Genetic modifications of EGLN1 reactivate HbF production in β<sup>0</sup>-thalassemia/HbE
Issued Date
2024-09-30
Resource Type
eISSN
24058440
Scopus ID
2-s2.0-85204383735
Journal Title
Heliyon
Volume
10
Issue
18
Rights Holder(s)
SCOPUS
Bibliographic Citation
Heliyon Vol.10 No.18 (2024)
Suggested Citation
Jan-ngam V., Boontha S., Tubsuwan A., Wongpalee S.P., Fanhchaksai K., Tantiworawit A., Charoenkwan P., Khamphikham P. Genetic modifications of EGLN1 reactivate HbF production in β<sup>0</sup>-thalassemia/HbE. Heliyon Vol.10 No.18 (2024). doi:10.1016/j.heliyon.2024.e38020 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/101374
Title
Genetic modifications of EGLN1 reactivate HbF production in β<sup>0</sup>-thalassemia/HbE
Corresponding Author(s)
Other Contributor(s)
Abstract
Reactivation of fetal hemoglobin (HbF, α2γ2) potentially alleviates clinical presentation in β-thalassemia. Prolyl hydroxylase domain enzymes (PHDs) play roles in the canonical oxygen-sensing pathway and maintain the stability of cellular hypoxia-inducible factor α (HIF-α) in response to low oxygen levels or hypoxia. Pharmacological inhibition of PHDs has been shown to increase HbF production in erythroid progenitors derived from healthy donors. Here, we demonstrated the relationship between PHD2, the main PHD isoform, and clinical phenotypes in β0-thalassemia/HbE disease. Although the targeted sequencing annotated several common variants within EGLN1, the gene encoding PHD2, none of these variants were located in the functional domains of PHD2 and were irrelevant to the clinical phenotypes. CRISPR-mediated EGLN1 modifications at the functional regions; however, led to significantly reduce PHD2 expression and increase HbF expression levels in severe β-thalassemia erythroblasts. Moreover, these beneficial phenotypes were independent to the two well-known HbF regulators including BCL11A and GATA1. Our findings introduce an additional mechanism for HbF regulation in β-thalassemia and propose that targeting the canonical oxygen-sensing pathway, particularly PHD2 functional domains, might offer a promising therapeutic strategy to β-thalassemia diseases.