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ResearchIn-Press PreviewHematologyInflammationOncology Open Access | 10.1172/JCI202856

Targeting GLP1R and IL17A suppresses obesity-induced leukemia in an oncogenic PTPN11 mutation-driven model

Reuben Kapur,1 Linke Li,2 Rahul Kanumuri,3 Kanaka Sai Ram Padam,1 Baskar Ramdas,1 Chiranjeevi Pasala,4 Gabriela Chiosis,4 Lakshmi Reddy Palam,1 Ramesh Kumar,1 Satoshi Koyama,2 Pradeep Natarajan,6 Laura S. Haneline,1 Zhi Yu,2 and Santhosh Kumar Pasupuleti1

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Kapur, R. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Li, L. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Kanumuri, R. in: PubMed | Google Scholar |

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Padam, K. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Ramdas, B. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Pasala, C. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Chiosis, G. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Palam, L. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Kumar, R. in: PubMed | Google Scholar |

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Koyama, S. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Natarajan, P. in: PubMed | Google Scholar |

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Haneline, L. in: PubMed | Google Scholar

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Yu, Z. in: PubMed | Google Scholar |

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America

2Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, United States of America

3Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, United States of America

4Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Kanagawa, Japan

6Program in Medical and Population Genetics and the Cardiovascular Disease I, Broad Institute of Harvard and MIT, Boston, United States of America

7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, United States of America

Find articles by Pasupuleti, S. in: PubMed | Google Scholar |

Published June 23, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI202856.
Copyright © 2026, Kapur et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 23, 2026 - Version history
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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.

Graphical Abstract
graphical abstract
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