Genome-wide screening identifies lipid metabolism as a contributor to CAR-T resistance in TP53-mutant B-cell acute lymphoblastic leukemia, suggesting new therapeutic targets.
Key Points
This research aims to investigate how TP53 mutations affect CAR-T therapy resistance in B-cell acute lymphoblastic leukemia through lipid metabolism.
Used isogenic CD19⁺ B-ALL cell lines with varying TP53 mutation statuses.
Performed genome-wide CRISPR/Cas9 screening to identify factors contributing to CAR-T resistance.
Assessed effects of the lipase inhibitor and a mitochondrial transport inhibitor on CAR-T sensitivity in different cell lines.
Identified TP53 mutations as promoting CAR-T resistance.
Findings showed that FATP2 enhances CAR-T resistance through increased lipid uptake.
TP53-mutant B-ALL cells exhibited increased levels of fatty acids and metabolites compared to CAR-sensitive cells.