Molecular pathogenesis of multiple myeloma and its premalignant precursor
W. Michael Kuehl, P. Leif Bergsagel
W. Michael Kuehl, P. Leif Bergsagel
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(10):3456-3463. https://doi.org/10.1172/JCI61188.
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Review Series

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.

Authors

W. Michael Kuehl, P. Leif Bergsagel

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Figure 2

Early and late disruption of the RB pathway.

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Early and late disruption of the RB pathway. The early dysregulation of ...
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.