Submitted May 9, 2006
Accepted September 26, 2006
Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification
Alicia D Volkheimer, J Brice Weinberg, Bethany E Beasley, John F Whitesides, Jon P Gockerman, Joseph O Moore, Garnett Kelsoe, Barbara K Goodman, and Marc C Levesque*
Dept of Medicine, Division of Hematology-Oncology, Duke University and Durham VA Medical Centers, Durham, NC
Human Vaccine Institute, Duke University and Durham VA Medical Centers, Durham, NC
Dept of Immunology, Duke University and Durham VA Medical Centers, Durham, NC
Dept of Pathology, Duke University and Durham VA Medical Centers, Durham, NC
Division of Rheumatology, Allergy & Clinical Immunology, Duke University and Durham VA Medical Centers, Durham, NC
* Corresponding author; email: marc.levesque{at}duke.edu.
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 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 six patients with somatically mutated CLL cell immunoglobulin genes and identified two patients with multiple related (oligoclonal) subgroups of CLL cells. We constructed genealogical 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.
