Immunoglobulin Gene Analysis of Mature B-Cell Malignancies: Reconsideration of Cellular Origin and Potential Antigen Involvement in Pathogenesis

Mature B-cell malignancies stem from B cells transformed at various developmental stages, accounting for the wide range of heterogeneous features observed in the different disease entities. Analysis of the immunoglobulin (Ig) genes can facilitate the identification of the normal B-cell counterpart of lymphomas and leukemias, as Ig genes acquire somatic hypermutation in germinal centers during the immune response to antigen. Therefore, lymphomas that derive from a naïve, pregerminal center B cell lack somatic hypermutation in the clonal Ig gene, whereas germinal center-derived lymphomas, such as diffuse large B-cell lymphoma and follicular lymphoma, display somatic hypermutation of their Ig genes. Furthermore, biases in the Ig variable heavy chain gene repertoire in B-cell malignancies can indicate a possible antigenic influence in pathogenesis. Much work has been accomplished in the past decade to characterize the Ig genes in different lymphoma entities, and the separation of chronic lymphocytic leukemia into two prognostic subgroups in the late 1990s based on the presence or absence of somatic hypermutation led to investigations of Ig genes in larger cohorts of previously uncharacterized entities, such as mantle cell lymphoma. This review will briefly discuss relevant aspects of normal B-cell development, and then focus on what can be ascertained from Ig studies of newly characterized entities, mantle cell lymphoma, hairy cell leukemia, lymphoplasmacytic lymphoma/ Waldenström's macroglobulinemia, and splenic marginal zone lymphoma, from the point of view of cellular origin and variable heavy chain gene restrictions as a sign of antigen involvement. Correlations with gene expression profiling data and the clinical implications of Ig gene studies, when relevant, will be mentioned. The recent evidence that an alternative pathway of gaining somatic hypermutation might exist is also considered, and the implications this has for understanding the cellular origin of B-cell malignancies.