Association of HLA-G Haplotype Risk Model with Treatment Free Survival In Chronic Lymphocytic Leukemia Patients

The human leukocyte antigen G (HLA-G) molecule exhibits limited tissue distribution and exerts multiple immunoregulatory functions. Since the net result of these effects is immunosuppression, HLA-G expression in tumor cells may favor their escape from antitumor immune responses, thus allowing tumor progression. The HLA-G protein 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. Demonstrating the extensive and proven prognostic role of HLA-G in various diseases and especially in B-CLL we investigated the role of the HLA-G haplotypes in B-CLL.

Genotyping was performed on the basis of examining exons 3, 4, 5, 7 and parts of the 3`UTR by pyrosequencing in 190 patients with B-CLL. In total, we found 17 different haplotypes in the cohort.

The haplotype distributions between 190 B-CLL patients and 190 healthy controls were not different, arguing that the haplotypes of HLA-G do not increase the susceptibility for B-CLL. However, combining four different haplotypes (*01:06, *01:12; *01:12 variant and *01:13N) we evaluated a risk score (0=no risk allele; 1=one risk allele; 2=two risk alleles) for TFS. 77 patients showed no risk allele, 90 patients one risk allele and 23 patients two risk alleles. The TFS for those patients with two risk alleles were significantly shorter (median TFS 33 months) than for those with one risk allele (median TFS 49 months) and those with no risk alleles (median TFS 88 months)(log rank test: p=0.03). In multivariate analysis we could show that the stage according to Binet (HR 1.7, 95% CI 1.2–2.6, p=0.005), CD38 status (HR 1.8, 95% CI 1.0–3.2, p=0.04) and the haplotype risk model (HR 1.7, 95% CI 1.1–2.6, p=0.011) were independent predictors for first therapy.

Our study is the first study demonstrating that the combination of different alleles of the HLA-G gene is associated with the risk of first therapy in B-CLL 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.