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.

• Authors: Emanuela M Ghia, Sonia Jain, George F Widhopf 2nd, Laura Z Rassenti, Michael J Keating, William G Wierda, John G Gribben, Jennifer R Brown, Kanti R Rai, John C Byrd, Neil E Kay, Andrew W Greaves, Thomas J Kipps
• Journal: Blood (Blood) Vol. 111 Issue 10 Pg. 5101-8 (May 15 2008) ISSN: 1528-0020 [Electronic] United States
• PMID: 18326815 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Complementarity Determining Regions
• Immunoglobulin Heavy Chains
• Immunoglobulin Variable Region

Topics

• Amino Acid Sequence
• B-Lymphocytes (immunology)
• Complementarity Determining Regions
• Humans
• Immunoglobulin Heavy Chains (genetics)
• Immunoglobulin Variable Region (genetics)
• Leukemia, Lymphocytic, Chronic, B-Cell (diagnosis, immunology)
• Molecular Epidemiology
• Prognosis