Isotype Class Switching and the Pathogenesis of Multiple Myeloma

Translocations at the immunoglobulin heavy chain locus (14q32) are now considered the commonest karyotypic change in multiple myeloma. These translocations are thought to be intimately involved in the pathogenesis of this disease. The heavy chain locus is strongly transcriptionally active in B and plasma cells and transfer of a potential oncogene to 14q32 would result in its dysregulation. Molecular characterization suggests that the majority of these breakpoints cluster in switch regions within the heavy chain locus. Switch regions are normally involved in the regulated process of isotype switching so that in myeloma the rearrangements are believed to be a result of so-called illegitimate (aberrant) switch recombination and are likely to be an early event in myeloma development. A legitimate switch recombination event occurs between two switch regions producing a hybrid switch; this is necessary for class switching to proceed on a productive allele. In this review we describe the process of isotype switching and how illegitimate class switching may be related to the pathogenesis of multiple myeloma.