Molecular aspects of multiple myeloma

Multiple myeloma (MM) is a B-cell neoplasm characterized by bone marrow inf iltration with malignant plasma cells, which synthesize and secrete monoclo nal immunoglobulin (Ig) fragments. Despite the considerable progress in the understanding of MM biology, the molecular basis of the disease remains el usive. The initial transformation is thought to occur in a post-germinal ce nter B-lineage cell, carrying a somatically hypermutated Ig heavy chain (IG H) gene. This plasmablastic precursor cell colonizes the bone marrow, propa gates clonally and differentiates into a slowly proliferating myeloma cell population, all under the influence of specific cell adhesion molecules and cytokines. Production of interleukin-6 by stromal cells, osteoblasts and, in some cases, neoplastic cells is an essential element of myeloma cell gro wth, with the cytokine stimulus being delivered intracellularly via the Jac k-STAT and ras signaling pathways. While karyotypic changes have been ident ified in up to 50% of MM patients, recent molecular cytogenetic techniques have revealed chromosomal abnormalities in the vast majority of examined ca ses. Translocations mostly involve illegal switch rearrangements of the IGH locus with various partner genes (CCND1, FGFR3, c-maf). Such events have b een assigned a critical role in MM development. Mutations in coding and reg ulatory regions, as well as aberrant expression patterns of several oncogen es (c-myc, ras) and tumor suppressor genes (p16, p15) have been reported. K ey regulators of programmed cell death (BCL-2, Fas), tumor expansion (metal loproteinases) and drug responsiveness (topoisomerase II alpha) have also b een implicated in the pathogenesis of this hematologic malignancy. A tumori genic role for human herpesvirus 8 (HHV8) was postulated recently, followin g the detection of viral sequences in bone marrow dendritic cells of MM pat ients. However, since several research groups were unable to confirm this o bservation, the role of HHV8 remains unclear. Translation of the advances i n MM molecular biology into novel therapeutic strategies is essential in or der to improve disease prognosis.