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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3137-3144.
Prepublished online as a Blood First Edition Paper on August 3, 2007; DOI 10.1182/blood-2007-02-073130.
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Submitted February 8, 2007
Accepted June 18, 2007
Non-stochastic pairing of immunoglobulin heavy and light chains expressed by chronic lymphocytic leukemia B cells is predicated on the heavy chain CDR3
George F. Widhopf II, Craig J. Goldberg, Traci L. Toy, Laura Z. Rassenti, William G. Wierda, John C. Byrd, Michael J. Keating, John G. Gribben, Kanti R. Rai, and Thomas J. Kipps*
The CLL Research Consortium, La Jolla, CA, United States
Moores UCSD Cancer Center, UCSD School of Medicine, La Jolla, CA, United States
Division of Hematology/Oncology, Department of Medicine, UCSD School of Medicine, La Jolla, CA, United States
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Division of Hematology and Oncology, The Ohio State University, Columbus, OH, United States
Cancer Research UK Med Oncology Unit, Barts and The London School of Medicine, London, United Kingdom
Division of Hematology/Oncology, Long Island Jewish Medical Center, New Hyde Park, NY, United States
* Corresponding author; email: tkipps{at}ucsd.edu.
We analyzed the immunoglobulin (Ig) variable heavy (IGHV) and variable light (VL) chain genes used by leukemia cells of 258 unrelated patients with chronic lymphocytic leukemia (CLL) found to express unmutated Ig heavy chains (IgH) encoded by a 51p1 allele of IGHV1-69 among 1,846 CLL patients examined. We found each had 98% homology to an identified germline IGKV or IGLV gene. Within the 258 IgH, we identified heavy chain CDR3 (HCDR3) motifs encoded by certain unmutated IGHD and IGHJ genes with restricted reading frames. Frequent and restricted use of particular IGKV and IGLV genes revealed non-stochastic pairing of disparate Ig light chains (IgL) with IgH that had restricted HCDR3 motifs designated CLL69A, B, C, and D. Eighty-six percent (19/22) of CLL cases that expressed motif CLL69B encoded by IGHD2-2/IGHJ6 had distinctive IgL encoded by IGKV1-39. Similarly, 83% (5/6) of samples with motif CLL69D encoded by IGHD2-2/IGHJ6 expressed IGKV3-11, 100% (25/25) with motif CLL69A encoded by IGHD3-16/IGHJ3 used IGKV3-20, and 77% (10/13) with motif CLL69C encoded by IGHD3-3/IGHJ6 expressed IGLV3-9. This study reveals non-stochastic pairing of IgH with particular IgL that is predicated upon Ig HCDR3 structure, providing compelling evidence for selection of antibodies expressed in CLL by conventional antigens.
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