KIR ligand C2 is associated with increased susceptibility to childhood ALL and confers an elevated risk for late relapse.

A role for HLA class I polymorphism in childhood acute lymphoblastic leukemia (ALL) has been suggested for many years, but unambiguous associations have not been found. Here, we show that the HLA-C-encoded supertypic epitope C2, which constitutes a high-affinity ligand for the inhibitory natural killer (NK) cell receptor KIR2DL1, is significantly increased in ALL patients (n = 320; P = .005). Stratification for ethnicity and disease subtype revealed a strong association of C2 with B-ALL in German cases (P = .0004). The effect was independent of KIR2DS1 and KIR2DL1 allelic polymorphism and copy number. Analysis of clinical outcome revealed a higher incidence of late relapse (> 2.5 years) with increasing number of C2 alleles (P = .014). Our data establish C2 as novel risk factor and homozygosity for C1 as protective for childhood B-ALL supporting a model in which NK cells are involved in immunosurveillance of pediatric B-ALL via interaction of KIR with HLA-C ligands.