Immunoglobulin Gene Rearrangement and Expression in B-CLL.

Abstract

The malignant cells from most patients with B cell chronic lymphocytic leukemia (B-CLL) and related small lymphocytic lymphomas (SLL) co-express B cell differentiation antigens and the pan-T lymphocytes surface antigen CD5 (Leu 1). As such, B-CLL and related lymphomas generally may be considered malignancies of the CD5 B cell, a minor B cell subpopulation implicated in the production of autoantibodies. These malignancies are distinctive in that high proportions of patients have neoplastic B cells that express surface immunoglobulin (Ig) bearing one or more cross reactive idiotypes (CRIs) that commonly are present on monoclonal IgM autoantibodies. Molecular studies indicate that the frequent occurrence of these CRIs in CD5 B cell malignancies is secondary to the non-random rearrangement and use of highly conserved Ig variable region genes (V genes) expressed with little or no somatic hypermutation. In addition, studies with other neoplastic CD5 B-CLL cell populations, not selected for their expression of autoantibody-associated CRIs, reveal that they too may express a restricted set of V genes that have not substantially diversified from those present in the germline DNA. Consistent with the distinct clonal origin of each B-CLL, the Ig heavy chain sequence of each leukemia population is unique at the junction between the variable and constant regions of the Ig molecule in the third complementarity determining region (CDR3). Generated during the process of Ig VH gene rearrangement, the nucleic acid sequence encoding CDR3 is formed by possible N-terminal base insertions, one of several D minigenes and one of six JH gene segments. Despite the potential for great diversity in this region, there are structural similarities in the CDR3 of Ig heavy chains expressed by B-CLL bearing a major CRI, designated G6. This contrasts with the marked variation noted in the CDR3 of Ig heavy chains produced by normal non-malignant B cells that also bear the G6-CRI and use the same VH genes as G6-reactive B-CLL. Coupled with the observed potential bias in antibody light chain and heavy chain pairing in B-CLL, these data suggest that the autoantibodies expressed in this disease may be selected based on antigen binding activity. Collectively, these studies indicate that non-stochastic Ig V gene rearrangement and subsequent selection may influence the Ig repertoire expressed in this common B cell malignancy.