NK cell genotype and phenotype at diagnosis of acute lymphoblastic leukemia correlate with postinduction residual disease

Abstract

Purpose: Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy.

Experimental design: The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically with postinduction MRD status.

Results: The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype were 2.85 times the odds in those with Tel-A/A genotype (P = 0.035). MRD-positive patients were more likely to have KIR2DL5A (P = 0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (P = 0.0074 and P = 0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (P = 0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (P = 0.038). Collectively, five NK cell-related factors (Tel-B-associated KIR2DL5A, NKp46, FASL, granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity.

Conclusions: Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control.

Figure 1

Simplified maps of the A and B KIR haplotypes on chromosome 19q13.4. Cen-B is KIR2DL2 positive and KIR2DL3 negative in the centromeric motifs and Tel-B is KIR3DS1 positive and KIR3DL1 negative in the telomeric motifs.

Figure 2

The five NK cell related factors were analyzed either singly or as composite in correlation with post-induction MRD. The composite model has a 100% sensitivity (or 100% true positivity) and an 80% specificity (or 20% false positivity).