Molecular pathogenesis of multiple myeloma and its premalignant precursor

Abstract

Multiple myeloma is a monoclonal tumor of plasma cells, and its development is preceded by a premalignant tumor with which it shares genetic abnormalities, including universal dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway. A complex interaction with the BM microenvironment, characterized by activation of osteoclasts and suppression of osteoblasts, leads to lytic bone disease. Intratumor genetic heterogeneity, which occurs in addition to intertumor heterogeneity, contributes to the rapid emergence of drug resistance in high-risk disease. Despite recent therapeutic advances, which have doubled the median survival time, myeloma continues to be a mostly incurable disease. Here we review the current understanding of myeloma pathogenesis and insight into new therapeutic strategies provided by animal models and genetic screens.

Figure 1. Interactions of MM tumor cells with the BM microenvironment.

Five kinds of cells in the BM microenvironment are depicted, as well as a few of the complex interactions among these cells and MM cells. Some of the critical survival and growth factors, such as IL-6, are made by more than one kind of BM cell. External stimuli, such as hypoxia and internal signals resulting from dysregulated MYC, stimulate HIF-1α and VEGF secretion, which in turn stimulate endothelial cells to secrete IGF-1. The hallmark uncoupling of bone remodeling is partially explained by an increase in osteoclast activity (mediated by RANKL/RANK interactions, decreased osteoprotegerin (OPG), and increased MIP-1α) and a decrease in osteoblast activity (mediated by DKK1 and IL-3). The resultant increase in osteoclast activity stimulates the survival and growth of MM cells, at least partially by increased IL-6. Potential therapeutic agents that directly inhibit some of these interactions include bisphosphonates (which inhibit osteoclast function), anti-RANKL antibody, anti-DKK1 antibody, and exogenous OPG.

Figure 2. Early and late disruption of the RB pathway.

The early dysregulation of a cyclin D gene provides the basis for the TC classification (see text for details). Yet most MGUSs and most MM tumors are minimally proliferative, perhaps a result of the inhibitory effects of p18INK4c, since p16INK4a usually is not expressed. Increased proliferation at late stages of progress sometimes is associated with inactivation of p18 or RB1, but most proliferative tumors have a paradoxically high level of p18INK4c expression and normal levels of RB1.

Figure 3. Model for molecular pathogenesis of MGUS and MM.

The initial transition (TR1) to a recognizable tumor involves two mostly non-overlapping pathways (IgH translocations versus multiple trisomies) that include primary events associated with dysregulated cyclin D expression in MGUS and MM. The transition from MGUS to MM (TR2) is associated with increased MYC expression and sometimes with activating mutations of K-RAS or chromosome 13 deletion. Early and late progression events for symptomatic MM tumors are shown.