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Genomic Analysis of Primary Plasma Cell Leukemia reveals Complex Structural Alterations and High Risk Mutational Patterns

ABSTRACT: Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype we performed whole exome sequencing of 23 patients with pPCL. For matched non-tumor control for each patient to exclude germline variants we used CD34+ cells from stem cell harvest (n=20) or cells obtained from buccal swabs (n=3). Tumor samples were from bone marrow derived CD138+ cells. Tumor samples were compared to the germline control to identify somatic abnormalities.

PROVIDER: EGAS00001003834 | EGA |

REPOSITORIES: EGA

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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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Genomic Analysis of Primary Plasma Cell Leukemia reveals Complex Structural Alterations and High Risk Mutational Patterns

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