Ig gene sequences in the study of clonality.

Investigations of normal and neoplastic B cells are being channelled into new directions by recent work on immunoglobulin variable region genes. Assembling of heavy and light chain genes introduces enormous heterogeneity into the third complementarity determining regions (CDR3s) of immunoglobulins. For reasons that will become apparent below, variation in CDR3s is especially broad in heavy chains. Moreover, antigen-driven somatic mutations introduce another layer of permutations in antibody structures during the immune response. These diversifying mechanisms have interesting clinical applications. Our understanding of the clonal origins of malignant B cells has been improved by analysis of V gene structures in leukemias, B-cell lymphomas and multiple myelomas. Detection of very small populations of malignant clones within a larger population of normal B cells is now possible with the cell-specific markers encoded by the unique V gene sequences of the CDR3. In this report I will try to give an overview of how the immunoglobulin repertoire is being generated, how the immunoglobulin genes can be analysed and sequenced, what the clinical applications are for multiple myeloma and I will speculate a little bit about what the future might bring.