Low FDX1 helps leukemia cells resist copper-induced death, and blocking ME1 may restore it
Leukemia cells with low FDX1 resist copper-driven cell death. Blocking the metabolic enzyme ME1 restored sensitivity to the copper ionophore elesclomol in lab models.
Summary
Acute myeloid leukemia (AML) is an aggressive blood cancer with poor survival after relapse. Researchers found higher serum copper in AML patients than in healthy controls, with higher copper associated with worse survival. FDX1, a mitochondrial protein, was reduced in AML, and lower expression was associated with poorer outcomes. Increasing FDX1 suppressed leukemia-cell growth and enhanced sensitivity to cuproptosis, a copper-dependent form of cell death. In mice, leukemia cells overexpressing FDX1 produced lower disease burden and longer survival. The reported mechanism involves mitochondrial damage and ROS/p53 signaling, which represses the metabolic enzyme ME1. ME1 inhibition restored cuproptosis sensitivity in FDX1-low cells, suggesting a possible combination with copper ionophores. The evidence combines observational patient data with preclinical experiments; therapeutic benefit in patients has not been established.
Detailed Summary
Acute myeloid leukemia (AML) remains difficult to treat. The source cites approximately 10% five-year overall survival for relapsed or refractory disease. Elevated serum copper has been associated with poor outcomes, motivating investigation of cuproptosis, a copper-dependent cell-death mechanism, as a potential therapeutic vulnerability.
Serum copper was higher in 126 AML patients than in 76 healthy controls. Among patients with survival information, the high-copper group (55 patients) had worse overall survival than the low-copper group (39 patients). Screening seven cuproptosis-related genes in peripheral blood mononuclear cells from 55 AML patients and 40 controls identified FDX1 as the most significantly downregulated. Bone marrow staining in 11 AML and 10 normal samples also showed reduced FDX1 protein. Public-dataset analyses linked lower FDX1 expression to poorer survival. Neither serum copper category nor FDX1 expression status was significantly associated with FAB subtype distribution in the clinical cohort.
In THP1 and MOLM13 leukemia cells, FDX1 overexpression reduced viability, decreased the proportion of S-phase cells and increased the G0/G1 fraction; knockdown produced the opposite effects. In NSG mice receiving FDX1-overexpressing MOLM13 cells, leukemia burden was lower and survival longer. Bone marrow, liver and spleen infiltration were reduced, with less splenomegaly and anemia. The reported mouse experiments used five animals per group.
In cell experiments, FDX1 overexpression enhanced sensitivity to elesclomol plus copper, whereas knockdown reduced it. Elesclomol-copper-induced death was rescued by the copper chelator TTM, but not by the ferroptosis inhibitor Fer-1 or the apoptosis inhibitors Z-VAD-FMK and BOC-D-FMK. These results support predominantly copper-dependent cuproptosis under the tested conditions.
The abstract and introduction report that FDX1 promotes mitochondrial damage and reactive oxygen species accumulation, activating p53, which transcriptionally represses ME1. ME1 was highly expressed in AML and supported leukemia-cell growth. ME1 inhibition restored cuproptosis sensitivity in FDX1-low cells and enhanced elesclomol efficacy. The introduction attributes sensitization to disrupted mitochondrial NAD+/NADH homeostasis and impaired delipoylation of lipoylated DLAT. The supplied excerpt does not establish the direction of the NAD+/NADH change or provide the detailed assays underlying these mechanistic conclusions.
The authors propose combining copper ionophores with ME1 inhibitors as a potential AML strategy. The evidence includes observational patient associations and preclinical experiments, not demonstrated treatment benefit in patients. Limitations of the available evidence include two described cell lines, engineered FDX1 expression in immunodeficient mouse xenografts and small mouse groups. Because the supplied text ends partway through the results, later experimental details and any in vivo ME1-inhibitor combination testing cannot be assessed.
Key Findings
- Serum copper was higher in 126 AML patients than in 76 healthy controls; among patients with survival data, high copper (n=55) was associated with worse overall survival than low copper (n=39).
- FDX1 was the most significantly downregulated of seven screened cuproptosis-related genes in AML blood cells (55 AML patients versus 40 controls), with reduced protein in bone marrow (11 AML versus 10 normal samples) and poorer survival associated with lower expression.
- FDX1 overexpression suppressed AML-cell viability, increased the G0/G1 fraction and decreased the S-phase fraction; in NSG mice it lowered leukemia burden, prolonged survival and reduced splenomegaly and anemia.
- FDX1 overexpression increased AML-cell sensitivity to elesclomol plus copper, whereas FDX1 knockdown reduced sensitivity.
- Elesclomol-copper-induced cell death was rescued by TTM but not by Fer-1, Z-VAD-FMK or BOC-D-FMK, supporting predominantly copper-dependent cuproptosis under the tested conditions.
- The reported mechanism links FDX1-induced mitochondrial damage and ROS accumulation to p53 activation and transcriptional repression of ME1.
- ME1 supported AML-cell growth, while its inhibition restored cuproptosis sensitivity in FDX1-low cells and enhanced elesclomol efficacy; the introduction links this effect to disrupted mitochondrial NAD+/NADH homeostasis and impaired DLAT delipoylation.
Methodology
The supplied excerpt describes serum copper measurements in 126 AML patients and 76 controls; PBMC gene-expression screening in 55 AML patients and 40 controls; and bone marrow immunohistochemistry in 11 AML and 10 normal samples. Public datasets included XENA, GEPIA and CCLE/DepMap. FDX1 knockdown and overexpression were studied in THP1 and MOLM13 cells using RT-qPCR, western blots, CCK-8 viability assays and flow-cytometric cell-cycle analysis. Cell-death inhibitor experiments used TTM, Fer-1, Z-VAD-FMK and BOC-D-FMK. Luciferase-expressing MOLM13 cells were injected into NSG mice, with bioluminescence imaging, survival analysis, tissue assessment, spleen weights and hemoglobin measurements. Figure 2 reports three independent experiments or five mice per group. Statistical methods included t tests, Mann-Whitney U tests, ANOVA and log-rank tests. Detailed methods for the ROS/p53/ME1 and NAD+/NADH findings are not included in the supplied excerpt.
Study Limitations
The described functional experiments use two AML cell lines and xenografts in immunodeficient mice, with five mice per group. The available mouse results involve engineered FDX1 overexpression. Because the supplied text is truncated during the results, it is not possible to determine whether later experiments tested an ME1-inhibitor combination in vivo. Patient data are observational and cannot establish that copper or FDX1 causes differences in outcomes; the survival comparison includes 94 patients with available follow-up. Detailed methods and results for several mechanistic claims are unavailable in the excerpt. Conflict-of-interest information was not supplied.
Enjoyed this summary?
Get the latest longevity research delivered to your inbox every week.
Enter your email to subscribe: