Abstract
Microarray analysis of the multiple myeloma (MM) miRNome has unraveled the differential expression of miRNAs in cytogenetic subgroups, their involvement in the tumor biology and their effectiveness in prognostic models. Herein, the small RNA transcriptional landscape in MM has been investigated exploiting the possibilities offered by small RNA-seq, including accurate quantification of known mature species, discovery and characterization of isomiRs, and miRNA-offset RNAs (moRNAs). Matched small RNA-seq and miRNA GeneChip® microarray expression profiles were obtained in a representative panel of 30 primary MM tumors, fully characterized for genomic aberrations and mutations. RNA-seq and microarray gave concordant estimations of known species. Enhanced analysis of RNA-seq data with the miR&moRe pipeline led to the characterization of 655 known and 17 new mature miRNAs and of 74 moRNAs expressed in the considered cohort, 5 of which (moR-150-3p, moR-24-2-5p, moR-421-5p, moR-21-5p, and moR-6724-5p) at high level. Ectopic expression of miR-135a-3p in t(4;14) patients, upregulation of moR-150-3p and moR-21-5p in t(14;16)/t(14;20) samples, and of moR-6724-1-5p in patients overexpressing CCND1 were uncovered and validated by qRT-PCR. Overall, RNA-seq offered a more complete overview of small non-coding RNA in MM tumors, indicating specific moRNAs that demand further investigations to explore their role in MM biology.
Highlights
Many studies highlighted the relevant role of micro-RNAs in the pathology of multiple myeloma (MM)[1]
Microarray and quantitative real-time PCR analyses of the miRNome of plasma cells (PCs) from primary MM tumors have unraveled the differential expression of miRNAs and miRNA clusters in specific molecular subgroups, exemplarily the marked upregulation of the miR-99b/let-7e/miR-125a-5p cluster in t (4;14)[2,3,4]
All PC dyscrasia cases were investigated by fluorescence in-situ hybridization for the major immunoglobulin heavy chain locus (IGH@) translocations and genetic lesions, and MM patients were stratified according to molecular prognostic stratification[25] (Supplementary Table 1)
Summary
Many studies highlighted the relevant role of micro-RNAs (miRNAs) in the pathology of multiple myeloma (MM)[1]. We and others have demonstrated the effectiveness of miRNA expression to predict outcome and to date, the investigation of miRNA expression in MM has been limited to microarray or PCR approaches. Albeit the cohorts and the number of investigated RNAs became increasingly extensive, the study of small RNA has still not exploited all the possibilities offered by next-generation sequencing. These include, but are not limited to, (i) improved detection of low-expressed mature species, (ii) accurate quantification of isomiRs11, and (iii) comprehensive investigation of miRNA-offset RNAs (moRNAs)[12,13].
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