Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection

Abstract

We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.

Figure 1

Amino acid sequences of IGHV3-21 mutated cases. Capital letters indicate amino acid changes resulting from R mutations. Hyphens indicate homology at that position to the reference IGHV3-21 amino acid sequence (accession number AB019439). Listed on the left is the designation for each CLL sample.

Figure 2

Comparison of the heavy chain mutational status in IGHV3-21 expressing IGKV or IGLV genes. The lines indicate the mean percent of IGHV homology in the UM IGKV or IGLV (mean percentage IGHV homology, 99.7% and 98%, respectively) and in the M IGKV or IGLV (mean percentage IGHV homology, 94.8% and 95.3%, respectively).

Figure 3

Comparison between median time from diagnosis to first treatment of study 1 cohort (N = 307)† and IGHV3-21 (N = 57) using cutoff = 98%. †Data are from Rassenti et al.

Figure 4

IGKV amino acid sequences of 5 cases with CLL cells expressing M-IGHV3-21 with HCDR3 motif1, U-IGLV3-21, and in-frame IGKV-J-KDE rearrangements. Capital letters indicate amino acid changes resulting from R mutations. Hyphens indicate homology at that position to the respective reference IGKV amino acid sequence. Listed on the left is the designation for each CLL sample.