Malignant T cells undergo metabolic reprogramming by creating a metabolic bypass through glucose-1,6-bisphosphate synthase PGM2L1 in cutaneous T cell lymphoma

Summary: Abstract Body: Metabolic reprogramming is a key factor in cancer progression. In cutaneous T cell lymphoma, especially the most frequent subtype mycosis fungoides (MF), elevated lactate dehydrogenase (LDH) levels are associated with poor prognosis, reflecting increased aerobic glycolysis. However, specific metabolic therapeutic targets for MF remain unidentified. In the current study, we identified that Phosphoglucomutase 2-like 1 (PGM2L1), a glucose-1,6-bisphosphate synthase, was highly expressed in the malignant T cells in MF tumors, while its expression is minimal in normal tissues and normal T cells. Moreover, PGM2L1 expression correlates with poor prognosis and elevated LDH levels in clinical data. Functional experiments revealed that PGM2L1 promotes tumor cell survival and resistance to apoptosis, as confirmed by in vivo experiments. Using isotope tracing and Seahorse metabolic assays, we demonstrated that PGM2L1 enhances glycolysis. The underlying mechanism involves PGM2L1 facilitating a metabolic bypass: it promotes glycogen consumption, and its product, glucose-1,6-bisphosphate, activates key glycolytic enzymes such as phosphofructokinase and pyruvate kinase, thereby increasing glycolytic flux. Additionally, PGM2L1 inhibits oxidative phosphorylation, reducing ROS production by regulating LDH activity. These findings suggest that PGM2L1 supports MF tumor progression by enhancing glycolysis through glycogen utilization and glycolytic enzyme activation, while suppressing oxidative phosphorylation and ROS-induced cell death. This metabolic reprogramming facilitates malignant T cells’ adaptation to unfavorable environmental conditions by altering their metabolic pathways. Consequently, understanding this process is crucial for developing effective therapeutic strategies to target malignant T cells. Yujie Wen^{1, 2}, Yi Jiang^{1, 2}, Mingjia Li^{1, 2}, Mengzhou Cao^{1, 2}, Yang Wang^{1, 2} 1. Department of Dermatology and Venereology, Peking University First Hospital, Beijing, Beijing, China. 2. National Clinical Research Center for Skin and Immune Diseases, Beijing, China. UV Biology/Injury and Non-melanoma Cancers