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

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 − CD38ᵈim 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.