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.
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.
Department of Biology, University of Padua, Padua, Italy.
Enrica
E
Calura
Department of Molecular Medicine, University of Padua, Padua, Italy.
Andrea
A
Bisognin
Department of Clinical Sciences and Community Health, University of Milan, and Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Martina
M
Manzoni
Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
Katia
K
Todoerti
Department of Clinical Sciences and Community Health, University of Milan, and Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Elisa
E
Taiana
Department of Biology, University of Padua, Padua, Italy.
Gabriele
G
Sales
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Gareth J
GJ
Morgan
Functional Genomics of Cancer Unit, Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
Giovanni
G
Tonon
Department of Experimental and Clinical Medicine, University of Study Magna Graecia, Catanzaro, Italy.
Nicola
N
Amodio
Department of Experimental and Clinical Medicine, University of Study Magna Graecia, Catanzaro, Italy.
Pierfrancesco
P
Tassone
Department of Clinical Sciences and Community Health, University of Milan, and Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Antonino
A
Neri
Department of Clinical Sciences and Community Health, University of Milan, and Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Luca
L
Agnelli
Department of Biology, University of Padua, Padua, Italy.
Chiara
C
Romualdi
Department of Molecular Medicine, University of Padua, Padua, Italy.
Stefania
S
Bortoluzzi
D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics*; D000090683:Hippo Signaling Pathway; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics*; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012189:Retrospective Studies
D050676:Core Binding Factor Alpha 2 Subunit; D035683:MicroRNAs; C493728:RUNX1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases
expression profiling; microRNA; multiple myeloma; t(4;14) translocation; transciptional regulatory network