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

Abstract

Abstractβ-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 created human disease cellular model systems for β-thalassemia, which accurately recapitulate the phenotype of patient erythroid cells. We also developed a high throughput compatible fluorometric-based assay for evaluating severity of disease phenotype and utilised the assay to demonstrate positive response of lines to verified reagents, providing validation for such applications.TMT-based comparative proteomics confirmed the same profile of proteins previously reported, whilst providing new insights into the altered molecular mechanisms in β-thalassemia erythroid cells, with upregulation of a wide range of biological pathways and processes observed.Overall, the lines provide a sustainable supply of disease cells as novel research tools, for identifying new therapeutic targets, and as screening platforms for novel drugs and therapeutic reagents.