BIOLOGICAL AND CLINICAL RELEVANCE OF MIRNA EXPRESSION SIGNATURES IN PRIMARY PLASMA CELL LEUKEMIA

Purpose: Plasma cell leukemia (PCL) is a very aggressive and rare hematological malignancy that can be distinguished into primary (pPCL), originating de novo, or secondary (sPCL), arising as a leukemic transformation of multiple myeloma (MM). Genomic and clinical differences between pPCL and MM have been demonstrated, mainly based on retrospective studies. This study was aimed at investigating the involvement of miRNAs in pPCL and their possible relationship with higher tumor aggressiveness. Experimental design: MiRNA expression profiles were analyzed in highly-purified malignant plasma cells from 18 pPCL cases included in a prospective clinical trial. MiRNA expression patterns were evaluated in comparison with a representative series of multiple myeloma (MM) patients, in relation to the most recurrent chromosomal abnormalities (as assessed by fluorescence in situ hybridization and single nucleotide polymorphism-array analysis), and in association with clinical outcome. MiRNA expression was also integrated with gene expression profiles and computational prediction of miRNA target genes in pPCL and MM samples in order to identify putative target genes of deregulated miRNAs. The functional role of a few identified miRNAs in plasma cell dyscrasia pathogenesis was explored by transfection of synthetic pre/anti-miRNAs in multiple myeloma cell lines. Results: We identified a series of deregulated miRNAs in pPCL (42 up- and 41 down-regulated) in comparison with MM. Some of them, based on their reported functions or putative target genes computed by integrative analysis, might have a role in the pathobiology of pPCL, such as miR-21, that was found to promote in vitro growth of MM cell lines. As regards chromosomal aberrations, the expression of some miRNAs mapped to hot-spot altered regions was associated with DNA copy number of the corresponding genomic loci; furthermore, TP53 deletion, a frequent cytogenetic lesion in our pPCL cohort, was found associated with a trend of down-regulation of miR-34a, whose tumor suppressor activity was demonstrated for the first time also in the context of MM. Finally, four miRNAs (miR-497, miR-106b, miR-181a* and miR-181b) were identified having expression levels correlated with treatment response, and four (miR-92a, miR-330-3p, miR-22, and miR-146a) with clinical outcome. Conclusions: Overall, this study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations.