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.

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