| Title: | Convergent Multistage Evidence Implicates the CCR2-Artemin Immune-Inflammation Axis in Acute Myeloid Leukemia |
| Journal: | Mediators of Inflammation |
| Published: | 31 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41624379/ |
| DOI: | https://doi.org/10.1155/mi/2476470 |
| URL: | https://onlinelibrary.wiley.com/doi/pdfdirect/10.1155/mi/2476470 |
Publication 18408
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Abstract
Background: The immune system and inflammatory proteins influence hematologic malignancies, but causal links with immune cell phenotypes are unclear.</p>
Methods: We applied a prespecified, multistage workflow: two-sample and multivariable Mendelian randomization (MVMR; 731 immune traits across 12 hematologic cancers), two-step mediation Mendelian randomization (MR) of 91 circulating inflammatory proteins, MAGMA/FUMA gene and pathway enrichment, and external validation with trait-specific genetic risk scores (GRSs) in UK Biobank (UKB). We then performed CCR2 perturbation assays in human monocytic leukemia cell line (THP-1) and immortalized bone marrow-derived macrophage (IBMDM) cells with artemin (ARTN) mRNA readouts and examined proteomic correlations for ARTN using the Olink inflammatory panel.</p>
Results: Eight immune phenotypes showed FDR-significant causal associations with malignancy, seven of which remained independent in MVMR. In acute myeloid leukemia (AML), CCR2 on CD62L + myeloid dendritic cells (DCs) was associated with lower risk, whereas BAFF-R and CD19 on transitional B cells were associated with higher risk, CD19 on IgD-CD38^dim B cells was associated with chronic myeloid leukemia (CML), and HLA-DR+ NK cells were protective in non-Hodgkin lymphoma (NHL). Mediation MR identified three protein mediators-CD40L, IL-33, and ARTN, with ARTN mediating the CCR2-AML association. GRS analyses reproduced risk directions, most prominently the protective CCR2-AML association. In THP-1 and IBMDM models, CCR2 inhibition or knockdown increased ARTN mRNA expression, functionally supporting a CCR2→ARTN regulatory relationship. Proteomic correlations positioned ARTN with immune-metabolic proteins (CLEC6A, SIGLEC6, NPC2, and MTHFD2). Pathway analyses highlighted membrane-proximal processes (external plasma membrane and IgG binding) and a 16p11.2 signal.</p>
Conclusion: This integrative analysis identified CCR2-ARTN as a mechanistically supported immune-inflammation axis contributing to AML risk, offering a potential therapeutic target and warrants direct validation in primary CD62L + myeloid DCs.</p>
7 Keywords
- Cell Line, Tumor
- Humans
- Inflammation
- Leukemia, Myeloid, Acute
- Mendelian Randomization Analysis
- Receptors, CCR2
- THP-1 Cells
9 Authors
- Yi Jin
- Hui-Min Lu
- Xing-Hao Yu
- Ming-Zhu Su
- Jun Li
- Xiao-Min Li
- Jian-Hua Jin
- Li-Ting Zhang
- Yue Wang
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