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Chronic Lymphocytic Leukemia B Cells Can Undergo Somatic Hypermutation and Intraclonal Immunoglobulin V_HDJ_H Gene Diversification

Carmela Gurrieri¹, Peter McGuire², Hong Zan¹, Xiao-Jie Yan², Andrea Cerutti¹, Emilia Albesiano², Steven L. Allen², Vincent Vinciguerra², Kanti R. Rai³, Manlio Ferrarini⁴, Paolo Casali¹ and Nicholas Chiorazzi²

¹ Division of Molecular Immunology, Department of Pathology, Cornell University Weill Medical College, and Immunology Program, Cornell University Weill Graduate School of Medical Sciences, New York, NY 10021
² North Shore-LIJ Research Institute and the Departments of Medicine, North Shore University Hospital and NYU School of Medicine, Manhasset, NY 11030
³ Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040
⁴ Division of Clinical Immunology, Istituto Nazionale per la Ricerca sul Cancro, Dipartimento di Oncologia Clinica e Sperimentale, Universita' di Genova, 16132 Genova, Italy

Address correspondence to Nicholas Chiorazzi, North Shore-LIJ Research Institute, 350 Community Dr., Manhasset, NY 11030. Phone: 516-562-1085; Fax: 516-562-1022. E-mail: nchizzi{at}nshs.edu or Paolo Casali, Cornell University Weill Medical College, 1300 York Ave., New York, NY 10021. Phone: 212-746-6460; Fax: 212-746-4483. E-mail: pcasali{at}med.cornell.edu

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5⁺ B lymphocyte that is thought not to undergo intraclonal diversification. Using V_HDJ_H cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1–35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their V_HDJ_H genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone.

Key Words: B lymphocyte • chronic lymphocytic leukemia • somatic hypermutation • Ig gene • V gene diversification

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