Allelic Polymorphisms of the KIR2DL2 Gene in Patients with Acute Myeloid Leukemia.

Reports on haploidentical hematopoietic stem cell transplantation in patients with acute myeloid leukemia (AML) have demonstrated that killer cell immunoglobulin-like receptor (KIR) disparity, defined as the absence of an HLA ligand that corresponds to the specificity of the expressed inhibitory KIRs, has a beneficial graft versus leukemia effect. KIRs are known for their highly allelic polymorphisms and haplotype diversity. Many reports have evaluated the clinical outcome in association with KIR genotypes; the presence of many incompatible ligands suggests great diversity in the KIR repertoire. Of note is the predominance of natural killer (NK) cell C1 homozygosity in the Korean population; the frequency of the KIR2DL2 and KIR2DS2 genes is lower in Koreans than in other populations, especially compared to Caucasian populations.

Therefore, we examined immunogenetic differences in the 2DL2 gene in NK cells between normal donors and patients, by directly sequencing the KIR2DL2 gene in 24 normal Korean BMT donors and 23 patients with AML. There were 26 men and 21 women with a median age of 38 years (range 11–67).

In total, 96 variants were genotyped at 65 known single nucleotide polymorphism (SNP) positions containing 31 novel variants: 1 in the 3' UTR, 79 in the introns, and 16 in the exons (non-synonymous: synonymous = 8:8). We identified two novel non-synonymous polymorphisms, BMT5520 (Thr221Ile) and BMT13191 (Arg266Cys), with allele frequencies of 0.125 and 0.174, and 0.042 and 0.087, in the donors and patients, respectively. Another non-synonymous SNP, rs2756923 (Ala333Thr) in exon 9, had allele frequencies of 0.104 and 0.065 in the donors and patients, respectively. The synonymous SNP rs586234 had allele frequencies of 0.396 and 0.435 in the donors and patients, respectively. We also identified seven noteworthy intronic polymorphisms that were present at high frequency in the donors and patients: IVS1+449G>A (0.182 and 0.217), rs2535715 (0.458 and 0.478), IVS4–220C>T (0.125 and 0.174), rs584872 (0.438 and 0.457), IVS7+203T>C (0.417 and 0.283), rs670770 (0.438 and 0.326), and rs670771 (0.458 and 0.478). Furthermore, we identified a putative novel polymorphic variant that contains a newly identified G allele at rs34790892, an A allele at rs673568 in exon 4, and a T allele at BMT13191 in exon 7. The haplotype frequencies indicated that variants with altered amino acid sequences at two positions, rs673568 and BMT13191, were present at lower frequencies in the patients than in the donors, suggesting that recombinant events in alleles may occur relatively more frequently within exon 4 than exon 7 in the Korean population.

Although polymorphisms of the KIR2DL2 gene were not specifically associated with AML, the allelic polymorphisms in rs673568 and BMT13191 found here might be sufficient to alter the properties and function of the Korean KIR2DL2 gene. Further evaluation is needed to reveal the association of ethnically lower frequency genes, such as both inhibitory KIR2DL2 and activating KIR2DS2 genes, with critical outcomes in patients with AML.

No relevant conflicts of interest to declare.