Association of HLA-G Haplotype Risk Model with Overall Survival In Acute Myeloid Leukemia Patients

The human leukocyte antigen G (HLA-G) molecule exhibits limited tissue distribution and exerts multiple immunosuppressive functions. Thus, HLA-G expression in tumor cells favors tumor immune escape and tumor progression. The HLA-G gene polymorphism is extremely restricted in comparison to the classical HLA antigens. However, specific HLA-G polymorphisms in exons 3, 4, 5, 7 and parts of the 3′UTR encode for different haplotypes/alleles. Because of the prognostic role of HLA-G in cancer, especially in B-CLL, we investigated here the role of the HLA-G haplotypes in acute myeloid leukemia (AML).

Genotyping was performed on the basis of examining exons 3, 4, 5, 7 and parts of the 3′UTR by pyrosequencing in 166 patients with AML. In total, we found 17 different haplotypes in the cohort.

The haplotype distributions between 166 AML patients and 190 healthy controls were significantly different in two alleles, arguing that these two haplotypes of HLA-G on the one hand increases (*01:06, p=0.042) and on the other hand decreases (*01:01:12 variante, p=0.0014) the susceptibility for AML. Next a risk model was generated for overall survival (OS) adapted to specific haplotypes/alleles of the HLA-G gene. The favorable group (A) consisted of the alleles *01:06 and *01:01:20 variant at codon 57 G (12 patients), the intermediate group (B) of *01:01:20, *01:04:10, *01:01:30 and *01:01:41 variant at codon 57 A (113 patients) and the unfavorable group (C) of the remaining 11 alleles (41 patients). The OS for patients in group C was significantly (p=0.02) shorter (median OS 613 days) than for those in group B (median OS 961 days) and A (median OS not reached). Multivariate analysis shows a trend that the risk HLA-G model (Hazard ratio (HR) 1.4, p=0.084) was an independent predictor next to the established prognostic factors cytogenetics (HR 2.1, p=0.001), age (HR 1.8, p=0.009), leucocytes (HR 1.6, p=0.026), ECOG stage (HR 1.5, p=0.006) and platelets (HR 2.1, p=0.015). Moreover, the new risk model was able to further subdivide patients with intermediate cytogenetic risk profile (median OS: group A not reached; group B 987 days; group C 624 days; p=0.10).

Our study is the first study demonstrating that the combination of different alleles of the HLA-G gene is associated with the overall survival in AML patients. This fact emphasizes the extensive role of this gene by the tumor escape mechanism and could be responsible for progress in other cancers.

No relevant conflicts of interest to declare.