Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia

Abstract

We recently identified a chronic lymphocytic leukemia (CLL) subgroup using the immunoglobulin variable heavy-chain (VH) gene VH3-21 with almost identical heavy-chain complementarity determining region 3s (HCDR3s) and preferential variable light-chain (VL) gene usage, suggesting recognition of a common antigen epitope in this subset. To further explore the B-cell receptors (BCRs) in CLL, we characterized 407 VH rearrangements amplified from 346 CLLs regarding VH, diversity (D), and joining (JH) gene usage and performed multiple alignment of the HCDR3 sequences. These analyses revealed 3 small subsets (2 VH1-69 groups, 7 cases; and 1 VH1-2 group, 5 cases) with highly restricted HCDR3 features including identical VH/D/JH usage, HCDR3 lengths, and shared N-sequences, in addition to the VH3-21 group (22 cases). Furthermore, another 3 groups (9 VH1-3+ cases, 3 VH1-18+ cases, and 5 VH4-39+ cases) had essentially identical VH/D/JH use and similar HCDR3 lengths but less conserved N-regions. Analysis in all 6 of these subgroups showed restriction in VL gene use, whereas no association between VH and VL usage was found in cases without HCDR3 similarities. Altogether, structurally similar HCDR3s associated with preferential VL gene usage implies selection of BCRs, especially in subsets showing high HCDR3 similarities, thus pointing to restricted antigen recognition sites and possibly involvement of specific antigens in CLL development.