Targeting GLP-1R and IL-17A suppresses obesity-induced leukemia in an oncogenic PTPN11 mutation-driven model

Area of Science:

• Hematology
• Immunology
• Metabolic disease

Background:

• Obesity is linked to hematopoietic malignancies, but its specific role in mutation-driven myeloid leukemias is not well understood.
• Elevated BMI and waist-to-hip ratio are associated with type 2 diabetes, increased IL-17A, and reduced GLP-1R expression.

Purpose of the Study:

• To investigate the mechanistic link between obesity and SHP2-mutant myeloid leukemias.
• To evaluate a potential therapeutic strategy involving dual therapy.

Main Methods:

• Analysis of UK Biobank data from over 440,000 individuals.
• Transplantation of PTPN11 (Shp2E76K/+) mutant hematopoietic stem/progenitors into obese mice.
• Assessment of therapeutic efficacy using anti-IL-17A antibody and GLP-1R agonist.

Main Results:

• Obesity traits correlated with increased risk of myeloid malignancies and elevated IL-17A.
• Metabolic inflammation in obese mice accelerated leukemogenesis via myeloid cell expansion, lipid rewiring, IL-17A activation, and M2-like TAM accumulation.
• Dual therapy reduced M2-like TAMs, restored antigen presentation and T-cell responses, and decreased leukemic burden.

Conclusions:

• IL-17A-driven, metabolism-coupled immunosuppression is a key mechanism linking obesity to SHP2-mutant myeloid leukemias.
• Dual therapy targeting IL-17A and GLP-1R presents a promising therapeutic strategy for high-risk obese patients.