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 Blood, 15 February 2007, Vol. 109, No. 4, pp. 1559-1567.
Prepublished online as a Blood First Edition Paper on November 2, 2006; DOI 10.1182/blood-2006-05-020644.

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IMMUNOBIOLOGY

Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification

Alicia D. Volkheimer1, J. Brice Weinberg1, Bethany E. Beasley1, John F. Whitesides3, Jon P. Gockerman1, Joseph O. Moore1, Garnett Kelsoe4, Barbara K. Goodman5, and Marc C. Levesque2

1 Department of Medicine, Division of Hematology-Oncology, Duke University and Durham VA Medical Centers, Durham, NC; 2 Division of Rheumatology, Allergy and Clinical Immunology, Duke University and Durham VA Medical Centers, Durham, NC; 3 Human Vaccine Institute, Duke University and Durham VA Medical Centers, Durham, NC; 4 Department of Immunology, Duke University and Durham VA Medical Centers, Durham, NC; 5 Department of Pathology, Duke University and Durham VA Medical Centers, Durham, NC

Somatic mutations of immunoglobulin genes characterize mature memory B cells, and intraclonal B-cell diversification is typically associated with expansion of B-cell clones with greater affinity for antigen (antigen drive). Evidence for a role of antigen in progression of intraclonal chronic lymphocytic leukemia (CLL) cell diversification in patients with mutated immunoglobulin genes has not been previously presented. We performed a single-cell analysis of immunoglobulin heavy and light chains in 6 patients with somatically mutated CLL-cell immunoglobulin genes and identified 2 patients with multiple related (oligoclonal) subgroups of CLL cells. We constructed genealogic trees of these oligoclonal CLL-cell subgroups and assessed the effects of immunoglobulin somatic mutations on the ratios of replacement and silent amino acid changes in the framework and antigen-binding regions (CDRs) of the immunoglobulin heavy and light chains from each oligoclonal CLL-cell population. In one subject, the amino acid changes were consistent with an antigen-driven progression of clonally related CLL-cell populations. In the other subject, intraclonal diversification was associated with immunoglobulin amino acid changes that would have likely lessened antigen affinity. Taken together, these studies support the hypothesis that in some CLL cases intraclonal diversification is dependent on antigen interactions with immunoglobulin receptors.


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