Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis

Multiple myeloma is a post-germinal centre plasma cell tumour that is usually preceded by a pre-malignant condition, monoclonal gammopathy of undetermined significance. Both are characterized by hyperdiploidy and recurrent immunoglobulin gene translocations that all result in the direct or indirect dysregulation of the CCND/RB1 pathway. Analysis of the translocation breakpoints suggests that they most frequently occur as a result of an error during class switch recombination, but also VDJ recombination, and sometimes somatic hypermutation. A rearrangement of the MYC locus is identified in nearly one half of untreated patients with MM, most frequently (>60 %) those with hyperdiploidy, and less frequently (<25 %) those with t(11;14). The rearrangements juxtapose MYC to super-enhancers from elsewhere in the genome, resulting in dysregulated expression of MYC. One-third of the rearrangements involve an immunoglobulin gene enhancer (IGH > IGL >> IGK), and two-thirds one of a variety of non-immunoglobulin gene enhancers that are frequently associated with plasma cell gene expression (e.g., PRDM1, IGJ, FAM46C, TXNDC5, FOXO3). It is likely that early rearrangements of the MYC locus cause the progression of monoclonal gammopathy to multiple myeloma in many patients, and that late rearrangements of the MYC locus, frequently involving an immunoglobulin gene enhancer, contribute to further, often extramedullary, tumour growth.