INSIGHT INTO THE ORIGIN AND CLONAL HISTORY OF B-CELL TUMORS AS REVEALED BY ANALYSIS OF IMMUNOGLOBULIN VARIABLE REGION GENES

Recombination of V-H, D-H and J(H) genes is a unique first step in nor mal B-cell development. Subsequent differentiation to a mature plasma cell is accompanied by further events in the Ig genes, including V-L-J (L) joining, somatic hypermutation and isotype switching. Chromosomal changes leading to B-cell rumors can occur at many points in this sequ ence, and may be partly a consequence of the genetic mobility and muta bility permitted in order to generate a diverse antibody repertoire. V genes of neoplastic B cells may reflect the point of maturation reach ed by the B cell of origin, prior to transformation. Analysis of tumor s therefore provides useful information on V-gene patterns in normal B cells, and may add another dimension to classification of B-cell tumo rs. Transformation may also preserve cell populations normally destine d to die by apoptosis. Tumor cells arrested in the site where somatic hypermutation and isotype switch are occurring can still be subject to these processes, and could be influenced by persisting antigen. Howev er, mutation is silenced at the point of exit to the periphery, leadin g to fixed mutational patterns in rumors of mature B cells. V-gene ana lysis provides an invaluable tool for understanding the genesis of neo plastic change. It also has a clear clinical relevance in tracking tum or cells, measuring residual disease, and finally in offering the oppo rtunity of developing vaccines for treatment.