now rich for the rational design of HbF inducers.

Figure 1

The β-globin genes are encoded from a single cluster and under strict developmental control. There are 2 developmental switches in expression from the cluster, from embryonic-to-fetal during the first trimester of conception, and from fetal-to-adult around the time of birth.

Figure 2

Genome-wide association studies have revealed 3 loci consistently associated with HbF level and β-globin disorder severity, across various ethnic backgrounds. These include the β-globin cluster itself on chromosome 11, the HBS1L-MYB intergenic interval on chromosome 6, and BCL11A on chromosome 2. A representative Manhattan plot is shown from the CSSCD cohort. Figure courtesy of Guillaume Lettre (Montreal Heart Institute).

Figure 3

The BCL11A network as a schematic target for various potential therapeutic modalities. BCL11A is shown occupying sequences within the β-globin cluster distal from the γ-globin genes themselves. It is subject to transcriptional activation by KLF1, which itself may be a target of c-Myb. BCL11A interacts with the NuRD nucleosome remodeling and deacetylase complex, which includes the ATPases CHD3/4 and histone deacetylases HDAC1/2 as well as MBD2. BCL11A also interacts with erythroid transcription factors including GATA1, FOG1, and SOX6. BCL11A could conceptually be therapeutically targeted by various strategies including: (1) decreasing its steady-state level, such as by preventing its activation by KLF1, or by RNA interference; (2) interfering with protein–protein interactions such as between BCL11A and GATA1; (3) interfering directly with BCL11A's protein–DNA interactions; (4) allosteric inhibitors of BCL11A itself or various partners; (5) active-site inhibitors of partner proteins with enzymatic activity such as HDAC1/2 and CHD3/4; (6) blocking associated chromatin reader modules, such as PHD fingers and chromodomains on CHD3/4 and MBD domain on MBD2; (7) direct genome editing, such as of critical BCL11A binding regulatory elements; and (8) as part of combination therapy with additional targets such as low-dose demethylase therapy.