Patterns of Microrna in Plasma Cells: From Normal Differentiation to Multiple Myeloma

Background: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression either via the degradation of target mRNAs or the inhibition of protein translation. miRNAs have been involved in fine-tuning critical cellular processes and play critical roles in cell differentiation and tumor development. Furthermore, there is an increasing recognition of the role of miRNAs in multiple myeloma, a plasma cell (PC) malignancy characterized by an accumulation of malignant PCs within the bone marrow. However, little is known about miRNA expression during human PCD as well as about the full extent to which individual miRNAs regulate fundamental processes during PCD. A complete delineation of miRNA and their target expression during normal PCD is essential to understand the role of miRNAs in plasma cell malignancies.

Methods: We analyzed the expression profile of miRNAs and mRNAs during human plasma cell differentiation (PCD) to infer miRNA-target relationships, as well as in multiple myeloma tumor plasma cells. We developed a method and an R package, that uses miRNA and mRNA expression profiles across PCD cell subpopulations to infer candidate miRNA-target interactions that could be active and functional in PCD. We inferred miRNA-target relationships from sequence-based prediction, experimentally validated target interactions curated from the literature, published data from miRNA perturbation experiments and inverse expression relationships between miRNAs and their target mRNAs.

Results: Our results reveal 63 miRNAs with significant temporal changes in their expression during normal PCD. We derived a high-confidence network of 295 target relationships comprising 47 miRNAs and 147 targets. These relationships include new examples of miRNAs that are likely to coordinately regulate multiple members of critical pathways associated with PCD. Notably, we identify new miRNAs that coordinately regulate important pathways in PCD, including members of miR-30 and miR-29 families, miR-106b and miR-16, which regulates IRF4/PRDM1 axis, active DNA methylation pathway, TGF-b signaling pathway, autophagy, ZBTB4/EZH2 axis and cell cycle progression. Furthermore, our work demonstrates that 28 PCD stage-specific miRNAs are aberrantly overexpressed in multiple myeloma cells (MMCs) compared to their normal counterpart and/or are associated with high risk myeloma, suggesting that MMCs frequently acquired expression changes in miRNAs already undergoing dynamic expression modulation during normal PCD. Finally, expression of some targets of these PCD - MM miRNAs is correlated with clinical outcome of uniformly treated MM patients.

Conclusions: Altogether, our results demonstrate that miRNAs may be important in controlling PCD and malignant plasma cell biology.