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

ABSTRACT We examined the chronic lymphocytic leukemia (CLL) cells of 2,457 patients evaluated by the CLL Research Consortium and found 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 were 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 to that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n=30) versus unmutated IGHV3-21 (n=33). Of seven examined cases that used Ig encoded by IGHV3-21 / IGLV3-21 , we found that five had a functionally-rearranged IGKV allele that apparently had incurred antigen-driven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing /