Alberto Risueño Pérez - Gredos - Universidad de Salamanca

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636 Leukemia microRNAs in myeloma NC Gutiérrez et al pathway, which is a potent inducer of IL-6. IRAK1 (IL-1 receptor-associated kinase) activates and recruits TRAF6 to the IL-1 receptor complex, 45,46 and PELI2 is a scaffold protein probably involved in the IL-1 signalling through its interaction with the complex containing IRAK kinases and TRAF6. 47 Both IRAK1 and PELI2 display two matches to the miR-146a and miR-135b respectively, which increases the prediction specificity. In addition, IRAK1 is a validate target of miR-146a. 48,49 Concerning MM with t(14;16) four genes (GPD2, GLCCI1, FNDC3B and ASH2L) were targeted by miR-1 (Table 3). A role in cancer has been reported for all of them, although an involvement in myeloma biology has not been found. Among the potential miRNA–mRNA interactions detected in MM patients with monosomy 13, it should be noted that miR-19a and miR-19b, belonging the miR-17B92 cluster, target the overexpressed IGF1 transcript (Table 4). Likewise, MAPK6 is targeted by three of the miRNAs downregulated in MM with monosomy 13 (miR-19a, miR-let-7b and miR-374a). As MAPK route and IGFR1 pathway have important roles in the control of MM cell biology, the investigation of these miRNAs interactions would be interesting. 50,51 When we applied this stringent approach to the 11 miRNAs deregulated in all MM comparing with normal PC no predicted miRNA–mRNA interactions fulfilled the filters, but miR-10a and its predicted target BACH2, and miR-135b and its putative target CD47 were very close to the established thresholds. The transcription factor BACH2, together with other factors such as BLIMP1 appears to constitute a main transcriptional regulatory network for the terminal differentiation of B cells to PC. 52 CD47 is an integrin-associated protein which modulates cell activation and adhesion. 53,54 Our group has reported that CD47 upregulation is only present in PC from MM, but not in PC from Waldenstrom’s macroglobulinemia. 55 The potential role of miR-10a and miR-135b in the CD47 and BACH2 expression deserves to be explored. It is interesting to note that CCND2, which was upregulated both in MM subtypes t(4;14), t(14;16) and monosomy 13, have target sites for several miRNA significantly deregulated in these cytogenetic subtypes. It has been proposed that dysregulation of a CYCLIN D gene is a unifying oncogenic event in MM. 5 About 45% of MM express CCND2, particularly those MM with t(14;16) and t(4;14). However, the mechanism responsible for the increased expression of CCND2 in MM often remains unknown. Therefore, it could be speculated that the underexpression of miR-196b, miR-135b, miR-320, miR-20a, miR-19b, miR-19a and miR-15a found in many MM (see Supplementary Tables) could contribute to the overexpression of their predicted target CCND2. Noteworthy, miR-15a and miRNA-19a were the only ones selected using the stringent analysis and displayed three and two sites in the 3 0 UTR (Table 4). These results are supported by a recent study, which demonstrates that the transfection of myeloma cells with the pre-miRNA-15a results in CCND2 inhibition. 15 Unfortunately, although the presence of perfect seed pairing and other bioinformatic criteria predict miRNA regulation more likely led to mRNA degradation, false positives cannot be ruled out. On the other hand, the possibility that there are additional redundant indirect pathways also contributing to their degradation should be kept in mind. Hence the functional characterization of the results obtained by using bioinformatic analysis is of paramount importance. In summary, these results indicate that miRNA expression is deregulated in myeloma cells, and what is more important, that the miRNA pattern of expression in MM seems to be associated with specific genetic abnormalities. Of particular interest is our finding of the upregulation of the cluster miR-1/miR-133a in MM samples with t(14;16), which supports a role for miRNAs in the pathogenic pathways of MM putatively delineated by chromosomal aberrations. In addition, the strategy proposed of finding potential miRNA–mRNA interactions could be useful to identify relevant protein-coding genes in MM pathogenesis that can be regulated by miRNAs. Conflict of interest The authors declare no conflict of interest. Acknowledgements This study was partially supported by Spanish FIS (PI080568) and ‘Gerencia Regional de Salud, Junta de Castilla y León’ (GRS202/ A08) grants, and the Spanish Myeloma Network Program (RD06/ 0020/0006). M.E.S. was supported by the ‘Ministerio de Sanidad y Consumo (Contrato de Técnicos de Apoyo a la Investigación, CA08/00212). J.D.L.R. was supported by Junta de Castilla y León grant (CSI07A09). We are grateful to ‘Grupo Español de Mieloma’ clinicians for providing MM samples; to JA Pérez-Simón and F Sánchez-Guijo for providing healthy bone marrow samples; to I. Isidro, T Prieto, A Antón and M Hernández for technical assistance; and to E Bandrés and MD Odero for their support in the data analysis. References 1 Chng WJ, Glebov O, Bergsagel PL, Kuehl WM. Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol 2007; 20: 571–596. 2 Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. 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Proc Natl Acad Sci USA 1998; 95: 14863–14868. 25 Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98: 5116–5121. 26 Goeman JJ, van de Geer SA, de KF, van Houwelingen HC. A global test for groups of genes: testing association with a clinical outcome. Bioinformatics 2004; 20: 93–99. 27 Gutierrez NC, Lopez-Perez R, Hernandez JM, Isidro I, Gonzalez B, Delgado M et al. Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia. Leukemia 2005; 19: 402–409. 28 Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003; 31: e15. 29 Xiao F, Zuo Z, Cai G, Kang S, Gao X, Li T. miRecords: an integrated resource for microRNA-target interactions. Nucleic Acids Res 2009; 37: D105–D110. 30 Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell 2009; 136: 642–655. 31 Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 2005; 33: 1290–1297. 32 Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 2005; 122: 553–563. 33 Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433: 769–773. 34 Wang X, Wang X. Systematic identification of microRNA functions by combining target prediction and expression profiling. Nucleic Acids Res 2006; 34: 1646–1652. 35 Huang JC, Babak T, Corson TW, Chua G, Khan S, Gallie BL et al. Using expression profiling data to identify human microRNA targets. Nat Methods 2007; 4: 1045–1049. 36 Li SC, Tang P, Lin WC. Intronic microRNA: discovery and biological implications. 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Oncogene 2006; 25: 6520–6527. 46 Song KW, Talamas FX, Suttmann RT, Olson PS, Barnett JW, Lee SW et al. The kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells. Mol Immunol 2009; 46: 1458–1466. 47 Moynagh PN. The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling. Trends Immunol 2009; 30:33–42. 48 Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaBdependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006; 103: 12481–12486. 49 Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 2008; 10: R101. 50 Maiso P, Ocio EM, Garayoa M, Montero JC, Hofmann F, Garcia- Echeverria C et al. 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Gene expression profiling of B-lymphocyte and plasma cell populations from Waldenström’s macroglobulinemia comparison with expression patterns of the same cell-counterparts from other B-cell neoplasms. Leukemia 2007; 21: 541–549. Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu) 637 Leukemia
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Bioinformática aplicada a estudios
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Alberto Risueño Pérez - Gredos - Universidad de Salamanca

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