Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia

Purpose: To determine the origin and relationship of the rare IgG(+) variant of chronic lymphocytic leukemia (CLL) to the two common IgM(+)IgD(+) subsets that are distinguished by expression of unmutated or mutated V-H genes, with the former having a worse prognosis. Experimental Design: IgG(+) CLL cells were characterized using phenotypic, functional, and immunogenetic analyses. Results: IgG(+) CLL was phenotypically similar to mutated IgM(+)IgD(+) CLL (M-CLL) and variably expressed CD38 (4 of 14). ZAP-70, a tyrosine kinase preferentially expressed in unmutated CLL, was found in only 2 of 14 cases. The ability to signal via surface IgM (sIgM) varies between the main subsets of CLL and is associated with expression of ZAP-70. In IgG(+) CLL, 9 of 14 responded to engagement of slgG with no apparent requirement for expression of CD38 or ZAP-70. However, signal capacity correlated with intensity of sIgG expression. Most switched immunoglobulin variable region genes were somatically mutated without intraclonal variation, and no case expressed activation-induced cytidine deaminase. Derivation from a postgerminal center B cell is, therefore, likely, and a relationship with M-CLL is suggested. This is supported by a shared biased usage of the V4-34 gene. Similar bias in normal B cells developed with age, providing an expanded population for transforming events. However, conserved sequences detected in the CDR3 of V4-34-encoded gamma chains were not found M-CLL, indicating no direct path of isotype switch from M-CLL. Conclusion: IgG(+) CLL is likely to arise from an age-related expanded pool of B cells, on a path parallel to M-CLL, and perhaps with a similar clinical course.