| Title: | Targeting GLP1R and IL17A suppresses obesity-induced leukemia in an oncogenic PTPN11 mutation-driven model |
| Journal: | Journal of Clinical Investigation |
| Published: | 23 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42334870/ |
| DOI: | https://doi.org/10.1172/jci202856 |
| URL: | http://www.jci.org/articles/view/202856/files/pdf |
Publication 20557
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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 (interleukin-17A), reduced GLP-1R (glucagon like peptide 1 receptor) expression, and heightened risk of myeloid malignancies. Transplantation of protein tyrosine phosphatase non-receptor type 11, PTPN11 (Shp2E76K/+) mutant hematopoietic stem/progenitors into obese mice demonstrated that metabolic inflammation accelerates 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, Tyk2-mediated IFNγ signaling, reactivated T-cell responses, and reducing leukemic burden. These findings establish IL-17A driven, metabolism-coupled immunosuppression as a mechanistic link between obesity and SHP2-mutant myeloid leukemias, highlighting a tractable therapeutic strategy for high-risk obese patients.</p>
14 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
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
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