Chromosome translocations in multiple myeloma

Multiple myeloma (MM), a malignant tumor of somatically mutated, isotype-sw itched plasma cells (PC), usually arises from a common benign PC tumor call ed Monoclonal Gammopathy of Undetermined Significance (MGUS). MM progresses within the bone marrow, and then to an extramedullary stage from which MM cell lines are generated. The incidence of IgH translocations increases wit h the stage of disease: 50% in MGUS, 60-65% in intramedullarly MM, 70-80% i n extramedullary MM, and > 90% in MM cell lines. Primary, simple reciprocal IgH translocations, which are present in both MGUS and MM, involve many pa rtners and provide an early immortalizing event. Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cy clin D1), 6p2l (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf). They are mediated primarily by errors in IgH switch recombination and less ofte n by errors in somatic hypermutation, with the former dissociating the intr onic and 3 ' enhancer(s), so that potential oncogenes can be dysregulated o n each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Seco ndary translocations, which sometimes do not involve Ig loci, are more comp lex, and are not mediated by errors in B cell specific DNA modification mec hanisms. They involve other chromosomal partners, notably 8q24 (c-myc), and are associated with tumor progression. Consistent with MM being the malign ant counterpart of a long-lived PC, oncogenes dysregulated by primary IgH t ranslocations in MM do not appear to confer an anti-apoptotic effect, but i nstead increase proliferation and/or inhibit differentiation. The fact that so many different primary transforming events give rise to tumors with the same phenotype suggests that there is only a single fate available for the transformed cell.