GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells
Abstract Chronic myeloid leukemia (CML) harboring BCR/ABL-T315I mutation has been a challenging obstacle for targeted therapy due to the acquired resistance to tyrosine kinase inhibitor (TKI)-based therapy. Thus, it is especially urgent to investigate more effective therapeutic targets to overcome T...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-05-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02502-z |
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| Summary: | Abstract Chronic myeloid leukemia (CML) harboring BCR/ABL-T315I mutation has been a challenging obstacle for targeted therapy due to the acquired resistance to tyrosine kinase inhibitor (TKI)-based therapy. Thus, it is especially urgent to investigate more effective therapeutic targets to overcome T315I-induced resistance. Here, we reported that BCR/ABL-T315I mutant CML cells possessed a long-term proliferative capacity and tolerance to metabolic stress. Importantly, we also found that selenoamino acid metabolism was increased in the bone marrows of BCR/ABL-T315I patients compared with non-T315I patients by GSEA from RNA-Seq data. Indeed, GPX1 was highly expressed in T315I mutant cells, while knockout of GPX1 significantly suppressed cell proliferation and triggered apoptosis under glucose-deprived condition. GPX1 knockout showed decreased cell metabolism signaling as well as mitochondrial gene expression by RNA-Seq. Mechanistically, GPX1 maintained mitochondrial activity and oxygen consumption rate (OCR), retaining mitochondrial redox homeostasis and oxidative phosphorylation (OXPHOS). Additionally, mercaptosuccinic acid (MSA), a GPX inhibitor, inhibited CML colony formation and induced cell apoptosis under glucose-free condition. Therefore, GPX1 is a promising therapeutic target to overcome drug resistance induced by the T315I mutation, which provides a novel approach for BCR/ABL-T315I CML treatment by disturbing mitochondrial OXPHOS. |
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| ISSN: | 2058-7716 |