An integrative genomic approach reveals coordinated expression of intronic miR-335, miR-342, and miR-561 with deregulated host genes in multiple myeloma

<p>Abstract</p> <p>Background</p> <p>The role of microRNAs (miRNAs) in multiple myeloma (MM) has yet to be fully elucidated. To identify miRNAs that are potentially deregulated in MM, we investigated those mapping within transcription units, based on evidence that intronic miRNAs are frequently coexpressed with their host genes. To this end, we monitored host transcript expression values in a panel of 20 human MM cell lines (HMCLs) and focused on transcripts whose expression varied significantly across the dataset.</p> <p>Methods</p> <p>miRNA expression was quantified by Quantitative Real-Time PCR. Gene expression and genome profiling data were generated on Affymetrix oligonucleotide microarrays. Significant Analysis of Microarrays algorithm was used to investigate differentially expressed transcripts. Conventional statistics were used to test correlations for significance. Public libraries were queried to predict putative miRNA targets.</p> <p>Results</p> <p>We identified transcripts specific to six miRNA host genes (<it>CCPG1</it>, <it>GULP1</it>, <it>EVL</it>, <it>TACSTD1</it>, <it>MEST</it>, and <it>TNIK</it>) whose average changes in expression varied at least 2-fold from the mean of the examined dataset. We evaluated the expression levels of the corresponding intronic miRNAs and identified a significant correlation between the expression levels of <it>MEST</it>, <it>EVL</it>, and <it>GULP1 </it>and those of the corresponding miRNAs miR-335, miR-342-3p, and miR-561, respectively. Genome-wide profiling of the 20 HMCLs indicated that the increased expression of the three host genes and their corresponding intronic miRNAs was not correlated with local copy number variations. Notably, miRNAs and their host genes were overexpressed in a fraction of primary tumors with respect to normal plasma cells; however, this finding was not correlated with known molecular myeloma groups. The predicted putative miRNA targets and the transcriptional profiles associated with the primary tumors suggest that <it>MEST</it>/miR-335 and <it>EVL/</it>miR-342-3p may play a role in plasma cell homing and/or interactions with the bone marrow microenvironment.</p> <p>Conclusion</p> <p>Our data support the idea that intronic miRNAs and their host genes are regulated dependently, and may contribute to the understanding of their biological roles in cancer. To our knowledge, this is the first evidence of deregulated miRNA expression in MM, providing insights that may lead to the identification of new biomarkers and altered molecular pathways of the disease.</p

La patria degli altri

I concetti di "patria" e di "alterità" declinati attraverso diverse culture e letterature.The ideas and concepts of "Homeland" and "Alterity" declined through different cultures and literatures

DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome

DIS3 gene mutations occur in roughly 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), which occur in approximately 40% of MM cases. Despite several reports on the prevalence of DIS3 mutations, their contribution to the pathobiology of MM remains largely unknown. We took advantage of the large public CoMMpass dataset to investigate the spectrum of DIS3 mutations in MM and its impact on the transcriptome and clinical outcome. We found that the clinical relevance of DIS3 mutations strictly depended on the co-occurrence of del(13q). In particular, bi-allelic DIS3 lesions significantly affected progression-free survival, independently of other predictors of poor clinical outcome, while mono-allelic events mostly affected overall survival. As expected, DIS3 mutations affect the MM transcriptome involving cellular processes and signaling pathways associated with RNA metabolism, and the deregulation of a large number of long non-coding RNA, among which we identified five distinct transcripts as independent predictors of poorer overall survival and nine of worse progression-free survival, with two (AC015982.2 and AL445228.3) predicting both unfavorable outcomes. These findings strongly prompt further studies investigating the relevance of these long non-coding RNA in MM