GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells

Chronic myeloid leukemia that carries the BCR/ABL-T315I mutation presents a significant hurdle in the realm of targeted therapy because the mutation leads to resistance against treatments based on tyrosine kinase inhibitors. Consequently, there is a pressing need to explore and identify more effective therapeutic targets that can circumvent this T315I-induced resistance.

In this study, we observed that CML cells with the BCR/ABL-T315I mutation exhibited a sustained ability to proliferate over extended periods and demonstrated a tolerance to conditions of metabolic stress. Notably, our analysis of RNA sequencing data through Gene Set Enrichment Analysis revealed an increase in selenoamino acid metabolism within the bone marrow samples obtained from patients with the BCR/ABL-T315I mutation when compared to patients without this specific mutation. Consistent with this observation, we found that the expression of glutathione peroxidase 1 (GPX1) was markedly elevated in cells harboring the T315I mutation.

Furthermore, when we genetically knocked out GPX1, we observed a significant suppression of cell proliferation and an induction of programmed cell death, particularly under conditions where glucose was scarce. Gene expression profiling through RNA sequencing following GPX1 knockout indicated a reduction in cell metabolism signaling pathways as well as the expression of mitochondrial genes. Mechanistically, we determined that GPX1 plays a crucial role in maintaining mitochondrial activity and the oxygen consumption rate, DX3-213B thereby preserving mitochondrial redox homeostasis and oxidative phosphorylation.

Additionally, we found that mercaptosuccinic acid, an inhibitor of GPX1, effectively inhibited the formation of CML colonies and induced cell apoptosis when glucose was absent. Taken together, these findings suggest that GPX1 represents a promising therapeutic target for overcoming drug resistance caused by the T315I mutation. This research offers a novel strategy for the treatment of BCR/ABL-T315I positive CML by disrupting mitochondrial oxidative phosphorylation.