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Transcriptome analysis reveals significant differences between primary plasma cell leukemia and multiple myeloma even when sharing a similar genetic background

ABSTRACT: Primary plasma cell leukemia (pPCL) is a highly aggressive plasma cell dyscrasia characterized by short remissions and very poor survival. Deletions of 17p13 are much more frequent in pPCL than in multiple myeloma (MM). Although the 17p deletion is associated with poor outcome and extramedullary disease in MM, its presence does not confer the degree of aggressiveness observed in pPCL. The comprehensive exploration of the transcriptome, including isoform expression and RNA splicing events, may provide novel information about biological differences between the two diseases carrying a 17p deletion. Transcriptomic studies were carried out with the Human Transcriptome Array in nine newly diagnosed pPCL and ten MM samples, all of which harbored the 17p deletion. Unsupervised cluster analysis clearly distinguished pPCL from MM samples. Indeed, 3,584 genes and 20,033 isoforms were found to be deregulated between pPCL and MM, most of which were underexpressed in pPCL. Pathway enrichment analysis at the gene and isoform levels revealed seven overlapping pathways mainly related to mRNA processing. There were 2,727 significantly deregulated isoforms of non-differentially expressed genes. Strangely enough, significant differences were observed in the expression of spliceosomal machinery components between pPCL and MM, in respect of the gene and isoform expression, and of the alternative splicing events. Furthermore, most of the deregulated exons have binding sites for most serine/arginine-rich proteins. In summary, transcriptome analysis revealed significant differences in the relative abundance of isoforms between pPCL and MM, even when they both had the 17p deletion. Importantly, the mRNA processing pathway including RNA splicing machinery emerged as one of the most remarkable mechanisms underlying the biological differences between the two entities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131216 | GEO | 2019/10/29

REPOSITORIES: GEO

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Project description:Primary plasma cell leukemia (pPCL) is a rare and very aggressive form of plasma cell dyscrasias. To date, no information of microRNA expression in pPCL has been reported. To investigate the role of miRNAs in pPCL, we analyzed global miRNA expression profiles of highly purified malignant plasma cells from 18 previously untreated patients included in a prospective clinical trial. MiRNA expression patterns were evaluated in the context of the molecular abnormalities of the disease and in comparison with a representative cohort of multiple myeloma (MM) patients. We identified a series of deregulated miRNAs in pPCL (42 up-regulated and 41 down-regulated) which may have a putative role in contributing to tumor progression in MM. Furthermore, we integrated miRNA and gene expression data with computational prediction of miRNA targets, finding that miRNAs differentially expressed between MM and pPCL could regulate genes with important functions in cancer. Overall, our study represents the first attempt to investigate the involvement of miRNAs in pPCL and may contribute to develop functional approaches to investigate the activity of deregulated miRNAs in aggressive forms of plasma cell dyscarsias and their possible role as novel therapeutic targets. This series of microarray experiments contains the microRNA profiles of purified plasma cells (PCs) obtained from 39 multiple myeloma (MM) and 18 primary plasma cell leukemia (pPCL) at diagnosis. PCs were purified from bone marrow specimens, after red blood cell lysis with 0.86% ammonium chloride, using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by morphology and flow cytometry and was > 90% in all cases. 500 nanograms of total RNA was processed in accordance with the manufacturer's protocols (Agilent Technologies) to generate Cy3-labelled RNA, which were purified on chromatography columns (Micro Biospin 6, Bio-Rad, Hercules, CA) and then hybridized on an Agilent microarray (G4470B) at 55M-BM-!C for 17 hr in a rotating oven. Images at 5 um resolution were generated using an Agilent scanner G2505B. The Feature Extraction 10.7.3.1 software (Agilent Technologies) was used to obtain the microarray raw-data. The raw gTotalGeneSignal has been recalculated using the procedures described in Agilent Feature Extraction Software version 10.1 manual. Non-human probes, miRNAs flagged as M-CM-^RabsentM-CM-^S (i.e. expressed below background levels) throughout the whole dataset and miRNAs expired according to Sanger miRBase Release 15 (April 2010) were discarded, and a quantile normalization was applied on raw data using the aroma.light package for Bioconducor. The data were then converted to obtain positive values throughout the dataset, at a minimum value of 1, and log2 transformed.

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Transcriptome analysis reveals significant differences between primary plasma cell leukemia and multiple myeloma even when sharing a similar genetic background

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