Convergent Multistage Evidence Implicates the CCR2-Artemin Immune-Inflammation Axis in Acute Myeloid Leukemia

  • Mediators Inflamm. 2026 Jan 31:2026:2476470. doi: 10.1155/mi/2476470.
Yi Jin  1  2  3  4 ,  Hui-Min Lu  5 ,  Xing-Hao Yu  6 ,  Ming-Zhu Su  1  2 ,  Jun Li  1  2 ,  Xiao-Min Li  1  2 ,  Jian-Hua Jin  1  2  3  7 ,  Li-Ting Zhang  1  2  3 ,  Yue Wang  1  2  3  7
Affiliations
  • 1. Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, Jiangsu, China, ujs.edu.cn.
  • 2. The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, Jiangsu, China, xzmc.edu.cn.
  • 3. Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, Jiangsu, China, ujs.edu.cn.
  • 4. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China, xzmc.edu.cn.
  • 5. Department of Outpatient and Emergency, The First Affiliated Hospital of Soochow University, Suzhou, 215123, Jiangsu, China, sdfyy.cn.
  • 6. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215123, Jiangsu, China, sdfyy.cn.
  • 7. Jiangsu Province Key Laboratory of Tumor Biotherapy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China, xzmc.edu.cn.
PMID: 41624379 DOI: 10.1155/mi/2476470
Abstract

Background: The immune system and inflammatory proteins influence hematologic malignancies, but causal links with immune cell phenotypes are unclear.

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.

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.

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.

Keywords
ARTN; CCR2; Mendelian randomization; acute myeloid leukemia; genetic risk score; immune cells; mediation analysis.
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