The Immunoglobulin genes and Chronic Lymphocytic Leukemia (CLL)

Abstract

The somatic hypermutation (SMH) status of the immunoglobulin (Ig) V_H genes can divide chronic lymphocytic leukemia (CLL) into two prognostic subsets, with mutated V_H genes display superior survival compared to unmutated cases. Biased V_H gene usage has also been reported in CLL which may reflect antigen selection. In a V_H gene analysis of 265 CLL cases we confirmed the prognostic impact of the V_H mutation status and found preferential V_H gene usage in both the mutated and unmutated subset. Interestingly, CLL cases rearranging one particular V_H gene, V_H3-21, displayed poor outcome despite that two-thirds showed mutated V_H genes. Many of the V_H3-21 utilizing cases expressed λ light chains, rearranged a V_λ2-14 gene, and had homologous complementarity determining region 3s (CDR3s), implying recognition of a common antigen epitope. We thus believe that the cases rearranging the VH₃-21 gene comprises an additional CLL entity. We further analyzed the VH gene rearrangements and, specifically, the heavy chain CDR3 sequences in 346 CLL cases to investigate the role of antigens in CLL. We identified six new subgroups with similar HCDR3 features and restricted VL gene usage as in the VH₃-21-using group. Our data indicate a limited number of antigen recognition sites in these subgroups and give further evidence for antigen selection in the development of CLL. Different mutational cutoffs have been used to distinguish mutated CLL in addition to the 2% cutoff. Using three levels of somatic mutations we divided 323 CLLs into subsets with divergent survival (<2%, 2–5% and >5% mutations). This division revealed a low-mutated subgroup (2–5%) with inferior outcome that would have been masked using the traditional 2% cutoff. A 1513A/C polymorphism in the P2X₇ receptor gene was reported to be more frequent in CLL, but no difference in genotype frequencies was revealed in our 170 CLL cases and 200 controls. However, CLL cases with the 1513AC genotype showed superior survival than 1513AA cases and this was in particular confined to CLL with mutated VH genes. In summary, we could define new prognostic subgroups in CLL using Ig gene rearrangement analysis. This also allowed us to gain insights in the biology and potential role of antigen involvement in the pathogenesis of CLL.