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Title: Disentangling the microRNA regulatory milieu in multiple myeloma: integrative genomics analysis outlines mixed miRNA-TF circuits and pathway-derived networks modulated in t(4;14) patients
Authors: Calura, Enrica 
Bisognin, Andrea 
Manzoni, Martina
Todoerti, Katia
Taiana, Elisa
Sales, Gabriele 
Morgan, Gareth J
Tonon, Giovanni
Amodio, Nicola
Tassone, Pierfrancesco
Neri, Antonino
Agnelli, Luca
Romualdi, Chiara 
Bortoluzzi, Stefania 
Keywords: expression profiling;microRNA;multiple myeloma;t(4;14) translocation;transciptional regulatory network
Mesh headings: Gene Regulatory Networks;MicroRNAs;Multiple Myeloma
Secondary Mesh headings: Core Binding Factor Alpha 2 Subunit;ErbB Receptors;Gene Expression Profiling;Humans;Prospective Studies;Protein-Serine-Threonine Kinases;Retrospective Studies
Issue Date: 19-Jan-2016
Journal: Oncotarget 
The identification of overexpressed miRNAs in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. miRNA and gene expression profiles of two large representative MM datasets, available from retrospective and prospective series and encompassing a total of 249 patients at diagnosis, were analyzed by means of in silico integrative genomics methods, based on MAGIA2 and Micrographite computational procedures. We first identified relevant miRNA/transcription factors/target gene regulation circuits in the disease and linked them to biological processes. Members of the miR-99b/let-7e/miR-125a cluster, or of its paralog, upregulated in t(4;14), were connected with the specific transcription factors PBX1 and CEBPA and several target genes. These results were validated in two additional independent plasma cell tumor datasets. Then, we reconstructed a non-redundant miRNA-gene regulatory network in MM, linking miRNAs, such as let-7g, miR-19a, mirR-20a, mir-21, miR-29 family, miR-34 family, miR-125b, miR-155, miR-221 to pathways associated with MM subtypes, in particular the ErbB, the Hippo, and the Acute myeloid leukemia associated pathways.
DOI: 10.18632/oncotarget.6151
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