The normal developmental transition from the synthesis of fetal hemoglobin (HbF; α2γ2) to adult hemoglobin (HbA; α2β2), called hemoglobin switching, begins several weeks before birth and is largely complete by six months of age. In normal adults, HbF accounts for less than 1 percent of total hemoglobin. HbF is not uniformly distributed among all erythrocytes; it is restricted to a small population called F-cells. Some healthy adults have persistently elevated levels of HbF that are of no consequence. This variation in HbF production is genetically determined.1 Large deletions of the β-globin gene cluster are one extreme cause of this variation. These Mendelian forms of hereditary persistence of fetal hemoglobin (HPFH) with pancellular distribution of HbF are uncommon and do not explain the common, heterocellular variation in HbF that is inherited as a quantitative genetic trait. Several HbF quantitative trait loci are known, including polymorphisms in the regulatory region of HBG2 (the Gγ-globin gene), the HBS1L-MYB intergenic region, and intron 2 of BCL11A. For example, polymorphisms of BCL11A account for 7 to 12 percent of the variance in HbF in sickle cell anemia.2,3 Because persistently high levels of HbF can ameliorate the course of sickle cell anemia and β-thalassemia, the therapeutic potential of HbF induction has been recognized for decades.
BCL11A is a transcription factor that is highly expressed in the brain, B lymphocytes, and the adult erythroid lineage. It is an important “silencer” of γ-globin gene expression. Successful preclinical efforts have already been undertaken to induce HbF production by inhibition of BCL11A. All the functions of BCL11A are not known, however, and the effects of BCL11A inhibition in humans remain to be understood. Two related manuscripts begin to address this important issue. Dr. Anindita Basak and colleagues report three patients with microdeletions of 2p15-p16.1 causing haploinsufficiency of BCL11A. These patients had an autism spectrum disorder with developmental delay, dysmorphic facies, and some age-related neurologic decline. All had significant elevation of HbF (15%-30%) but otherwise apparently normal hematologic and immunologic function. Additional studies, including analysis of human brain RNA sequencing data sets, strongly implicated BCL11A as a candidate gene for disorders of human neurodevelopment. Dr. Alister Funnell and colleagues described an additional three patients with similar microdeletions. These patients also had neurodevelopmental abnormalities and persistent elevation of HbF (5%-7%). All had an approximately twofold reduction of BCL11A transcripts, consistent with monoallelic expression, but one patient had intact BCL11A genes. This individual had a deletion downstream of BCL11A that reduced its expression. Inspection of this region identified novel erythroid-specific regulatory elements. Dr. Funnell and colleagues speculate that these elements may be required for normal erythroid BCL11A expression, while the loss of separate elements in the developing brain could explain the neurological phenotype of BCL11A insufficiency.
In Brief
In summary, these two reports indicate that haploinsufficiency of BCL11A in humans, whether by deletion of the gene itself or its regulatory sequences, results in persistent expression of HbF throughout life. Some of these patients with microdeletions affecting BCL11A have levels of HbF that would be high enough to ameliorate the severity of sickle cell anemia and β-thalassemia. These reports do not indicate whether HbF was distributed in a heterocellular or pancellular pattern, the latter being ideal for such disease-modifying therapies.4 These human data support ongoing efforts to develop targeted, HbF-inducing therapy for patients with β-hemoglobinopathies by inhibition of BCL11A.5 However, the role of BCL11A in human neurodevelopment raises significant concerns about the safety of this approach. Therapeutic manipulation of BCL11A will need to be specifically targeted to the erythroid lineage to avoid “off-target” effects in the brain.
References
Competing Interests
Dr. Quinn indicated no relevant conflicts of interest.
