Gene expression profiling of GLP1R-IL17A axis in obesity driven PTPN11-mutant leukemia

Obesity-associated metabolic inflammation contributes to the progression of PTPN11-mutant myeloid leukemia through activation of the IL-17A–mediated inflammatory axis and suppression of GLP-1R signaling. In this study, mRNA-seq was performed on hematopoietic and immune cell populations from a murine transplantation model of Shp2E76K/+ leukemia under obese conditions, with or without treatment using an anti-IL-17A antibody and a GLP-1R agonist. Transcriptomic analysis reveals that obesity promotes leukemogenesis by enhancing myeloid expansion, lipid metabolic reprogramming, and immunosuppressive remodeling characterized by M2-like tumor-associated macrophage accumulation, T cell exhaustion, and impaired antigen presentation. Therapeutic targeting of the GLP-1R–IL-17A axis restores immune function, including Ciita-dependent antigen presentation and IFNγ signaling, and reduces leukemic burden. These data provide insight into the molecular mechanisms linking obesity-driven inflammation to leukemia progression and identify potential therapeutic targets.