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PubMed2026

Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia.

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the antileukemic efficacy of the FLT3 inhibitor gilteritinib was markedly reduced by dietary vitamin E, which attenuated ferroptosis. This study highlights ferroptosis as a vulnerability in FLT3-mutant acute myeloid leukaemia and suggests that high vitamin E intake may compromise tyrosine kinase inhibitor efficacy partly by suppressing ferroptosis.

Ferroptosis↗

PubMed2016

Malonate as a ROS product is associated with pyruvate carboxylase activity in acute myeloid leukaemia cells.

BACKGROUND: The role of anaplerotic nutrient entry into the Krebs cycle via pyruvate carboxylase has been the subject of increased scrutiny and in particular whether this is dysregulated in cancer. Here, we use a tracer-based NMR analysis involving high-resolution (1)H-(13)C-HSQC spectra to assess site-specific label incorporation into a range of metabolite pools, including malate, aspartate and glutamate in the acute myeloid leukaemia cell line K562. We also determine how this is affected following treatment with the redeployed drug combination of the lipid-regulating drug bezafibrate and medroxyprogesterone (BaP). RESULTS: Using the tracer-based approach, we assessed the contribution of pyruvate carboxylase (PC) vs. pyruvate dehydrogenase (PDH) activity in the derivation of Krebs cycle intermediates. Our data show that PC activity is indeed high in K562 cells. We also demonstrate a branched entry to the Krebs cycle of K562 cells with one branch running counterclockwise using PC-derived oxaloacetate and the other clockwise from the PDH activity. Finally, we show that the PC activity of K562 cells exclusively fuels the ROS-induced decarboxylation of oxaloacetate to malonate in response to BaP treatment; resulting in further Krebs cycle disruption via depletion of oxaloacetate and malonate-mediated inhibition of succinate dehydrogenase (SDH) resulting in a twofold reduction of fumarate. CONCLUSIONS: This study extends the interest in the PC activity in solid cancers to include leukaemias and further demonstrates the value of tracer-based NMR approaches in generating a more accurate picture of the flow of carbons and metabolites within the increasingly inappropriately named Krebs cycle. Moreover, our studies indicate that the PC activity in cancer cells can be exploited as an Achilles heel by using treatments, such as BaP, that elevate ROS production.

AML↗

PubMed2016

Tracer-Based Metabolic NMR-Based Flux Analysis in a Leukaemia Cell Line.

High levels of reactive oxygen species (ROS) have a profound impact on acute myeloid leukaemia cells and can be used to specifically target these cells with novel therapies. We have previously shown how the combination of two redeployed drugs, the contraceptive steroid medroxyprogesterone and the lipid-regulating drug bezafibrate exert anti-leukaemic effects by producing ROS. Here we report a 13C-tracer-based NMR metabolic study to understand how these drugs work in K562 leukaemia cells. Our study shows that [1,2-13C]glucose is incorporated into ribose sugars, indicating activity in oxidative and non-oxidative pentose phosphate pathways alongside lactate production. There is little label incorporation into the tricarboxylic acid cycle from glucose, but much greater incorporation arises from the use of [3-13C]glutamine. The combined medroxyprogesterone and bezafibrate treatment decreases label incorporation from both glucose and glutamine into α-ketoglutarate and increased that for succinate, which is consistent with ROS-mediated conversion of α-ketoglutarate to succinate. Most interestingly, this combined treatment drastically reduced the production of several pyrimidine synthesis intermediates.

NMR spectroscopy↗

PubMed2026

Predicting bloodstream infection by plasma cell-free metagenomic sequencing: a prospective cohort study.

BACKGROUND: Patients receiving myelosuppressive chemotherapy or haematopoietic cell transplantation are at high risk for life-threatening bloodstream infections. A novel pre-emptive treatment paradigm guided by pathogen detection before symptoms appear might reduce this risk, but no validated screening test is available. This study evaluated the sensitivity and specificity of plasma microbial cell-free DNA metagenomic sequencing (mcfDNA-Seq) for predicting bloodstream infections in children and adolescents receiving therapy for high-risk leukaemia. METHODS: In this prospective cohort study, between Aug 9, 2017, and Feb 28, 2022, leftover clinical plasma samples were prospectively collected up to once per day from patients who were younger than 25 years, receiving care for leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA), and at high risk for life-threatening bloodstream infections. mcfDNA-Seq was used to identify pathogen DNA in blood samples obtained during the 7 days before to 1 day after bloodstream infection onset, and in control samples from the same population in the absence of fever or infection. The testing laboratory was masked to sample status. Primary outcomes were predictive sensitivity of mcfDNA-Seq for detecting the expected bloodstream infection pathogen during the 3 days preceding the day of bloodstream infection onset, with a prespecified favourable sensitivity of 50%, and predictive specificity of mcfDNA-Seq in control samples. Exploratory analyses comprised assessing sensitivity and specificity restricted to bacteria or common bloodstream infection pathogens, and after applying a data-derived DNA fragment concentration cutoff; estimating the predictive sensitivity on each of the 7 days before bloodstream infection onset; identifying clinical characteristics that affected predictive sensitivity or specificity; and examining the clinical relevance of additional organisms identified by mcfDNA-Seq during bloodstream infection episodes. Diagnostic sensitivity was also assessed on samples collected on the day of, or day after, diagnosis of bloodstream infection. This study is registered with ClinicalTrials.gov, NCT03226158. FINDINGS: 94 evaluable bloodstream infections occurred in 60 (38%) of 158 enrolled participants; 19 episodes were previously described in the pilot phase of this study. The predictive sensitivity of mcfDNA-Seq was 51·9% (95% CI 40·5-63·1) for all bloodstream infection episodes, 53·8% (42·2-65·2) for bacterial infection only, and 51·9% (40·5-63·1) when applying a DNA fragment concentration cutoff of 140 molecules per μL. Sensitivity was lowest at day -7 and increased daily until the day of diagnosis. Diagnostic sensitivity was 81·3% (95% CI 71·0-89·1) for all bloodstream infection episodes and 83·1% (72·9-90·7) for bacterial infections only. Predictive specificity was 82·7% (95% CI 76·0-88·2), but improved to 88·9% (83·0-93·3) for common bloodstream infection pathogens, and to 93·8% (88·9-97·0) when also applying the DNA fragment concentration cutoff. Predictive sensitivity was higher in participants with acute lymphoblastic leukaemia (adjusted odds ratio [aOR] 11·1 [1·7-74·2] vs those with acute myeloid leukaemia), and it was lower in polymicrobial infections (aOR 0·0 [0·0-0·2] vs monomicrobial Gram-positive infections). Clinical false-positive results were positively associated with gastrointestinal disturbance alone (p=0·037) or combined with recent administration of high-dose cytarabine (p=0·012). Additional organisms identified by mcfDNA-Seq that were not identified by blood culture were less likely than expected organisms to have an increasing DNA concentration during the days preceding bloodstream infection diagnosis. INTERPRETATION: mcfDNA-Seq can detect causative pathogens before the onset of some bloodstream infection episodes in profoundly immunocompromised patients. Predictive specificity might be improved by restricting results to a subgroup of relevant organisms, excluding patients with high risk of false-positive results, or applying a higher concentration cutoff. Clinical trials are needed to evaluate mcfDNA-Seq-guided pre-emptive therapy for preventing life-threatening bloodstream infections in patients with high risk. FUNDING: The National Cancer Institute, American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, and Karius.

Adolescent↗

PubMed2026

Health-system burden of higher-risk myelodysplastic syndromes in England: a literature-based micro-cost analysis.

OBJECTIVES: To quantify the per-patient-per-month (PPPM) cost for each phase of care in higher-risk myelodysplastic syndromes (HR-MDS) and the overall cost of a base-case (illustrative) non-curative management pathway followed by a patient with HR-MDS in England. DESIGN: We conducted a retrospective, literature-based, micro-costing analysis from the National Health Service (NHS) England provider perspective using published sources and publicly available price lists. No individual-patient data were used. Based on literature, a base-case management pathway followed by a patient with HR-MDS was defined as a diagnostic work-up at month 0, 12 cycles of azacitidine (given for 7 days in each 28-day cycle), 5 months of post-hypomethylating agent (HMA) failure supportive care and 1 month of terminal care. SETTING: Healthcare resource utilisation was analysed for adults with HR-MDS who received first-line azacitidine in routine practice if cycle-level or phase-level transfusion and admission rates were reported in the literature. Patients who required allogeneic haematopoietic stem cell transplantation or whose HR-MDS transformed to acute myeloid leukaemia were excluded because the diagnostic and/or therapeutic pathways differ. Unit costs for 2024/2025 were taken from published English national sources and an English trust tariff. RESULTS: PPPM costs were £8721.58 during active azacitidine therapy, £5399.58 after HMA failure and £12 554.58 for hospital-dominant terminal care; a one-off diagnostic work-up with genomics cost £2710 to £2810. The total cost for the base-case management pathway was £146 921 per patient. An alternative pathway excluding genomic testing and assuming hospice-dominant terminal care reduced the total cost to approximately £136 840 to £140 990, depending on whether the lower or upper bound of hospice bed-day costs is applied. CONCLUSIONS: The direct NHS-provider cost burden of this non-curative HR-MDS management pathway is concentrated in azacitidine acquisition and administration during active treatment, transfusions and admissions after HMA failure and setting-dependent costs at the end of life. The total cost for the illustrative management pathway followed by a patient with HR-MDS (£146 921) is of a similar order to the estimate in the National Institute for Health and Care Excellence technology appraisal for azacitidine uprated to £124 848 for 2024/2025. This comparison is provided for context only and should not be interpreted as validation of the present model, given differences in population, model structure, treatment duration and price year. The phase-specific PPPM estimates can inform, subject to local validation and scenario testing, UK budget-impact analyses, service planning and future economic models.

Humans↗

PubMed2026

Coagulation activation is associated with genomic-instability-related features in TP53-mutated AML and MDS: routine laboratory patterns beyond classical disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of acute myeloid leukemia (AML) associated with poor prognosis. In TP53-mutated AML and myelodysplastic syndrome (MDS), however, the classical ISTH criteria rarely identify overt DIC, although bleeding and thrombotic complications are well documented in acute leukaemia. We hypothesized that these patients exhibit a lower-grade, subclinical coagulation activation that is associated with the underlying genomic-instability-related features of TP53-mutant disease. METHODS: We retrospectively analyzed 107 consecutive patients with TP53-mutated AML (n = 52) or high-risk MDS (MDS, n = 55), median age 65 years, diagnosed and initially evaluated at our centre between 2018 and 2025. Seven routine coagulation markers and 46 co-mutated genes were evaluated for associations with overall survival (OS) using univariate and multivariable Cox regression, continuous dose-response modeling, and unsupervised k-means clustering. Internal validity was assessed by 1000 bootstrap resamples. RESULTS: Overt DIC according to ISTH criteria was rare (15%). Subclinical activation was common: 50% of patients had a D-dimer ≥1 μg/mL, 41% a fibrinogen ≥4 g/L, and 29% an INR ≥1.2. In univariate analysis, D-dimer, fibrinogen, INR, prothrombin time, and activated partial thromboplastin time were each associated with OS (HR 1.33-1.38 per SD; all p < 0.05). Complex karyotype correlated with higher D-dimer (median 1.39 vs. 0.60 μg/mL, p = 0.022) and fibrinogen (3.91 vs. 2.53 g/L, p = 0.007), while TP53 variant allele frequency (VAF) showed modest positive correlations with D-dimer (ρ = 0.21), INR (ρ = 0.27), and PT (ρ = 0.27; all p < 0.05). Clustering identified three coagulation phenotypes: Silent (51%), Thrombo-inflammatory (31%), and Consumption-like (18%), showing a graded but statistically non-significant gradient in molecular features and a stepwise decline in median OS (14, 10 and 8 months; log-rank p = 0.041). After adjustment for complex karyotype, TP53 VAF, and favorable co-mutation count, the Consumption-like phenotype was associated with a non-significant increased risk (HR 1.83, 95% CI 0.92-3.65, p = 0.084), whereas favorable co-mutation pathways remained independently protective (HR 0.56, 95% CI 0.35-0.90, p = 0.016). CONCLUSION: In TP53-mutated AML/MDS, coagulation activation intensity is associated with the degree of genomic instability. The three phenotypes may add biological resolution beyond classical DIC and cytogenetic risk groups, but represent laboratory patterns rather than validated bleeding or thrombosis prediction tools. However, after accounting for genomic features, phenotypes were not independent predictors of outcome, with complex karyotype, TP53 VAF, and favorable co-mutation count driving prognosis. Because treatment intensity and other clinical confounders were not available, these survival associations are hypothesis-generating. Coagulation profiling remains inexpensive, widely accessible, and offers a practical window into disease biology that warrants prospective validation.

TP53↗