A Distinct Signature of Natural Killer Cell KIR Gene Frequencies In Secondary AML Compared with De Novo AML and Normal Controls

There is increasing evidence for the role of KIR genetics in predicting outcome of haematological malignancies. We recently showed that donor (but not recipient) KIR genes 2DS1, 3DS1 and 2DL5a are associated with significantly less relapse in AML patients following matched sibling allogeneic stem cell transplantation. Interestingly, this effect was not seen in patients with AML secondary to MDS but only in de novo AML.¹ To explore whether outcome of non-transplant treatment for AML might be affected by KIR genetics we performed KIR genotyping on the DNA sample archive from the Medical Research Council UK AML 10 and 15 trials. All patients underwent four courses of chemotherapy according to MRC protocols. KIR genotyping was performed using Qiagen SSP PCR KIR genotyping kits as previously described.¹ We measured KIR gene frequencies in AML samples obtained at diagnosis from 469 de novo AML, and 38 secondary AML and compared the gene distribution with that of a normal control population of 246 individuals. To allow for multiple comparisons, significance was set at p<0.01. The KIR gene frequencies of de novo AML did not differ significantly from those of the normal population but frequency of KIR 2DS2 was significantly lower in secondary AML compared to de novo AML (26% vs. 51% for KIR 2DS2, p=0.004 vs. 44% (111/246) for normal controls). There was some evidence that KIR 2DL2, which shows linkage disequilibrium with KIR 2DS2, was also reduced in secondary AML (32% v 54%, p=0.009). Rates of KIR 2DS2 and KIR 2DL2 were lower in both secondary groups: therapy-related AML (t-AML) and antecedent haematological disorders. Interestingly, patients with t-AML had lower rates of KIR HaploB than those without t-AML (27% v 67%, p=0.005). However, analyses of the AML cohort adjusted for known prognostic factors showed no significant prognostic effect of any single KIR group, or KIR B haplotype. These results suggest that inheritance of KIR 2DS2 may be protective for the development of secondary AML and that individuals lacking haplotype B KIR genes are more prone to develop t-AML. These observations raise the possibility that KIR gene inheritance determines the efficiency of immunosurveillance of AML by NK cells.