PB1874 STEREOTYPE ANTIGEN RECEPTORS IN B‐CELL LYMPHOPROLIFERATIVE DISEASES
Authors: Biderman B. , Julhakyan H. , Koroleva D. , Zvonkov E. , Nikitin E. , Sudarikov A. 
Published: June 2019

Background:

Studies over the last 20 years suggest a significant role of antigen stimulation in the pathogenesis of B‐cell lymphoproliferative diseases. Immunoglobulin gene heavy chain variable region (IGHV) repertoire narrowing is an evidence for the involvement of a limited set of antigens or superantigens in the development of lymphomas. For some diseases, e.g. chronic lymphocytic leukemia (CLL), the existence of more than 200 subgroups of tumor IGHV antigen‐binding sites, so called stereotypical antigen receptors (SAR), has been shown among unrelated cases. Most common subgroups (19 SARs) are responsible for more than 12% of all cases of CLL. For other lymphomas, the existence of SARs is also suggested.

Aims:

To compare the features of tumor IGHVs and possible SARs in CLL, mantle cell lymphoma (MCL) and in the splenic marginal zone lymphoma (SMZL).

Methods:

The study included samples of 680 patients with B‐CLL, 38 with SMZL and 40 with MCL directed to the National Research Center for Hematology for the genetic analysis between 2006 to 2019. The nucleotide sequences of the IGHV genes were determined according to ERIC protocol.

Results:

In CLL most common IGHV genes were IGHV1‐69, IGHV1‐2 (mostly unmutated) and IGHV3‐30, IGHV4‐34, IGHV3‐23 (mostly mutated) ‐ they occur in 40% of patients. The most common SARs were CLL#1 (genes of 1, 5 and 7 families, excluding IGHV1‐69), CLL#2 (IGHV3‐21), CLL#6,7,9 (IGHV1‐69). The most common SAR with mutated genes and, accordingly, with a favorable prognosis, was CLL # 4 (IGHV4‐34).

In MCL the most common genes were IGHV4‐34, IGHV3‐21, IGHV3‐23, IGHV3‐30, IGHV4‐59 ‐ 57% of all patients. At the same time, unlike in CLL, the IGHV4‐34 gene was often unmutated. We found 3 pairs of MCL patients with sequences of CDR3 regions that formally meet SAR characteristics: IGHV4‐34/IGHD2‐2/IGHJ6 (MCL#1), IGHV3‐21/ IGHD3‐3/IGHJ6 (MCL#2), IGHV4‐59/IGHJ6 (MCL#3). CDR3 of one patient was highly homologous to the rearrangement IGHV4‐34/IGHD1‐26/IGHJ6 (MCL#4) described in the literature.

In SMZL the most frequent gene was IGHV1‐2 ‐ 50% of all cases. Moreover, our sample of SMZL is characterized by a strict usage of IGHV1‐2∗04 allele, while in CLL this allele accounts for 25% of all cases only. Unlike in CLL, the frequencies of mutated and unmutated IGHV1‐2 cases were equal. Despite a strong narrowing of IGHV and IGHD repertoires in our SMZL sample (IGHD3‐3 and IGHD3‐10 genes are overrepresented), only 2 pairs of patients could have possible SARs (IGHV1‐2∗04/IGHD3‐3/IGHJ5 and IGHV1‐2∗04/IGHD3‐3/IGHJ5 rearrangements).

When comparing the sequences of SARs between the diseases, it was found that in the vast majority of cases they are highly disease‐specific both at the level of nucleotide and amino acid sequences. The only exclusion were MCL#1 and CLL#64D SARs formed by the same set of genes, having similar amino acid motifs and differ only in length.

Summary/Conclusion:

Our results suggest that antigens crucial for the pathogenesis of B‐cell malignancies could be disease‐specific. More data obtained from the extended samples of non‐CLL patients are required to assess the role of SARs in pathogenesis of these diseases and may also contribute to the development of new diagnostic and prognostic markers.