Targeting GLP-1R and IL-17A suppresses obesity-induced leukemia in an oncogenic PTPN11 mutation–driven model
Reuben Kapur, Linke Li, Rahul Kanumuri, Kanaka Sai Ram Padam, Baskar Ramdas, Chiranjeevi Pasala, Gabriela Chiosis, Lakshmi Reddy Palam, Ramesh Kumar, Satoshi Koyama, Pradeep Natarajan, Laura S. Haneline, Zhi Yu, Santhosh Kumar Pasupuleti
Reuben Kapur, Linke Li, Rahul Kanumuri, Kanaka Sai Ram Padam, Baskar Ramdas, Chiranjeevi Pasala, Gabriela Chiosis, Lakshmi Reddy Palam, Ramesh Kumar, Satoshi Koyama, Pradeep Natarajan, Laura S. Haneline, Zhi Yu, Santhosh Kumar Pasupuleti
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Research Article Hematology Inflammation Oncology

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

Abstract

Obesity is increasingly implicated in hematopoietic malignancies, yet its role in mutation-driven myeloid leukemias remains unclear. Using UK Biobank data from over 440,000 individuals, we found obesity traits including elevated BMI and waist-to-hip ratio were associated with type 2 diabetes, increased plasma IL-17A levels, reduced glucagon-like peptide 1 receptor (GLP-1R) expression, and heightened risk of myeloid malignancies. Transplantation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11) (Shp2E76K/+) mutant hematopoietic stem/progenitor cells into obese mice demonstrated that metabolic inflammation accelerated leukemogenesis via myeloid cell expansion, lipid metabolic rewiring, IL-17A activation, and accumulation of M2-like tumor-associated macrophages (TAMs), accompanied by T cell exhaustion and impaired antigen presentation. Notably, dual therapy with an anti–IL-17A antibody and a GLP-1R agonist reversed these effects by reducing M2-like TAMs, restoring Ciita-dependent antigen presentation and Tyk2-mediated IFN-γ signaling, reactivating T cell responses, and reducing leukemic burden. These findings establish IL-17A–driven, metabolism-coupled immunosuppression as a mechanistic link between obesity and protein tyrosine phosphatase 2–mutant (SHP2-mutant) myeloid leukemias, highlighting a tractable therapeutic strategy for patients with obesity at high risk for other diseases and their complications.

Authors

Reuben Kapur, Linke Li, Rahul Kanumuri, Kanaka Sai Ram Padam, Baskar Ramdas, Chiranjeevi Pasala, Gabriela Chiosis, Lakshmi Reddy Palam, Ramesh Kumar, Satoshi Koyama, Pradeep Natarajan, Laura S. Haneline, Zhi Yu, Santhosh Kumar Pasupuleti

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Figure 11

Combination of GLP-1R agonist and anti–IL-17A antibody therapy reverses inflammatory and metabolic dysregulation in ATMs of Ob/Ob mice bearing Shp2E76K/+-mutant HSC/Ps.

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Combination of GLP-1R agonist and anti–IL-17A antibody therapy reverses ...
(A) Differential gene expression analysis of ATMs from Combo-treated versus vehicle-treated Ob/Ob mice, identifying 1,156 downregulated and 936 upregulated genes. (B) Flow cytometry plots and quantification of CD45+F4/80+ ATMs following vehicle or Combo therapy. (C and D) GSEA hallmark pathway enrichment showing reversal of inflammatory response and metabolic signatures in ATMs upon Combo therapy. (E and F) KEGG pathway analysis demonstrates suppression of IL-17, TNF, and DNA repair pathways, along with other metabolic and immune-related programs, in ATMs from Combo-treated mice. (G and H) Expression of de novo lipogenesis genes (Fas, Nr1h2, Nr1h3, and Insig1) and fatty acid oxidation genes (Acaa2, Cpt1a, Etfb, and Etfa) in ATMs from WT and Ob/Ob mice bearing Shp2E76K/+ HSC/Ps and treated with the indicated drugs. n = 3–4 mice per group. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001, by 1-way ANOVA followed by Tukey’s post hoc test. Data are presented as the mean ± SEM.