UK Biobank and Preclinical Study Links Obesity to Myeloid Leukemia, Identifies Dual GLP-1R/IL-17A Strategy

Key Highlights

• Higher BMI and waist-to-hip ratio were each associated with an increased incidence of myeloid malignancies among 440,982 UK Biobank participants.¹
• Obesity-related inflammation promoted the expansion of PTPN11-mutant hematopoietic cells and accelerated leukemogenesis in experimental models.¹
• Combined GLP-1R agonism and IL-17A blockade reduced mutant myeloid cells, leukemic stem and progenitor populations, and inflammatory signaling.¹
• The researchers said the findings raise the possibility of repurposing existing metabolic and anti-inflammatory therapies for high-risk myeloid leukemias.²

Obesity-associated metabolic inflammation was linked to the development and progression of PTPN11-mutant myeloid leukemia, according to a study published in The Journal of Clinical Investigation.¹ Combined glucagon-like peptide 1 receptor (GLP-1R) agonism and interleukin-17A (IL-17A) blockade also reduced leukemic burden in preclinical models.

The findings suggest that obesity may function as an active biological contributor to leukemia progression rather than solely as a clinical risk factor.¹ As Reuben Kapur, PhD, stated in an accompanying press release, the study establishes obesity as “an active biological driver linking metabolism, inflammation and cancer.”²

The researchers integrated epidemiologic, genomic, and proteomic analyses with experiments in genetically engineered models. The UK Biobank analysis included 440,982 unrelated participants with exome-sequencing data and anthropometric measurements of BMI or waist-to-hip ratio. Participants were followed for a median of approximately 13.5 years.¹

Investigators also transplanted hematopoietic stem and progenitor cells carrying the activating Shp2E76K/+ mutation into lean and obese recipients. After increased mutant-cell engraftment was observed in the obese group, the investigators administered the GLP-1R agonist beinaglutide, an anti–IL-17A antibody, either treatment alone, or the combination for 30 days.¹

Study Findings

Each 1-SD increase in BMI was associated with a 9% higher incidence of myeloid malignancies (HR, 1.09; 95% CI, 1.02-1.17; P = .02), and each 1-SD increase in waist-to-hip ratio was associated with a 12% higher incidence (HR, 1.12; 95% CI, 1.03-1.23; P = .01).¹ Participants with obesity and type 2 diabetes had a greater risk than lean participants without diabetes (HR, 1.51; 95% CI, 1.08-2.13; P = .02).¹

In a proteomic analysis of approximately 50,000 UK Biobank participants without hematologic malignancies at baseline, those with both obesity and diabetes had IL-17A levels 0.14 SD higher than those without both conditions (95% CI, 0.10-0.18; P < .001). They also had lower plasma GLP-1R levels.¹

In experimental models, obesity increased the expansion of Shp2E76K/+-mutant cells, immature myeloid cells, and leukemic stem and progenitor populations. Obese recipients also developed hepatosplenomegaly, increased inflammatory cytokine levels, and an acute myeloid leukemia–like phenotype. Median overall survival was 190 days among obese recipients compared with 240 days among lean recipients (P = .03).¹

Combination treatment increased the proportion of normal hematopoietic cells and reduced the proportion of Shp2E76K/+-mutant cells in peripheral blood and bone marrow. It also reduced Th17 cells, myeloid infiltration, leukemic stem and progenitor compartments, body weight, fasting blood glucose, visceral adipose tissue, and hepatosplenomegaly.¹

Compared with either monotherapy, the combination produced the most extensive transcriptional changes, including suppression of IL-17, TNF, JAK/STAT, and NF-κB signaling. Dual treatment also reduced M2-like tumor-associated macrophages and markers of T-cell exhaustion while increasing CD4+ and CD8+ T-cell populations.¹

Clinical Implications

According to the study authors, the findings identify IL-17A–driven, metabolism-coupled immunosuppression as a mechanistic link between obesity and PTPN11-mutant myeloid leukemias.¹ The results suggest that simultaneously targeting metabolic dysfunction and chronic inflammation may disrupt the microenvironment supporting mutant hematopoietic cell expansion.¹

The researchers also noted in a press release that both pathways can be targeted with existing medications: IL-17A inhibitors are used to treat autoimmune diseases, and GLP-1R agonists are used to manage diabetes and obesity.² They said these agents could potentially be repurposed, alone or in combination, to improve metabolic health, restore antitumor immunity, and reduce leukemia progression.²

The treatment results remain preclinical. The research team plans to conduct clinical studies to determine whether combined IL-17A inhibition and GLP-1R agonism can safely and effectively benefit patients with obesity-associated leukemia and to identify which patients may be most likely to benefit.²

Expert Commentary

“Because these therapies are already available and have established safety profiles, our results raise the possibility of repurposing them either alone or in combination to improve outcomes for patients with high-risk myeloid leukemias,” Santhosh K. Pasupuleti, PhD, assistant research professor of pediatrics at Indiana University School of Medicine and co-senior author of the study, said in a press release. “This strategy could help reduce leukemia progression while simultaneously improving metabolic health and restoring anti-tumor immunity.”²

References

1. Kapur R, Li L, Kanumuri R, et al. Targeting GLP-1R and IL-17A suppresses obesity-induced leukemia in an oncogenic PTPN11 mutation–driven model. J Clin Invest. Published June 23, 2026. doi:10.1172/JCI202856
2. Indiana University School of Medicine. Press release on targeting obesity-associated metabolic inflammation in leukemia. Newswise. July 13, 2026. https://www.newswise.com/articles/iu-study-finds-obesity-fuels-leukemia-but-a-combo-using-popular-weight-loss-drugs-may-stop-it/?sc=sphr&xy=10049363