B cell maturation in relation to multiple myeloma

Maturation of a normal B-cell precursor to a mature plasma cell involves rearrangement and somatic mutation of the immunoglobulin variable (V) region genes. These events occur at distinct stages of development, and when a B cell undergoes neoplastic transformation, the genetic imprint reflects the clonal history of the cell of origin. Sequence analysis of V-genes can reveal bias as compared with the available repertoire, possibly reflecting a role for superantigen in stimulation of certain B cells. It can also indicate if the tumour cell has encountered the site of somatic mutation in the germinal centre, and if this mechanism is still active post-transformation. Analysis may also reveal a potential influence of persistent antigen in driving tumour growth. Genetic evidence supports the concept that tumour cells are not frozen at a single point of differentiation, but are able to move through certain limited stages. For myeloma, V-gene analysis indicates that the malignant cell population is likely to be derived from an antigen-selected plasma cell, but that a less mature minor B cell population of identical sequence may coexist. In contrast, benign plasma cell tumours can include B cells still undergoing somatic mutation. In both malignant and benign disease, transcripts of clonally-related alternative isotypes have been identified V-gene analysis is contributing to the diagnosis, monitoring and understanding of B-cell tumours, and may facilitate the development of rational approaches to therapy.