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
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Enrica Calura1,*, Andrea Bisognin2,*, Martina Manzoni3, Katia Todoerti4, Elisa Taiana3, Gabriele Sales1, Gareth J. Morgan5, Giovanni Tonon6, Nicola Amodio7, Pierfrancesco Tassone7, Antonino Neri3, Luca Agnelli3,**, Chiara Romualdi1,** and Stefania Bortoluzzi2,**
1 Department of Biology, University of Padua, Padua, Italy
2 Department of Molecular Medicine, University of Padua, Padua, Italy
3 Department of Clinical Sciences and Community Health, University of Milan, and Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
4 Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
5 Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
6 Functional Genomics of Cancer Unit, Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
7 Department of Experimental and Clinical Medicine, University of Study Magna Graecia, Catanzaro, Italy
* The first two authors equally contributed to this work
** A substantial contribution to the conception, design, execution and writing of this work was equally provided by these three groups. LA, CR, SB have therefore to be considered co-last authors
Luca Agnelli, email:
Keywords: multiple myeloma, transciptional regulatory network, t(4;14) translocation, microRNA, expression profiling
Received: August 05, 2015 Accepted: September 30, 2015 Published: October 19, 2015
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.
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