HLA Alleles Repertoire in Russian CLL Patients
Authors: Biderman Bella V. , Khamaganova Ekaterina G , Likold Ekaterina B , Abdrakhimova Alena R , Leonov Evgeny A , Sudarikov Andrey B , Savchenko Valery G. 
Published: November 2019

Introduction. Chronic lymphocytic leukemia (CLL) is one of the most common lymphoproliferative diseases in Europe and the USA. The mutational status of the immunoglobulin heavy chain variable region genes (IGHV) has long been known as an important factor for long-term prognosis in CLL. The variety of the rearranged IGHV structure variants in CLL cells is very limited and differs significantly from that in normal B cells. About 30% of all cases of CLL have immunoglobulin receptors with very similar nucleotide sequences. These quasi-identical receptors are called stereotyped. The most common 20 subtypes of stereotyped antigen receptors (SARs) are presented in 12% of all CLL cases. HLA-complex plays a central role in the formation of the immune response. Associations of specific HLA-alleles with different malignant, autoimmune and infectious diseases have been described. However, possible relationship of HLA phenotype to the development of CLL and the association of HLA alleles with disease are not completely understood.
Aim. To study the repertoire of HLA alleles in Russian CLL patients with the most common SARs.
Patients and methods. The study included 50 CLL patients with the most common IGHV genes and SARs, followed up at the National Research Center for Hematology from 2008 to 2019. Two groups of healthy donors were selected as control - one from Moscow (1507) and other from Eastern Siberia (296). The mutational status of IGHV and the SARs were determined according to European Research Initiative in CLL (ERIC) criteria. HLA-typing in 5 loci (HLA-A, -B, -C, -DRB1, -DQB1) was performed using Luminex 200 system (Luminex, TX, USA) with Lifecodes HLA SSO typing kits (Immucor, CT, USA). HLA frequencies were compared using chi-square test. ARLEQUIN software package, version 3.5 was used for statistical analysis.
Results. All patients enrolled in the study had unmutated IGHV genes. In 43 of them, homology with the germline gene was 100%, and in 7 - it was in the range of 98.6-99.7%. IGHV genes of 46 patients (92%) belonged to the 1st family. In 14 (28%) patients CLL#1 SAR, associated with the most aggressive course of the disease, was expressed. Nine patients (18%) each belonged to the CLL#3 and CLL#6 subtypes. The remaining patients expressed CLL#5, 7H, 12 and 28A SARs. No significant differences in the frequency of HLA-A alleles were found between CLL patients and both donor groups. HLA-B*18, HLA-B*52 and HLA-C*12:02 were found significantly more often in CLL patients than in donors. In the DRB1 locus, differences were observed in the two allelic groups. In CLL patients HLA-DRB1*15 was twice more frequent than in healthy donors, HLA-DRB1*13, on the contrary, was twice less frequent. No significant differences were found for DQB1 locus. Most common HLA haplotype frequencies were also calculated. DRB1*15-DQB1*06 haplotype was significantly 2 times more frequent in CLL patients than in donors. Furthermore, A*02-B*07-C*07-DRB1*15-DQB1*06 and A*25-B*18-C*12-DRB1*15-DQB1* 06 were more frequent, but these data were not statistically significant probably due to the small patient sample (Table 1). No significant differences were found between the SAR subtypes of CLL patients in the studied cohort.
Discussion. Despite a small sample, we were able to detect 4 predictive and 1 protective HLA allele for CLL patients. Our data disagree with the data of researchers from the United States and France and partially match those obtained by Iranian scientists. This might be explained by two reasons. First, HLA allele frequencies are differ between various populations. Second, we studied a small selected sample - all patients had unmutated IGHV genes, mainly from the same V gene family, and belonged to a cohort with an aggressive course of the disease. Further studies on extended samples of CLL patients are required to assess possible associations of HLA alleles with CLL subtypes and the course of the disease.

Disclosures
No relevant conflicts of interest to declare.