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Oncotarget. 2016 Jan 19;7(3):2367-78. doi: 10.18632/oncotarget.6151.

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.

Author information

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.

Abstract

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.

KEYWORDS:

expression profiling; microRNA; multiple myeloma; t(4;14) translocation; transciptional regulatory network

PMID:
26496024
PMCID:
PMC4823041
DOI:
10.18632/oncotarget.6151
[Indexed for MEDLINE]
Free PMC Article

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