Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype.

Autor: Daniels DE; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Ferrer-Vicens I; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Hawksworth J; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Andrienko TN; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Finnie EM; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Bretherton NS; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Ferguson DCJ; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Oliveira ASF; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Szeto JA; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Wilson MC; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Brewin JN; Haematology Department, King's college Hospital NHS Foundation, London, SE5 9RS, UK.; Red Cell Biology Group, Kings College London, London, SE5 9NU, UK., Frayne J; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK. Jan.Frayne@Bristol.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Oct 06; Vol. 14 (1), pp. 6260. Date of Electronic Publication: 2023 Oct 06.
DOI: 10.1038/s41467-023-41961-9
Abstrakt: β-thalassemia is a prevalent genetic disorder causing severe anemia due to defective erythropoiesis, with few treatment options. Studying the underlying molecular defects is impeded by paucity of suitable patient material. In this study we create human disease cellular model systems for β-thalassemia by gene editing the erythroid line BEL-A, which accurately recapitulate the phenotype of patient erythroid cells. We also develop a high throughput compatible fluorometric-based assay for evaluating severity of disease phenotype and utilize the assay to demonstrate that the lines respond appropriately to verified reagents. We next use the lines to perform extensive analysis of the altered molecular mechanisms in β-thalassemia erythroid cells, revealing upregulation of a wide range of biological pathways and processes along with potential novel targets for therapeutic investigation. Overall, the lines provide a sustainable supply of disease cells as research tools for identifying therapeutic targets and as screening platforms for new drugs and reagents.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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