Blessing in disguise; a case of Hereditary Persistence of Fetal Hemoglobin

Shaukat, Irfan; Pudal, Amrit; Yassin, Sayf; Höti, Naseruddin; Mustafa, Sadaf

doi:10.1080/20009666.2018.1536241

Cited by 6 publications

(4 citation statements)

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“…Yet another unsolved but potentially critical issue is the expression of fetal and/or embryonic hemoglobin and the control of its switching. Several studies, however, have reported that individuals with hereditary persistence of fetal hemoglobin are mostly asymptomatic and that the condition is primarily non-pathogenic [ 50 , 51 ], and that this problem could be possibly solved by the activation of the globin switching genes, such as KLF1 and BCL11a [ 52 , 53 ], and elongating the hematopoietic differentiation periods [ 48 ]. Further studies on scaling up and producing robust amounts of RBCs are also necessary and could possibly be achieved using a bioreactor or through monitoring the metabolite level and replenishing depleted cytokines on a regular basis [ 21 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

In vitro erythrocyte production using human-induced pluripotent stem cells: determining the best hematopoietic stem cell sources

et al. 2023

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Background Blood transfusion is an essential part of medicine. However, many countries have been facing a national blood crisis. To address this ongoing blood shortage issue, there have been efforts to generate red blood cells (RBCs) in vitro, especially from human-induced pluripotent stem cells (hiPSCs). However, the best source of hiPSCs for this purpose is yet to be determined. Methods In this study, hiPSCs were established from three different hematopoietic stem cell sources—peripheral blood (PB), cord blood (CB) and bone marrow (BM) aspirates (n = 3 for each source)—using episomal reprogramming vectors and differentiated into functional RBCs. Various time-course studies including immunofluorescence assay, quantitative real-time PCR, flow cytometry, karyotyping, morphological analysis, oxygen binding capacity analysis, and RNA sequencing were performed to examine and compare the characteristics of hiPSCs and hiPSC-differentiated erythroid cells. Results hiPSC lines were established from each of the three sources and were found to be pluripotent and have comparable characteristics. All hiPSCs differentiated into erythroid cells, but there were discrepancies in differentiation and maturation efficiencies: CB-derived hiPSCs matured into erythroid cells the fastest while PB-derived hiPSCs required a longer time for maturation but showed the highest degree of reproducibility. BM-derived hiPSCs gave rise to diverse types of cells and exhibited poor differentiation efficiency. Nonetheless, erythroid cells differentiated from all hiPSC lines mainly expressed fetal and/or embryonic hemoglobin, indicating that primitive erythropoiesis occurred. Their oxygen equilibrium curves were all left-shifted. Conclusions Collectively, both PB- and CB-derived hiPSCs were favorably reliable sources for the clinical production of RBCs in vitro, despite several challenges that need to be overcome. However, owing to the limited availability and the large amount of CB required to produce hiPSCs, and the results of this study, the advantages of using PB-derived hiPSCs for RBC production in vitro may outweigh those of using CB-derived hiPSCs. We believe that our findings will facilitate the selection of optimal hiPSC lines for RBC production in vitro in the near future.

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Section: Discussionmentioning

confidence: 99%

In vitro erythrocyte production using human-induced pluripotent stem cells: determining the best hematopoietic stem cell sources

et al. 2023

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“…26 Additional evidence for the disease-modifying properties of HbF are supported by the observation that patients with HbS who co-inherited a genetic variant producing hereditary persistence of fetal haemoglobin (HbS-HPFH) are relatively asymptomatic. 27,28 The presence of HbF in sickle RBCs delays deoxy-HbS polymerization. Several HPFH variants are produced by inherited deletions in binding sites for cis-acting factors in the HBB locus producing a decrease in HbA production.…”

Section: Fda-approved Treatments For Scdmentioning

confidence: 99%

“…In 1948, Dr. Janet Watson observed the delayed onset of clinical symptoms in early infancy due to higher HbF levels during the first year of life 26 . Additional evidence for the disease‐modifying properties of HbF are supported by the observation that patients with HbS who co‐inherited a genetic variant producing hereditary persistence of fetal haemoglobin (HbS‐HPFH) are relatively asymptomatic 27,28 . The presence of HbF in sickle RBCs delays deoxy‐HbS polymerization.…”

Section: Fda‐approved Treatments For Scdmentioning

confidence: 99%

Sickle cell disease: progress towards combination drug therapy

2021

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Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues characterized the A to T substitution in DNA producing the GAG to GTG codon and replacement of glutamic acid with valine in the sixth position of the b S -globin chain. The establishment of Comprehensive Sickle Cell Centers in the United States in the 1970s was an important milestone in the development of treatment strategies and describing the natural history of sickle cell disease (SCD) comprised of genotypes including homozygous haemoglobin SS (HbSS), HbSb 0 thalassaemia, HbSC and HbSb + thalassaemia, among others. Early drug studies demonstrating effective treatments of HbSS and HbSb 0 thalassaemia, stimulated clinical trials to develop disease-specific therapies to induce fetal haemoglobin due to its ability to block HbS polymerization. Subsequently, hydroxycarbamide proved efficacious in adults with SCA and was Food and Drug Administration (FDA)-approved in 1998. After two decades of hydroxycarbamide use for SCD, there continues to be limited clinical acceptance of this chemotherapy drug, providing the impetus for investigators and pharmaceutical companies to develop non-chemotherapy agents. Investigative efforts to determine the role of events downstream of deoxy-HbS polymerization, such as endothelial cell activation, cellular adhesion, chronic inflammation, intravascular haemolysis and nitric oxide scavenging, have expanded drug targets which reverse the pathophysiology of SCD. After two decades of slow progress in the field, since 2018 three new drugs were FDA-approved for SCA, but research efforts to develop treatments continue. Currently over 30 treatment intervention trials are in progress to investigate a wide range of agents acting by complementary mechanisms, providing the rationale for ushering in the age of effective and safe combination drug therapy for SCD. Parallel efforts to develop curative therapies using haematopoietic stem cell transplant and gene therapy provide individuals with SCD multiple treatment options. We will discuss progress made towards drug development and potential combination drug therapy for SCD with the standard of care hydroxycarbamide.

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“…Elevated fetal hemoglobin (HbF; α 2 γ 2 ) plays an important role in improving the clinical course and general well-being of patients with sickle cell anemia (SCA) or β-thalassemia. [1][2][3][4] Earlier studies revealed that even patients with the same genotype could have large heterogeneity in the degree of anemia. 5 A primary modifier for clinical heterogeneity among patients with SCA or β-thalassemia may be the individual differences in the HbF levels.…”

Section: Introductionmentioning

confidence: 99%

Association of polymorphisms in the HBG1‐HBD intergenic region with HbF levels

Huang

Han

et al. 2020

Clinical Laboratory Analysis

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Background: Increased levels of fetal hemoglobin (HbF) can improve the clinical course of the patients with sickle cell anemia (SCA) or β-thalassemia. The HBG1-HBD intergenic region plays an important role in this process. However, very few studies investigated whether the variations in this region have an effect on HbF expression. Methods:We retrieved all the SNP data in the HBG1-HBD intergenic region and defined the haplotype blocks, then performed cluster analysis and selected a tagSNP.A total of 500 normal individuals and 300 β-thalassemia carriers were enrolled. After routine blood and hemoglobin capillary electrophoresis testing, β-thalassemia mutations were detected using PCR-reverse dot blot. The genotypes of the rs4910736 (A > C) and rs10128556 (C > T) were determined using Sanger sequencing; the relationship between the two SNPs and the levels of HbF was analyzed.Results: Two haplotype blocks were constructed. Block 1 included seven haplotypes divided into two groups M and N by 11 tagSNPs, among which rs4910736 was selected as a tagSNP, while block 2 included three haplotypes. We found that the haplotypes of block 1 were statistically associated with HbF levels, but the non-tagSNP rs10128556 was shown to be more strongly associated with HbF levels than rs4910736. Conclusion:This work proved that the haplotypes in the HBG1-HBD intergenic region and SNP rs10128556 are both statistically associated with HbF levels, revealing the association of polymorphisms in the HBG1-HBD intergenic region with HbF levels.

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Blessing in disguise; a case of Hereditary Persistence of Fetal Hemoglobin

Cited by 6 publications

References 13 publications

In vitro erythrocyte production using human-induced pluripotent stem cells: determining the best hematopoietic stem cell sources

In vitro erythrocyte production using human-induced pluripotent stem cells: determining the best hematopoietic stem cell sources

Sickle cell disease: progress towards combination drug therapy

Association of polymorphisms in the HBG1‐HBD intergenic region with HbF levels

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