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miR-29a and miR-142-3p downregulation and diagnostic implication in human acute myeloid leukemia

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Abstract

Expression profiling of microRNAs (miRNAs) in most diseases might be popular and provide the possibility for diagnostic implication, but few studies have accurately quantified the expression level of dysregulated miRNAs in acute myeloid leukemia (AML). In this study, we analyzed the peripheral blood mononuclear cells (PBMCs) from 10 AML patients (subtypes M1 to M5) and six normal controls by miRNA microarray and identified several differentially expressed miRNAs. Among them miR-29a and miR-142-3p were selectively encountered in Northern blot analysis and their significantly decreased expression in AML was further confirmed. Quantitative real-time PCR in 52 primarily diagnosed AML patients and 100 normal controls not only verified the expression properties of these 2 miRNAs, but also established that the expression level of miR-142-3p and miR-29a in PBMCs could be used as novel diagnostic markers. A better diagnostic outcome was achieved by combining miR-29a and miR-142-3p with about 90% sensitivity, 100% specificity, and an area under the ROC curve (AUC) of 0.97. Our results provide insights into the involvement of miRNAs in leukemogenesis, and offer candidates for AML diagnosis and therapeutic strategy.

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References

  1. Frankfurt O, Licht JD, Tallman MS (2007) Molecular characterization of acute myeloid leukemia and its impact on treatment. Curr Opin Oncol 19:635–649

    Article  PubMed  Google Scholar 

  2. Haferlach T, Bacher U, Haferlach C, Kern W, Schnittger S (2007) Insight into the molecular pathogenesis of myeloid malignancies. Curr Opin Hematol 14:90–97

    Article  PubMed  CAS  Google Scholar 

  3. Chang TC, Mendell JT (2007) MicroRNAs in vertebrate physiology and human disease. Annu Rev Genomics Hum Genet 8:215–239

    Article  PubMed  CAS  Google Scholar 

  4. Stefani G (2007) Roles of microRNAs and their targets in cancer. Expert Opin Biol Ther 7:1833–1840

    Article  PubMed  CAS  Google Scholar 

  5. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102:13944–13949

    Article  PubMed  CAS  Google Scholar 

  6. Marton S, Garcia MR, Robello C, Persson H, Trajtenberg F, Pritsch O et al (2008) Small RNAs analysis in CLL reveals a deregulation of miRNA expression and novel miRNA candidates of putative relevance in CLL pathogenesis. Leukemia 22:330–338

    Article  PubMed  CAS  Google Scholar 

  7. Rabinowits G, Gerçel-Taylor C, Day JM, Taylor DD, Kloecker GH (2010) Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 10:42–46

    Article  Google Scholar 

  8. Iorio MV, Casalini P, Tagliabue E, Ménard S, Croce CM (2008) MicroRNA profiling as a tool to understand prognosis, therapy response and resistance in breast cancer. Eur J Cancer 44:2753–2759

    Article  PubMed  CAS  Google Scholar 

  9. Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE (2009) The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol 112:55–59

    Article  PubMed  CAS  Google Scholar 

  10. Osaki M, Takeshita F, Ochiya T (2008) MicroRNAs as biomarkers and therapeutic drugs in human cancer. Biomarkers 13:658–670

    Article  PubMed  CAS  Google Scholar 

  11. Marcucci G, Radmacher MD, Maharry K, Mrózek K, Ruppert AS, Paschka P et al (2008) MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1919–1928

    Article  PubMed  CAS  Google Scholar 

  12. Whitman SP, Maharry K, Radmacher MD, Becker H, Mrózek K, Margeson D et al (2010) FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. doi:10.1182/blood-2010-05-283648

  13. Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Löwenberg B (2008) MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 111:5078–5085

    Article  PubMed  CAS  Google Scholar 

  14. Debernardi S, Skoulakis S, Molloy G, Chaplin T, Dixon-McIver A, Young BD (2007) MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis. Leukemia 21:912–916

    PubMed  CAS  Google Scholar 

  15. Dixon-McIver A, East P, Mein CA, Cazier JB, Molloy G, Chaplin T et al (2008) Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukemia. PLoS ONE 3:e2141

    Article  PubMed  Google Scholar 

  16. Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S et al (2010) Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA 107:7473–7478

    Article  PubMed  CAS  Google Scholar 

  17. Liu S, Wu LC, Pang J, Santhanam R, Schwind S, Wu YZ et al (2010) Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia. Cancer Cell 17:333–347

    Article  PubMed  CAS  Google Scholar 

  18. Pulikkan JA, Dengler V, Peramangalam PS, Peer Zada AA, Müller-Tidow C, Bohlander SK et al (2010) Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia. Blood 115:1768–1778

    Article  PubMed  CAS  Google Scholar 

  19. Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C et al (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci USA 105:3945–3950

    Article  PubMed  CAS  Google Scholar 

  20. Chen CZ, Li L, Lodish HF, Bartel DP (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–86

    Article  PubMed  CAS  Google Scholar 

  21. Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT et al (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33:e179

    Article  PubMed  Google Scholar 

  22. Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL et al (2008) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358:353–361

    Article  PubMed  CAS  Google Scholar 

  23. Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, Zhuang SM (2010) Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 51:836–845

    PubMed  CAS  Google Scholar 

  24. Rasmussen KD, Simmini S, Abreu-Goodger C, Bartonicek N, Di Giacomo M, Bilbao-Cortes D et al (2010) The miR-144/451 locus is required for erythroid homeostasis. J Exp Med 207:1351–1358

    Article  PubMed  CAS  Google Scholar 

  25. Merkerova M, Belickova M, Bruchova H (2008) Differential expression of microRNAs in hematopoietic cell lineages. Eur J Haematol 381:304–310

    Article  Google Scholar 

  26. Choong ML, Yang HH, McNiece I (2007) MicroRNA expression profiling during human cord blood-derived CD34 cell erythropoiesis. Exp Hematol 35:551–564

    Article  PubMed  CAS  Google Scholar 

  27. Isken F, Steffen B, Merk S, Dugas M, Markus B, Tidow N et al (2008) Identification of acute myeloid leukaemia associated microRNA expression patterns. Br J Haematol 140:153–161

    Article  PubMed  CAS  Google Scholar 

  28. Georgantas RW 3rd, Hildreth R, Morisot S, Alder J, Liu CG, Heimfeld S et al (2007) CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. Proc Natl Acad Sci USA 104:2750–2755

    Article  PubMed  CAS  Google Scholar 

  29. le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A et al (2007) Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J 26:3699–3708

    Article  PubMed  CAS  Google Scholar 

  30. Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L et al (2010) Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res 70:367–377

    Article  PubMed  CAS  Google Scholar 

  31. Popovic R, Riesbeck LE, Velu CS, Chaubey A, Zhang J, Achille NJ et al (2009) Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 113:3314–3322

    Article  PubMed  CAS  Google Scholar 

  32. Garzon R, Pichiorri F, Palumbo T, Iuliano R, Cimmino A, Aqeilan R et al (2006) MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci USA 103:5078–5083

    Article  PubMed  CAS  Google Scholar 

  33. Zhang X, Lian Z, Padden C, Gerstein MB, Rozowsky J, Snyder M et al (2009) A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster. Blood 113:2526–2534

    Article  PubMed  CAS  Google Scholar 

  34. Valastyan S, Chang A, Benaich N, Reinhardt F, Weinberg RA (2010) Concurrent suppression of integrin alpha5, radixin, and RhoA phenocopies the effects of miR-31 on metastasis. Cancer Res 70:5147–5154

    Article  PubMed  CAS  Google Scholar 

  35. Clapé C, Fritz V, Henriquet C, Apparailly F, Fernandez PL, Iborra F et al (2009) miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice. PLoS ONE 4:e7542

    Article  PubMed  Google Scholar 

  36. Shigoka M, Tsuchida A, Matsudo T, Nagakawa Y, Saito H, Suzuki Y et al (2010) Deregulation of miR-92a expression is implicated in hepatocellular carcinoma development. Pathol Int 60:351–357

    Article  PubMed  CAS  Google Scholar 

  37. Shinozaki A, Sakatani T, Ushiku T, Hino R, Isogai M, Ishikawa S et al (2010) Downregulation of microRNA-200 in EBV-associated gastric carcinoma. Cancer Res 70:4719–4727

    Article  PubMed  CAS  Google Scholar 

  38. Garzon R, Croce CM (2008) MicroRNAs in normal and malignant hematopoiesis. Curr Opin Hematol 15:352–358

    Article  PubMed  CAS  Google Scholar 

  39. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E et al (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 104:15805–15810

    Article  PubMed  CAS  Google Scholar 

  40. Mott JL, Kobayashi S, Bronk SF, Gores GJ (2007) mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26:6133–6140

    Article  PubMed  CAS  Google Scholar 

  41. Park SY, Lee JH, Ha M, Nam JW, Kim VN (2009) miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol 16:23–29

    Article  PubMed  CAS  Google Scholar 

  42. Verrier JD, Lau P, Hudson L, Murashov AK, Renne R, Notterpek L (2010) Peripheral myelin protein 22 is regulated post-transcriptionally by miRNA-29a. Glia 57:1265–1279

    Article  Google Scholar 

  43. Pekarsky Y, Santanam U, Cimmino A, Palamarchuk A, Efanov A, Maximov V et al (2006) Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res 66:11590–11593

    Article  PubMed  CAS  Google Scholar 

  44. Zhao JJ, Lin J, Lwin T, Yang H, Guo J, Kong W et al (2010) microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood 115:2630–2639

    Article  PubMed  CAS  Google Scholar 

  45. Kapinas K, Kessler CB, Ricks T, Gronowicz G, Delany AM (2010) miR-29 modulates WNT signaling in human osteoblasts through a positive feedback loop. J Biol Chem 285:25221–25231

    Article  PubMed  CAS  Google Scholar 

  46. Gebeshuber CA, Zatloukal K, Martinez J (2009) miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep 10:400–405

    Article  PubMed  CAS  Google Scholar 

  47. Wu H, Neilson JR, Kumar P, Manocha M, Shankar P, Sharp PA, Manjunath N (2007) miRNA profiling of naïve, effector and memory CD8 T cells. PLoS ONE 2:e1020

    Article  PubMed  Google Scholar 

  48. Bellon M, Lepelletier Y, Hermine O, Nicot C (2009) Deregulation of microRNA involved in hematopoiesis and the immune response in HTLV-I adult T-cell leukemia. Blood 113:4914–4917

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 30970616 and No. 3072106) and grants from the Specific Found of National Laboratory of China (No. 3060204).

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Correspondence to Jun-Wu Zhang.

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Fang Wang, Xiao-Shuang Wang and Gui-Hua Yang contributed equally to the study.

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Wang, F., Wang, XS., Yang, GH. et al. miR-29a and miR-142-3p downregulation and diagnostic implication in human acute myeloid leukemia. Mol Biol Rep 39, 2713–2722 (2012). https://doi.org/10.1007/s11033-011-1026-5

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  • DOI: https://doi.org/10.1007/s11033-011-1026-5

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