Inhibitory HLA‐C/KIR2DL2 Interactions and KIR Allelic Polymorphisms Are Associated With Susceptibility to Philadelphia Chromosome‐Negative Myeloproliferative Neoplasms

Background Immune surveillance is increasingly recognized as a determinant of clonal selection in Philadelphia chromosome‐negative myeloproliferative neoplasms (MPN). While HLA‐restricted adaptive immune effects have been described, the contribution of inherited variation in natural killer (NK)‐cell regulatory pathways remains less well defined. We investigated whether killer immunoglobulin‐like receptor (KIR) allelic polymorphisms and HLA–KIR receptor–ligand interactions are associated with susceptibility to MPN. Methods We performed high‐resolution next‐generation sequencing‐based KIR genotyping in 167 Bulgarian patients with Philadelphia chromosome‐negative MPN, including 137 with JAK2 V617F‐positive disease and 30 with CALR‐mutated disease, and in 97 healthy controls. All subjects had prior high‐resolution typing for HLA‐A, ‐B, and ‐C. Associations between KIR alleles and disease status were evaluated using additive generalized linear models adjusted for age and sex. HLA–KIR receptor–ligand interactions were analyzed using biologically defined interaction models. Results Several KIR allelic associations with MPN susceptibility were identified, although some involved low‐frequency variants. Across analyses, the most consistent finding was that inhibitory KIR2DL2, together with HLA‐C2 ligands, was associated with increased susceptibility to MPN overall and within mutation‐defined subgroups, with the strongest signal observed in CALR‐mutated disease. In contrast, the absence of KIR2DL2 was associated with a lower risk in both JAK2 V617F‐positive and CALR‐mutated MPN. These findings are consistent with a model in which inherited inhibitory NK‐cell signaling may influence early immune escape of emerging mutant clones. Conclusion Inherited variation in KIR genes and HLA–KIR inhibitory interactions may contribute to susceptibility to Philadelphia chromosome‐negative MPN. The findings support a possible role for NK‐cell regulatory pathways in early MPN pathogenesis, but should be considered hypothesis‐generating and require validation in larger independent cohorts. Trial Registration The author has confirmed clinical trial registration is not needed for this submission.