High-Risk Multiple Myeloma Is Characterized by Uniform Over-Expression of Mirnas and Increased Copy Number and Expression of Argonaute 2, A Master Regulator of Mirna Maturation and B-Cell Development.

MicroRNAs (miRNAs) are non-coding RNAs that regulate mRNA expression. miRNAs often act synergistically to repress target genes and their deregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression miRNA and mRNA in cancer has not been studied in detail.

We used whole genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma (MM) to correlate miRNA expression profiles with a validated mRNA-based risk stratification, proliferation index, and pre-defined gene sets.

In stark contrast to mRNAs, we discovered that all tested and expressed miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P <.01) and proliferation index (P < .05) (Shaughnessy et al. Blood. 2007,109:2276). Surprisingly, although chromosome 13 is deleted in ∼50% of patients with MM (Shaughnessy et al. Blood. 2000,96:1505 and Tricot et al. Blood. 1995,86:4250), 2 of the 10 expressed miRNAs that map to chromosome 13 were expressed at significantly higher levels in MM samples than in normal samples (FDR<0.1), and the other eight were expressed at marginally higher levels. In line with this observation, miRNAs at chromosome 13, such as hsa-miR-17-5p and hsa-miR-16, were significantly positively associated with the risk score and the proliferation index. Gene Set Enrichment Analysis revealed that global miRNA expression level was associated with numerous pre-defined high-risk cancer gene sets, such as a gene set containing the genes up-regulated in multiple types of undifferentiated cancers (Rhodes et al. Proc Natl acad Sci. 2004,101:9309), and a gene set that we previously defined as up-regulated in proliferation subgroup of MM (Zhan et al. Blood. 2006,108:2020). Finally, increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs (Liu et al. Science. 2004,305:1437; O'Carroll et al. Genes Dev. 2007,21:1999 and Diederichs et al. Cell. 2007,131:1097) and a component of the 70-gene mRNA risk model (Shaughnessy et al. Blood. 2007,109:2276), is driven by DNA copy number gains in MM. Silencing AGO2 dramatically decreased viability in MM cell lines.

Our novel findings suggest that all expressed miRNAs, rather than selected miRNAs, synergistically function to regulate progression of disease of MM and that this may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function.

van Rhee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shaughnessy:Myelozix: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.