Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

Abstract

Fetal hemoglobin (HbF) usually consists of 4 to 10% of total hemoglobin in adults of African descent with sickle cell anemia. Rarely, their HbF levels reach more than 30%. High HbF levels are sometimes a result of β-globin gene deletions or point mutations in the promoters of the HbF genes. Collectively, the phenotype caused by these mutations is called hereditary persistence of fetal hemoglobin, or HPFH. The pancellularity of HbF associated with these mutations inhibits sickle hemoglobin polymerization in most sickle erythrocytes so that these patients usually have inconsequential hemolysis and few, if any, vasoocclusive complications. Unusually high HbF can also be associated with variants of the major repressors of the HbF genes, BCL11A and MYB. Perhaps most often, we lack an explanation for very high HbF levels in sickle cell anemia.

Delta‐globin gene expression improves sickle cell disease in a humanised mouse model

“…The average level of HbF considered to completely inhibit sickling is 30% (10 pg for cell), 16 and 20% is considered a satisfactory therapeutic level sufficient to prevent occlusive vessel crises and a clinical meaningful end point in children under hydroxyurea treatment 32,33 . In our present mice, the HbA2 expression level was under the 20% threshold.…”

“…Gene addition therapy has produced encouraging results, 13 but remains a largely experimental approach that is difficult to apply in developing countries, where the disease is more frequent. HbF reactivation has long been sought as an approach to mitigate the clinical symptoms of beta‐thalassemia and SCD 14‐16 . Despite decades of research, only hydroxyurea is currently used in the clinic as a pharmacological agent capable of increasing HbF production 17 .…”

Genetic polymorphisms and protein levels in vocal fold leukoplakia: a systematic review

“…The rs11886868 C/T BCL11A and rs4671393 A/G BCL11A SNP are in intron 2 of the BCL11A gene and are associated with BCL11A production ( 38 ). This protein has been related to many diseases such as type II diabetes, intellectual disability, β-hemoglobinopathies, cancer, and hematological malignancies, but the mechanisms by which BCL11A is connected to these diseases are not yet completely understood ( 39 ).…”

“…This protein has been related to many diseases such as type II diabetes, intellectual disability, β-hemoglobinopathies, cancer, and hematological malignancies, but the mechanisms by which BCL11A is connected to these diseases are not yet completely understood ( 39 ). BCL11A is a reducer of fetal hemoglobin gene expression ( 38 ) and it remains active in adulthood ( 40 ). Individuals with the AG or GG genotypes of the rs4671393 A/G BCL11A SNP are more likely to have a high concentration of BCL11A ( 6 ), which leads to a low level of fetal hemoglobin ( 38 ), and consequently anemia.…”

HbA2 induction: the merit of pancellularity in sickle cell disease

“…Inducing HbF levels of ~40% by CRISPR/Cas‐9 disruption of the BCL11A erythroid enhancer has ‘cured’ sickle cell anaemia and β‐thalassaemia — at least in the short term 14 . High HbF levels might not always be sufficient; 15 a better approach would be to correct the HbS mutation. Accomplishing this by homology‐directed repair was inefficient but an enhanced approach with high efficiency is entering clinical trials (http://ClinicalTrials.gov Identifier: NCT04774536); base‐editing the HbS mutation is also a possibility 16 .…”