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Structural and Functional Features of the B-Cell Receptor in IgG-Positive Chronic Lymphocytic Leukemia

Authors' Affiliations: ¹ Molecular Immunology Group, Tenovus Research Laboratory, Cancer Sciences Division, Southampton General Hospital; ² Department of Haematology, Southampton University Hospitals Trust; ³ Cancer Research UK Clinical Centre, Southampton, United Kingdom; and ⁴ Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom

Requests for reprints: Kathleen N. Potter, Cancer Sciences Division, Southampton General Hospital, Somers Cancer Research Building, Mailpont 891, Tremona Road, Southampton SO16 6YD, United Kingdom. E-mail: kp1{at}soton.ac.uk.

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 sIgG 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 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.

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