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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5101-5108.
Prepublished online as a Blood First Edition Paper on March 7, 2008; DOI 10.1182/blood-2007-12-130229.
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Submitted December 20, 2007
Accepted March 3, 2008
Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal-center leukemogenic selection
Emanuela M. Ghia, Sonia Jain, George F. Widhopf, 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, and Thomas J. Kipps*
Moores Cancer Center, Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
Division of Biostatistics and Bioinformatics, University of California, San Diego, La Jolla, CA, United States
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Centre for Medical Oncology, Barts and The London School of Medicine, London, England, United Kingdom
Medical Oncology, Dana Farber Cancer Institute, Boston, MA, United States
Hematology/Oncology, Long Island Jewish Medical Center, New Hyde Park, NY, United States
Medicine, The Ohio State University, Columbus, OH, United States
Division of Hematology, Mayo Clinic, Rochester, MN, United States
* Corresponding author; email: tkipps{at}ucsd.edu.
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 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 prior to undergoing Ig-receptor editing and post germinal-center leukemogenic selection.
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