DOI: 10.6084/m9.figshare.30023305.v1
title: Plasma metabolic landscape unveils key regulators of leukemia subtype progression

description: Leukemia is driven by metabolic reprogramming, yet the specific causal roles of plasma metabolites in distinct leukemia subtypes remain unclear. This study employed Mendelian randomization (MR) to explore potential causal links between 690 plasma metabolites (and 143 metabolite ratios) and four leukemia subtypes: ALL, AML, CLL, and CML. Genetic variants from genome-wide association studies served as instrumental variables. Multiple MR approaches, including IVW, MR-Egger, and Weighted Median, along with sensitivity analyses, were applied to ensure robust results. Our findings revealed subtype-specific metabolite associations. In ALL, metabolites such as 3-Hydroxyisobutyrate and γ-Glutamylglutamate showed positive associations, while Phosphocholine and Ceramide showed negative associations. AML was positively linked to GlcNAc/GalNAc and negatively to 1-Methylnicotinamide. CLL showed positive associations with Butyrate/Isobutyrate and Androstenediol Monosulfate, and negative ones with Docosatrienoate and α-Tocopherol to Sulfate ratio. CML exhibited negative associations with Cysteine-Glutathione disulfide and Piperine. Our MR study provides a comprehensive evaluation of the metabolomic landscape of leukemia, identifying subtype-specific causal associations involving pathways such as energy metabolism, amino acid metabolism, lipid signaling, and redox homeostasis. These findings offer insights into potential plasma biomarkers and therapeutic targets, revealing distinct metabolic vulnerabilities that warrant further investigation for precision treatment strategies across leukemia subtypes. Leukemia is a type of cancer that affects the blood and bone marrow, and it can involve changes in how the body’s cells use energy and nutrients. In this study, we looked at how different chemicals in the blood, called metabolites, might be linked to various types of leukemia. By using a method called Mendelian randomization, we analyzed genetic data to explore if certain metabolites play a direct role in causing leukemia. We found that each type of leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML), is associated with unique changes in metabolism. For example, ALL showed links to altered energy use and redox balance (important for controlling cell damage), while AML was connected to changes in sugar metabolism. CLL and CML had associations with lipid metabolism and oxidative stress, which can affect how cells grow and survive. These findings are important because they suggest potential new biomarkers (measurable signs) in the blood that could help doctors diagnose leukemia more accurately or develop targeted treatments. Understanding the specific metabolic changes in each type of leukemia may also open up new approaches to personalized medicine, where treatments are tailored to the metabolic needs of each patient’s leukemia subtype. This study applied Mendelian randomization to evaluate causal links between plasma metabolites and four leukemia subtypes.Genetic instruments were derived from GWAS data for 690 metabolites and 143 metabolite ratios.Distinct metabolic profiles were identified for ALL, AML, CLL, and CML. ALL was linked to altered energy production, amino acid metabolism, and redox balance.AML showed associations with glycosylation-related metabolites; CLL and CML were linked to lipid metabolism and oxidative stress markers.Findings highlight potential biomarkers and metabolic targets for subtype-specific leukemia therapies. This study applied Mendelian randomization to evaluate causal links between plasma metabolites and four leukemia subtypes. Genetic instruments were derived from GWAS data for 690 metabolites and 143 metabolite ratios. Distinct metabolic profiles were identified for ALL, AML, CLL, and CML. ALL was linked to altered energy production, amino acid metabolism, and redox balance. AML showed associations with glycosylation-related metabolites; CLL and CML were linked to lipid metabolism and oxidative stress markers. Findings highlight potential biomarkers and metabolic targets for subtype-specific leukemia therapies.