There appear to be two pathways involved in the early pathogenesis of premalignant MGUS and malignant MM tumors. Nearly half of these tumors are non-hyperdiploid and most have IgH translocations that involve five recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (c-maf) and 20q11 (mafB). The remaining tumors are hyperdiploid and contain multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19 and 21, but infrequently have IgH translocations involving the five recurrent loci. Dysregulated expression of cyclin D1, D2 or D3 appears to occur as an early event in virtually all of these tumors, providing a unifying pathogenic event. This may render the cells more susceptible to prolif-erative stimuli, resulting in selective expansion as a result of interaction with bone marrow stromal cells that produce IL-6 and other cytokines. Delineation of the mechanisms mediating MM cell proliferation, survival and migration in the bone marrow microenvironment may both enhance understanding of pathogenesis and provide the framework for identification and validation of novel molecular targets.

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