title: High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2.
abstract: MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function.
authors.affiliation: Donna D and Donald M Lambert Laboratory for Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Owen
authors.initials: O
authors.lastname: Stephens
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wu
authors.forename: David R
authors.initials: DR
authors.lastname: Williams
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Cartron
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Bijay
authors.initials: B
authors.lastname: Nair
authors.forename: Sarah
authors.initials: S
authors.lastname: Waheed
authors.forename: Mauricio
authors.initials: M
authors.lastname: Pineda-Roman
authors.forename: Yazan
authors.initials: Y
authors.lastname: Alsayed
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
mesh_terms: D017209:Apoptosis / Q000235:genetics; D060565:Argonaute Proteins; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000235:genetics; D018570:Risk Assessment; D053668:Syndecan-1 / Q000378:metabolism
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; D035683:MicroRNAs; D009841:Oligonucleotides; C508241:SDC1 protein, human; D053668:Syndecan-1
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