High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2

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.

[1]  M. Czech.  MicroRNAs as therapeutic targets. , 2006, The New England journal of medicine.

[2]  Jan-Fang Cheng,et al.  Dicer, Drosha, and outcomes in patients with ovarian cancer. , 2008, The New England journal of medicine.

[3]  D. Lavelle,et al.  Histone deacetylase inhibitors increase p21WAF1 and induce apoptosis of human myeloma cell lines independent of decreased IL‐6 receptor expression , 2001, American journal of hematology.

[4]  Jörg Hackermüller,et al.  Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. , 2007, Blood.

[5]  B. Barlogie,et al.  Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16·3;q32) in multiple myeloma , 2004, British journal of haematology.

[6]  F. Slack,et al.  Inhibiting microRNA function in vivo. , 2009 .

[7]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[8]  E. Wiemer,et al.  miRNAs and cancer , 2006, Journal of RNAi and gene silencing : an international journal of RNA and gene targeting research.

[9]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[10]  C. Croce,et al.  MicroRNA profiling as a tool to understand prognosis, therapy response and resistance in breast cancer. , 2008, European journal of cancer.

[11]  D. Melton,et al.  "Stemness": Transcriptional Profiling of Embryonic and Adult Stem Cells , 2002, Science.

[12]  John Crowley,et al.  The molecular classification of multiple myeloma. , 2006, Blood.

[13]  C. Croce,et al.  MicroRNAs in the pathogeny of chronic lymphocytic leukaemia , 2007, British journal of haematology.

[14]  D. Haber,et al.  Dual Role for Argonautes in MicroRNA Processing and Posttranscriptional Regulation of MicroRNA Expression , 2007, Cell.

[15]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[16]  B. Barlogie,et al.  Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. , 1995, Blood.

[17]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[18]  T. Golub,et al.  Impaired microRNA processing enhances cellular transformation and tumorigenesis , 2007, Nature Genetics.

[19]  K. Tarte,et al.  Generation of polyclonal plasmablasts from peripheral blood B cells: a normal counterpart of malignant plasmablasts. , 2002, Blood.

[20]  Charles P. Lin,et al.  MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. , 2009, Blood.

[21]  K. Tarte,et al.  Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation. , 2003, Blood.

[22]  A. Hatzigeorgiou,et al.  TarBase: A comprehensive database of experimentally supported animal microRNA targets. , 2005, RNA.

[23]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  C. Croce,et al.  MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis , 2008, Proceedings of the National Academy of Sciences.

[25]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[26]  J. Doudna,et al.  A three-dimensional view of the molecular machinery of RNA interference , 2009, Nature.

[27]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[29]  B. Barlogie,et al.  High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. , 2000, Blood.

[30]  J. M. Thomson,et al.  Argonaute2 Is the Catalytic Engine of Mammalian RNAi , 2004, Science.

[31]  Yongsheng Huang,et al.  A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. , 2006, Blood.

[32]  C. Croce,et al.  MicroRNAs in the ontogeny of leukemias and lymphomas , 2009, Leukemia & lymphoma.

[33]  Anton J. Enright,et al.  A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. , 2007, Genes & development.

[34]  L. Platanias,et al.  Growth inhibition of a human myeloma cell line by all-trans retinoic acid is not mediated through downregulation of interleukin-6 receptors but through upregulation of p21(WAF1). , 1999, Blood.

[35]  P. Brown,et al.  Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  G. Tsongalis,et al.  MicroRNAs: novel biomarkers for human cancer. , 2009, Clinical chemistry.

[37]  A. Neri,et al.  Integrative high‐resolution microarray analysis of human myeloma cell lines reveals deregulated miRNA expression associated with allelic imbalances and gene expression profiles , 2009, Genes, chromosomes & cancer.