Leucine, autoimmune diseases, and circulating mediators shape the causal landscape of lymphoid malignancies.

INTRODUCTION: While genetic abnormalities underlying lymphoid malignancies (LM) are well-characterized, the environmental and metabolic determinants driving LM remain largely unexplored. Autoimmune diseases are known risks, yet the specific circulating mediators and potential protective dietary factors linking these conditions to LM require systematic elucidation. OBJECTIVES: This study aimed to comprehensively screen for causal risk factors of LM, identify the metabolic mediators bridging autoimmune diseases and LM, and validate the therapeutic potential of leucine as a protective factor. METHODS: We conducted a systematic Mendelian randomization analysis using 10,090 GWAS traits obtained from the IEU OpenGWAS project, including 2,568 plasma proteins and 662 plasma metabolites, to identify potential causal determinants of LM. Findings were validated using the large-scale UK Biobank cohort (n=502,175) and further supported by multi-omics data (plasma proteomics (Olink; n = 53,014) and metabolomics (NMR; 486,813)) within the same population. Mechanisms were further verified via in vitro assays on LM cell lines and in vivo experiments using a MH/NRASG12D B-cell precursor acute lymphoblastic leukemia (BCP-ALL) mouse model. RESULTS: We identified autoimmune diseases-specifically hyperthyroidism and membranous nephropathy, as novel risk factors for LM. Mediation analysis revealed that promotilin, monounsaturated fatty acids (MUFAs), and glucose serves as key circulating mediators driving this risk. Conversely, leucine emerged as a protective metabolic factor. High-leucine conditions suppressed proliferation and induced apoptosis in LM cell lines, while dietary leucine supplementation prolonged survival and alleviated anemia and thrombocytopenia in the BCP-ALL mouse models. In patient cohorts, higher plasma leucine levels were associated with improved outcomes in non-Ph B-ALL and prolonged survival in CAR-T-treated B-cell lymphoma patients. Mechanistically, leucine exposure induced metabolic reprogramming characterized by the suppression of lipid biosynthesis pathways and reduced SREBF1/FASN-mediated de novo lipogenesis; pharmacological FASN inhibition recapitulated the anti-tumor effects of leucine. CONCLUSION: Autoimmune diseases increase LM susceptibility through specific metabolic mediators. Leucine functions as a potent protective agent and prognostic biomarker. These findings suggest that dietary leucine supplementation represents a promising and readily translatable therapeutic strategy for managing LM and enhancing CAR-T therapy efficacy.