Annals of Hematology

, Volume 94, Issue 7, pp 1081–1092 | Cite as

MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation

  • Ciprian TomuleasaEmail author
  • Shigeo Fuji
  • Andrei Cucuianu
  • Markus Kapp
  • Valentina Pileczki
  • Bobe Petrushev
  • Sonia Selicean
  • Alina Tanase
  • Delia Dima
  • Ioana Berindan-Neagoe
  • Alexandru Irimie
  • Hermann Einsele
Review Article


Allogeneic hematopoietic stem cell transplantation (HCT) is a well-established treatment for many malignant and non-malignant hematological disorders. As frequent complication in up to 50 % of all patients, graft-versus-host disease (GVHD) is still the main cause for morbidity and non-relapse mortality. Diagnosis of GVHD is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally recognized consensus has yet been established. Here, microRNAs (miRs) represent an interesting tool since miRs have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we could assume that miRs play a key role in the pathogenesis of acute GVHD, and their detection might be an interesting possibility in the early diagnosis and monitoring of acute GVHD. Recent studies additionally demonstrated the implication of miRs in the pathogenesis of acute GVHD. In this review, we aim to summarize the previous reports of miRs, focusing on the pathogenesis of acute GVHD and possible implications in diagnostic approaches.


Stem cell transplantation Biomarkers MicroRNAs Graft-versus-host disease 



The current paper is supported by an international grant, Romania–European Economical Space (Norway), which was awarded to Andrei Cucuianu and Ciprian Tomuleasa (contract 1/16.01.2014). This paper was published under the frame of European Social Fund, Human Resources Development Operational Programme 2007–2013, Project number POSDRU 159/1.5/138776. The authors gratefully acknowledge the help of Mrs Cornelia Braicu with the figure drawing.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Gyurkocza B, Rezvani A, Storb RF (2010) Allogeneic hematopoietic cell transplantation: the state of the art. Expert Rev Hematol 3(3):285–99PubMedCentralPubMedGoogle Scholar
  2. 2.
    Kanate AS, Pasquini MC, Hari PN, Hamadani M (2014) Allogeneic hematopoietic cell transplant for acute myeloid leukemia: Current state in 2013 and future directions. World J Stem Cells 6(2):69–81PubMedCentralPubMedGoogle Scholar
  3. 3.
    Baron F, Storb R (2004) Allogeneic hematopoietic cell transplantation as treatment for hematological malignancies: a review. Springer Semin Immunopathol 26(1-2):71–94PubMedGoogle Scholar
  4. 4.
    Baron F, Storb R, Little MT (2003) Hematopoietic cell transplantation: five decades of progress. Arch Med Res 34(6):528–44PubMedGoogle Scholar
  5. 5.
    Storb R (2004) History of pediatric stem cell transplantation. Pediatr Transplant 8(Suppl 5):5–11PubMedGoogle Scholar
  6. 6.
    Staal FJ, Baum C, Cowan C, Dzierzak E, Hacein-Bey-Abina S, Karlsson S, Lapidot T, Lemischka I, Mendez-Ferrer S, Mikkers H, Moore K, Moreno E, Mummery CL, Robin C, Suda T, Van Pel M, Vanden Brink G, Zwaginga JJ, Fibbe WE (2011) Stem cell self-renewal: lessons from bone marrow, gut and iPS toward clinical applications. Leukemia 25(7):1095–102PubMedGoogle Scholar
  7. 7.
    Saulnier N, Di Campli C, Zocco MA, Di Gioacchino G, Novi M, Gasbarrini A (2005) From stem cell to solid organ. Bone marrow, peripheral blood or umbilical cord blood as favorable source? Eur Rev Med Pharmacol Sci 9(6):315–24PubMedGoogle Scholar
  8. 8.
    Szydlo R, Goldman JM, Klein JP, Gale RP, Ash RC, Bach FH, Bradley BA, Casper JT, Flomenberg N, Gajewski JL, Gluckman E, Henslee-Downey PJ, Hows JM, Jacobsen N, Kolb HJ, Lowenberg B, Masaoka T, Rowlings PA, Sondel PM, van Bekkum DW, van Rood JJ, Vowels MR, Zhang MJ, Horowitz MM (1997) Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol 15(5):1767–77PubMedGoogle Scholar
  9. 9.
    Kato S, Yabe H, Yasui M, Kawa K, Yoshida T, Watanabe A, Osugi Y, Horibe K, Kodera Y (2000) Allogeneic hematopoietic transplantation of CD34+ selected cells from an HLA haplo-identical related donor. A long-term follow-up of 135 patients and a comparison of stem cell source between the bone marrow and the peripheral blood. Bone Marrow Transplant 26(12):1281–90PubMedGoogle Scholar
  10. 10.
    Drobyski WR, Klein J, Flomenberg N, Pietryga D, Vesole DH, Margolis DA, Keever-Taylor CA (2002) Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts. Blood 1;99(3):806–14Google Scholar
  11. 11.
    Mehta J, Singhal S, Gee AP, Chiang KY, Godder K, Rhee FF, DeRienzo S, O’Neal W, Lamb L, Henslee-Downey PJ (2004) Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant 33(4):389–96PubMedGoogle Scholar
  12. 12.
    Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, O’Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Kørbling M, Keating M, Kantarjian H, Champlin R (1997) Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 15;89(12):4531–6Google Scholar
  13. 13.
    Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, Martin PJ, Sandmaier BM, Marr KA, Appelbaum FR, Storb R, McDonald GB (2010) Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 25;363(22):2091–101Google Scholar
  14. 14.
    Koh LP, Rizzieri DA, Chao NJ (2007) Allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors. Biol Blood Marrow Transplant 13(11):1249–67PubMedGoogle Scholar
  15. 15.
    Qian L, Wu Z, Shen J (2013) Advances in the treatment of acute graft-versus-host disease. J Cell Mol Med 17(8):966–75PubMedCentralPubMedGoogle Scholar
  16. 16.
    Horn B, Cowan MJ (2013) Unresolved issues in hematopoietic stem cell transplantation for severe combined immunodeficiency: need for safer conditioning and reduced late effects. J Allergy Clin Immunol 131(5):1306–11PubMedGoogle Scholar
  17. 17.
    Ziemer M (2013) Graft-versus-host disease of the skin and adjacent mucous membranes. J Dtsch Dermatol Ges 11(6):477–95PubMedGoogle Scholar
  18. 18.
    Peñas PF, Fernández-Herrera J, García-Diez A (2004) Dermatologic treatment of cutaneous graft versus host disease. Am J Clin Dermatol 5(6):403–16PubMedGoogle Scholar
  19. 19.
    Peñas PF, Zaman S (2010) Many faces of graft-versus-host disease. Australas J Dermatol 51(1):1–10PubMedGoogle Scholar
  20. 20.
    Cheung MC, Agarwal K (2013) Liver abnormalities in the immunosuppressed. Best Pract Res Clin Gastroenterol 27(4):597–618PubMedGoogle Scholar
  21. 21.
    Stift J, Baba HA, Huber E, Federmann B, Fischer HP, Schmitt-Graeff A, Baurmann H, Bethge W, Schirmacher P, Wrba F, Greinix H, Fend F, Schwerdtfeger R, Shulman HM, Wolff D, Longerich T, Liver Pathology Group of the German-Austrian-Swiss Working Group on GvHD (2014) Consensus on the histopathological evaluation of liver biopsies from patients following allogeneic hematopoietic cell transplantation. Virchows Arch 464(2):175–90PubMedGoogle Scholar
  22. 22.
    Schultz KR, Miklos DB, Fowler D, Cooke K, Shizuru J, Zorn E, Holler E, Ferrara J, Shulman H, Lee SJ, Martin P, Filipovich AH, Flowers ME, Weisdorf D, Couriel D, Lachenbruch PA, Mittleman B, Vogelsang GB, Pavletic SZ (2006) Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker Working Group Report. Biol Blood Marrow Transplant 12(2):126–37PubMedGoogle Scholar
  23. 23.
    Ye H, Lv M, Zhao X, Zhao X, Huang X (2012) Plasma level of lipopolysaccharide-binding protein is indicative of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Int J Hematol 95(6):680–8PubMedGoogle Scholar
  24. 24.
    Paczesny S, Raiker N, Brooks S, Mumaw C (2013) Graft-versus-host disease biomarkers: omics and personalized medicine. Int J Hematol 98(3):275–92PubMedCentralPubMedGoogle Scholar
  25. 25.
    Vander Lugt MT, Braun TM, Hanash S, Ritz J, Ho VT, Antin JH, Zhang Q, Wong CH, Wang H, Chin A, Gomez A, Harris AC, Levine JE, Choi SW, Couriel D, Reddy P, Ferrara JL, Paczesny S (2013) ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med 369(6):529–39PubMedCentralPubMedGoogle Scholar
  26. 26.
    Paczesny S (2013) Discovery and validation of graft-versus-host disease biomarkers. Blood 121(4):585–94PubMedCentralPubMedGoogle Scholar
  27. 27.
    Sjøqvist C, Snarski E (2013) Inflammatory markers in patients after hematopoietic stem cell transplantation. Arch Immunol Ther Exp (Warsz) 61(4):301–7Google Scholar
  28. 28.
    Goldberg JD, Giralt S (2013) Assessing response of therapy for acute and chronic graft-versus-host disease. Expert Rev Hematol 6(1):103–7PubMedGoogle Scholar
  29. 29.
    Sung AD, Chao NJ (2013) Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment. Stem Cells Transl Med 2(1):25–32PubMedCentralPubMedGoogle Scholar
  30. 30.
    Levine JE, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ferrara JL, Ho VT, Weisdorf DJ, Paczesny S (2012) Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood 119(16):3854–60PubMedCentralPubMedGoogle Scholar
  31. 31.
    Harris AC, Ferrara JL, Braun TM, Holler E, Teshima T, Levine JE, Choi SW, Landfried K, Akashi K, Vander Lugt M, Couriel DR, Reddy P, Paczesny S (2012) Plasma biomarkers of lower gastrointestinal and liver acute GVHD. Blood 119(12):2960–3PubMedCentralPubMedGoogle Scholar
  32. 32.
    Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T, Levine JE, Choi SW, Huber E, Landfried K, Akashi K, VanderLugt M, Reddy P, Chin A, Zhang Q, Hanash S, Paczesny S (2011) Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood 15;118(25):6702–8Google Scholar
  33. 33.
    Ranganathan P, Heaphy CE, Costinean S, Stauffer N, Na C, Hamadani M, Santhanam R, Mao C, Taylor PA, Sandhu S, He G, Shana’ah A, Nuovo GJ, Lagana A, Cascione L, Obad S, Broom O, Kauppinen S, Byrd JC, Caligiuri M, Perrotti D, Hadley GA, Marcucci G, Devine SM, Blazar BR, Croce CM, Garzon R (2012) Regulation of acute graft-versus-host disease by microRNA-155. Blood 119(20):4786–97PubMedCentralPubMedGoogle Scholar
  34. 34.
    Xiao B, Wang Y, Li W, Baker M, Guo J, Corbet K, Tsalik EL, Li QJ, Palmer SM, Woods CW, Li Z, Chao NJ, He YW (2013) Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease. Blood 122(19):3365–75PubMedCentralPubMedGoogle Scholar
  35. 35.
    Xie LN, Zhou F, Liu XM, Fang Y, Yu Z, Song NX, Kong FS (2014) Serum microRNA155 is increased in patients with acute graft-versus-host disease. Clin Transplant 28(3):314–23PubMedGoogle Scholar
  36. 36.
    Mendell JT (2005) MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle 4(9):1179–84PubMedGoogle Scholar
  37. 37.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 101(9):2999–3004PubMedCentralPubMedGoogle Scholar
  38. 38.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6(11):857–66PubMedGoogle Scholar
  39. 39.
    Kent OA, Mendell JT (2006) A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 25(46):6188–96PubMedGoogle Scholar
  40. 40.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6(4):259–69PubMedGoogle Scholar
  41. 41.
    Emmrich S, Pützer BM (2010) Checks and balances: E2F-microRNA crosstalk in cancer control. Cell Cycle 9(13):2555–67PubMedGoogle Scholar
  42. 42.
    Nan Y, Han L, Zhang A, Wang G, Jia Z, Yang Y, Yue X, Pu P, Zhong Y, Kang C (2010) MiRNA-451 plays a role as tumor suppressor in human glioma cells. Brain Res 1359:14–21PubMedGoogle Scholar
  43. 43.
    Dykxhoorn DM (2010) MicroRNAs and metastasis: little RNAs go a long way. Cancer Res 70(16):6401–6PubMedCentralPubMedGoogle Scholar
  44. 44.
    Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137(6):1005–17PubMedCentralPubMedGoogle Scholar
  45. 45.
    Hata T, Murakami K, Nakatani H, Yamamoto Y, Matsuda T, Aoki N (2010) Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochem Biophys Res Commun 396(2):528–33PubMedGoogle Scholar
  46. 46.
    Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L, Xiao T, Schafer J, Lee ML, Schmittgen TD, Nana-Sinkam SP, Jarjoura D, Marsh CB (2008) Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE 3(11), e3694PubMedCentralPubMedGoogle Scholar
  47. 47.
    Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, de Gruijl TD, Würdinger T, Middeldorp JM (2010) Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A 107(14):6328–33PubMedCentralPubMedGoogle Scholar
  48. 48.
    Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110(1):13–21PubMedGoogle Scholar
  49. 49.
    Black PH (1980) Shedding from normal and cancer-cell surfaces. N Engl J Med 303(24):1415–6PubMedGoogle Scholar
  50. 50.
    Li L, Masica D, Ishida M, Tomuleasa C, Umegaki S, Kalloo AN, Georgiades C, Singh VK, Khashab M, Amateau S, Li Z, Okolo P, Lennon AM, Saxena P, Geschwind JF, Schlachter T, Hong K, Pawlik TM, Canto M, Law J, Sharaiha R, Weiss CR, Thuluvath P, Goggins M, Shin EJ, Peng H, Kumbhari V, Hutfless S, Zhou L, Mezey E, Meltzer SJ, Karchin R, Selaru FM (2014) Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology 60(3):896–907PubMedGoogle Scholar
  51. 51.
    Pap E, Pállinger E, Pásztói M, Falus A (2009) Highlights of a new type of intercellular communication: microvesicle-based information transfer. Inflamm Res 58(1):1–8PubMedGoogle Scholar
  52. 52.
    Andrews NW (2000) Regulated secretion of conventional lysosomes. Trends Cell Biol 10(8):316–21PubMedGoogle Scholar
  53. 53.
    Del Conde I, Shrimpton CN, Thiagarajan P, López JA (2005) Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106(5):1604–11PubMedGoogle Scholar
  54. 54.
    Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9(8):581–93PubMedGoogle Scholar
  55. 55.
    Palazzolo G, Albanese NN, DI Cara G, Gygax D, Vittorelli ML, Pucci-Minafra I (2012) Proteomic analysis of exosome-like vesicles derived from breast cancer cells. Anticancer Res 32(3):847–60PubMedGoogle Scholar
  56. 56.
    Rak J, Guha A (2012) Extracellular vesicles—vehicles that spread cancer genes. Bioessays 34(6):489–97PubMedGoogle Scholar
  57. 57.
    Hou JM, Krebs M, Ward T, Sloane R, Priest L, Hughes A, Clack G, Ranson M, Blackhall F, Dive C (2011) Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol 178(3):989–96PubMedCentralPubMedGoogle Scholar
  58. 58.
    Schmidt B, Engel E, Carstensen T, Weickmann S, John M, Witt C, Fleischhacker M (2005) Quantification of free RNA in serum and bronchial lavage: a new diagnostic tool in lung cancer detection? Lung Cancer 48(1):145–7PubMedGoogle Scholar
  59. 59.
    Tsui NB, Ng EK, Lo YM (2002) Stability of endogenous and added RNA in blood specimens, serum, and plasma. Clin Chem 48(10):1647–53PubMedGoogle Scholar
  60. 60.
    Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL, Tait JF, Tewari M (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108(12):5003–8PubMedCentralPubMedGoogle Scholar
  61. 61.
    Turchinovich A, Weiz L, Langheinz A, Burwinkel B (2011) Characterization of extracellular circulating microRNA. Nucleic Acids Res 39(16):7223–33PubMedCentralPubMedGoogle Scholar
  62. 62.
    Jacob F, Monod J (1961) Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 3:318–56PubMedGoogle Scholar
  63. 63.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–54PubMedGoogle Scholar
  64. 64.
    Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136(4):642–55PubMedCentralPubMedGoogle Scholar
  65. 65.
    Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19(1):92–105PubMedCentralPubMedGoogle Scholar
  66. 66.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–33PubMedCentralPubMedGoogle Scholar
  67. 67.
    Rigoutsos I (2009) New tricks for animal microRNAS: targeting of amino acid coding regions at conserved and nonconserved sites. Cancer Res 69(8):3245–8PubMedGoogle Scholar
  68. 68.
    Kim YK, Kim VN (2007) Processing of intronic microRNAs. EMBO J 26(3):775–83PubMedCentralPubMedGoogle Scholar
  69. 69.
    Berezikov E (2011) Evolution of microRNA diversity and regulation in animals. Nat Rev Genet 12(12):846–60PubMedGoogle Scholar
  70. 70.
    Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, Brownstein MJ, Tuschl T, Margalit H (2005) Clustering and conservation patterns of human microRNAs. Nucleic Acids Res 33(8):2697–706PubMedCentralPubMedGoogle Scholar
  71. 71.
    Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23(20):4051–60PubMedCentralPubMedGoogle Scholar
  72. 72.
    Borchert GM, Lanier W, Davidson BL (2006) RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13(12):1097–101PubMedGoogle Scholar
  73. 73.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425(6956):415–9PubMedGoogle Scholar
  74. 74.
    Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the Microprocessor complex. Nature 432(7014):231–5PubMedGoogle Scholar
  75. 75.
    Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235–40PubMedGoogle Scholar
  76. 76.
    Schwarz DS, Hutvágner G, Du T, Xu Z, Aronin N, Zamore PD (2003) Asymmetry in the assembly of the RNAi enzyme complex. Cell 115(2):199–208PubMedGoogle Scholar
  77. 77.
    Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409(6818):363–6PubMedGoogle Scholar
  78. 78.
    Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–5PubMedGoogle Scholar
  79. 79.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–97PubMedGoogle Scholar
  80. 80.
    Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431(7006):343–9PubMedGoogle Scholar
  81. 81.
    Peters L, Meister G (2007) Argonaute proteins: mediators of RNA silencing. Mol Cell 26(5):611–23PubMedGoogle Scholar
  82. 82.
    Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Müller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408(6808):86–9PubMedGoogle Scholar
  83. 83.
    Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S, Inoue K, Enright AJ, Schier AF (2006) Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312(5770):75–9PubMedGoogle Scholar
  84. 84.
    Guo H, Ingolia NT, Weissman JS, Bartel DP (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466(7308):835–40PubMedCentralPubMedGoogle Scholar
  85. 85.
    Nishikura K (2006) Editor meets silencer: crosstalk between RNA editing and RNA interference. Nat Rev Mol Cell Biol 7(12):919–31PubMedCentralPubMedGoogle Scholar
  86. 86.
    Yang W, Chendrimada TP, Wang Q, Higuchi M, Seeburg PH, Shiekhattar R, Nishikura K (2006) Modulation of microRNA processing and expression through RNA editing by ADAR deaminases.Nat. Struct Mol Biol 13(1):13–21Google Scholar
  87. 87.
    Hunter T (1991) Cooperation between oncogenes. Cell 64(2):249–70PubMedGoogle Scholar
  88. 88.
    Weinberg RA (1991) Tumor suppressor genes. Science 254(5035):1138–46PubMedGoogle Scholar
  89. 89.
    Croce CM, Calin GA (2005) miRNAs, cancer, and stem cell division. Cell 122(1):6–7PubMedGoogle Scholar
  90. 90.
    Yamanaka S, Olaru AV, An F, Luvsanjav D, Jin Z, Agarwal R, Tomuleasa C, Popescu I, Alexandrescu S, Dima S, Chivu-Economescu M, Montgomery EA, Torbenson M, Meltzer SJ, Selaru FM (2012) MicroRNA-21 inhibits Serpini1, a gene with novel tumour suppressive effects in gastric cancer. Dig Liver Dis 44(7):589–96PubMedCentralPubMedGoogle Scholar
  91. 91.
    Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353(17):1793–801PubMedGoogle Scholar
  92. 92.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6(4):259–69PubMedGoogle Scholar
  93. 93.
    Calin GA, Croce CM (2007) Investigation of microRNA alterations in leukemias and lymphomas. Methods Enzymol 427:193–213PubMedGoogle Scholar
  94. 94.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 101(9):2999–3004PubMedCentralPubMedGoogle Scholar
  95. 95.
    Croce CM (2008) Oncogenes and cancer. N Engl J Med 358(5):502–11PubMedGoogle Scholar
  96. 96.
    Esteller M (2008) N Engl J Med 358(11):1148–59PubMedGoogle Scholar
  97. 97.
    Fandy TE, Gore SD (2010) Epigenetic targets in human neoplasms. Epigenomics 2(2):221–32PubMedGoogle Scholar
  98. 98.
    Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (2006) Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 20(16):2202–7PubMedCentralPubMedGoogle Scholar
  99. 99.
    Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, Yatabe Y, Takamizawa J, Miyoshi S, Mitsudomi T, Takahashi T (2005) Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci 96(2):111–5PubMedGoogle Scholar
  100. 100.
    Harris KS, Zhang Z, McManus MT, Harfe BD, Sun X (2006) Dicer function is essential for lung epithelium morphogenesis. Proc Natl Acad Sci U S A 103(7):2208–13PubMedCentralPubMedGoogle Scholar
  101. 101.
    Agirre X, Jiménez-Velasco A, San José-Enériz E, Garate L, Bandrés E, Cordeu L, Aparicio O, Saez B, Navarro G, Vilas-Zornoza A, Pérez-Roger I, García-Foncillas J, Torres A, Heiniger A, Calasanz MJ, Fortes P, Román-Gómez J, Prósper F (2008) Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34+ cells increases USF2-mediated cell growth. Mol Cancer Res 6(12):1830–40PubMedGoogle Scholar
  102. 102.
    Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, Croce CM, Fernández-Piqueras J, Malumbres M (2008) Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell 13(6):496–506PubMedGoogle Scholar
  103. 103.
    San José-Enériz E, Román-Gómez J, Jiménez-Velasco A, Garate L, Martin V, Cordeu L, Vilas-Zornoza A, Rodríguez-Otero P, Calasanz MJ, Prósper F, Agirre X (2009) MicroRNA expression profiling in imatinib-resistant chronic myeloid leukemia patients without clinically significant ABL1-mutations. Mol Cancer 8:69PubMedCentralPubMedGoogle Scholar
  104. 104.
    Woo JS, Alberti MO, Tirado CA (2014) Childhood B-acute lymphoblastic leukemia: a genetic update. Exp Hematol Oncol 3:16PubMedCentralPubMedGoogle Scholar
  105. 105.
    Teachey DT, Hunger SP (2013) Predicting relapse risk in childhood acute lymphoblastic leukaemia. Br J Haematol 162(5):606–20PubMedGoogle Scholar
  106. 106.
    Zanette DL, Rivadavia F, Molfetta GA, Barbuzano FG, Proto-Siqueira R, Silva-Jr WA, Falcão RP, Zago MA (2007) miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia. Braz J Med Biol Res 40(11):1435–40PubMedGoogle Scholar
  107. 107.
    Mi S, Lu J, Sun M, Li Z, Zhang H, Neilly MB, Wang Y, Qian Z, Jin J, Zhang Y, Bohlander SK, Le Beau MM, Larson RA, Golub TR, Rowley JD, Chen J (2007) MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc Natl Acad Sci U S A 104(50):19971–6PubMedCentralPubMedGoogle Scholar
  108. 108.
    Fulci V, Colombo T, Chiaretti S, Messina M, Citarella F, Tavolaro S, Guarini A, Foà R, Macino G (2009) Characterization of B- and T-lineage acute lymphoblastic leukemia by integrated analysis of microRNA and mRNA expression profiles. Genes Chromosom Cancer 48(12):1069–82PubMedGoogle Scholar
  109. 109.
    Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, Fabbri M, Coombes K, Alder H, Nakamura T, Flomenberg N, Marcucci G, Calin GA, Kornblau SM, Kantarjian H, Bloomfield CD, Andreeff M, Croce CM (2008) MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111(6):3183–9PubMedCentralPubMedGoogle Scholar
  110. 110.
    Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT, Chen P, Wang Y, Yan M, Qian Z, Neilly MB, Jin J, Zhang Y, Bohlander SK, Zhang DE, Larson RA, Le Beau MM, Thirman MJ, Golub TR, Rowley JD, Chen J (2008) Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci U S A 105(40):15535–40PubMedCentralPubMedGoogle Scholar
  111. 111.
    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(10):5078–85PubMedGoogle Scholar
  112. 112.
    Mrózek K, Bloomfield CD (2008) Clinical significance of the most common chromosome translocations in adult acute myeloid leukemia. J Natl Cancer InstMonogr (39):52-7Google Scholar
  113. 113.
    Irons RD, Kerzic PJ (2014) Cytogenetics in benzene-associated myelodysplastic syndromes and acute myeloid leukemia: new insights into a disease continuum. Ann N Y Acad Sci 1310:84–8PubMedGoogle Scholar
  114. 114.
    Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G (2010) Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A 107(16):7473–8PubMedCentralPubMedGoogle Scholar
  115. 115.
    Marcucci G, Radmacher MD, Maharry K, Mrózek K, Ruppert AS, Paschka P, Vukosavljevic T, Whitman SP, Baldus CD, Langer C, Liu CG, Carroll AJ, Powell BL, Garzon R, Croce CM, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD (2008) MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med 358(18):1919–28PubMedGoogle Scholar
  116. 116.
    Zhang W, Zhou T, Ma SF, Machado RF, Bhorade SM, G (2013) MicroRNAs implicated in dysregulation of gene expression following human lung transplantation. TranslRespir Med. 1(1)Google Scholar
  117. 117.
    Wilflingseder J, Regele H, Perco P, Kainz A, Soleiman A, Mühlbacher F, Mayer B, Oberbauer R (2013) miRNA profiling discriminates types of rejection and injury in human renal allografts. Transplantation 95(6):835–41PubMedCentralPubMedGoogle Scholar
  118. 118.
    Stanczyk J, Pedrioli DM, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE, Detmar M, Gay S, Kyburz D (2008) Altered expression of microRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis.Arthritis. Rheum 58(4):1001–9Google Scholar
  119. 119.
    Zhu J, Huang X, Su G, Wang L, Wu F, Zhang T, Song G (2014) High expression levels of microRNA-629, microRNA-525-5p and microRNA-516a-3p in paediatric systemic lupus erythematosus. Clin Rheumatol 33(6):807–15PubMedGoogle Scholar
  120. 120.
    Yan S, Yim LY, Lu L, Lau CS, Chan VS (2014) MicroRNA regulation in systemic lupus erythematosus pathogenesis. Immune Netw 14(3):138–48PubMedCentralPubMedGoogle Scholar
  121. 121.
    Xiao P, Dong C, Yue Y, Xiong S (2014) Dynamic expression of microRNAs in M2b polarized macrophages associated with systemic lupus erythematosus. Gene 547(2):300–9PubMedGoogle Scholar
  122. 122.
    Zan H, Tat C, Casali P (2014) MicroRNAs in lupus. Autoimmunity 47(4):272–85PubMedCentralPubMedGoogle Scholar
  123. 123.
    Liu X, Robinson SN, Setoyama T, Tung SS, D’Abundo L, Shah MY, Yang H, Yvon E, Shah N, Yang H, Konopleva M, Garcia-Manero G, McNiece I, Rezvani K, Calin GA, Shpall EJ, Parmar S (2014) FOXP3 is a direct target of miR15a/16 in umbilical cord blood regulatory T cells. Bone Marrow Transplant 49(6):793–9PubMedGoogle Scholar
  124. 124.
    Xie LN, Zhou F, Liu XM, Fang Y, Yu Z, Song NX, Kong FS (2014) Serum microRNA155 is increased in patients with acute graft-versus-host disease. Clin Transplant 28(3):314–23PubMedGoogle Scholar
  125. 125.
    Weissinger EM, Metzger J, Dobbelstein C, Wolff D, Schleuning M, Kuzmina Z, Greinix H, Dickinson AM, Mullen W, Kreipe H, Hamwi I, Morgan M, Krons A, Tchebotarenko I, Ihlenburg-Schwarz D, Dammann E, Collin M, Ehrlich S, Diedrich H, Stadler M, Eder M, Holler E, Mischak H, Krauter J, Ganser A (2014) Proteomic peptide profiling for preemptive diagnosis of acute graft-versus-host disease after allogeneic stem cell transplantation. Leukemia 28(4):842–52PubMedGoogle Scholar
  126. 126.
    Weissinger EM, Schiffer E, Hertenstein B, Ferrara JL, Holler E, Stadler M, Kolb HJ, Zander A, Zürbig P, Kellmann M, Ganser A (2007) Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood 109(12):5511–9PubMedGoogle Scholar
  127. 127.
    Rezvani AR, Storer BE, Storb RF, Mielcarek M, Maloney DG, Sandmaier BM, Martin PJ, McDonald GB (2011) Decreased serum albumin as a biomarker for severe acute graft-versus-host disease after reduced-intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 17(11):1594–601PubMedCentralPubMedGoogle Scholar
  128. 128.
    Shaiegan M, Iravani M, Babaee GR, Ghavamzadeh A (2006) Effect of IL-18 and sIL2R on aGVHD occurrence after hematopoietic stem cell transplantation in some Iranian patients. Transpl Immunol 15(3):223–7PubMedGoogle Scholar
  129. 129.
    Yamanaka S, Olaru AV, An F, Luvsanjav D, Jin Z, Agarwal R, Tomuleasa C, Popescu I, Alexandrescu S, Dima S, Chivu-Economescu M, Montgomery EA, Torbenson M, Meltzer SJ, Selaru FM (2012) MicroRNA-21 inhibits Serpini1, a gene with novel tumour suppressive effects in gastric cancer. Dig Liver Dis 44(7):589–96PubMedCentralPubMedGoogle Scholar
  130. 130.
    Li L, Zhou L, Li Y, Lin S, Tomuleasa C (2014) MicroRNA-21 stimulates gastric cancer growth and invasion by inhibiting the tumor suppressor effects of programmed cell death protein 4 and phosphatase and tensin homolog. J Buon 19(1):228–36PubMedGoogle Scholar
  131. 131.
    Xiao B, Wang Y, Li W, Baker M, Guo J, Corbet K, Tsalik EL, Li QJ, Palmer SM, Woods CW, Li Z, Chao NJ, He YW (2013) Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease. Blood 122(19):3365–75PubMedCentralPubMedGoogle Scholar
  132. 132.
    Wang L, Romero M, Ratajczak P, Lebœuf C, Belhadj S, Peffault de Latour R, Zhao WL, Socié G, Janin A (2013) Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia. Bone Marrow Transplant 48(6):849–53PubMedGoogle Scholar
  133. 133.
    Leonhardt F, Grundmann S, Behe M, Bluhm F, Dumont RA, Braun F, Fani M, Riesner K, Prinz G, Hechinger AK, Gerlach UV, Dierbach H, Penack O, Schmitt-Gräff A, Finke J, Weber WA, Zeiser R (2013) Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100. Blood 121(17):3307–18PubMedGoogle Scholar
  134. 134.
    Stickel N, Prinz G, Pfeifer D, Hasselblatt P, Schmitt-Graeff A, Follo M, Thimme R, Finke J, Duyster J, Salzer U, Zeiser R (2014) MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD. Blood 124(16):2586–95PubMedGoogle Scholar
  135. 135.
    Stickel N, Zeiser R (2014) Mikro-RNA: Rolle bei der Immunregulation nach allogener hämatopoetischer Stammzelltransplantation. Dtsch Med Wochenschr 139(33):1673–8PubMedGoogle Scholar
  136. 136.
    Xie LN, Zhou F, Liu XM, Fang Y, Yu Z, Song NX, Kong FS (2014) Serum microRNA155 is increased in patients with acute graft-versus-host disease. Clin Transplant 28(3):314–23PubMedGoogle Scholar
  137. 137.
    Wang L, Romero M, Ratajczak P, Lebœuf C, Belhadj S, Peffault de Latour R, Zhao WL, Socié G, Janin A (2013) Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia. Bone Marrow Transplant 48(6):849–53PubMedGoogle Scholar
  138. 138.
    Bernecker C, Halim F, Haase M, Willenberg HS, Ehlers M, Schott M (2013) MicroRNA expressions in PMBCs, CD4+, and CD8+ T-cells from patients suffering from autoimmune Addison’s disease. Horm Metab Res 45(8):599–604PubMedGoogle Scholar
  139. 139.
    Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, Li Z, Wu Z, Pei G (2009) MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 10(12):1252–9PubMedGoogle Scholar
  140. 140.
    Picascia A, Grimaldi V, Pignalosa O, De Pascale MR, Schiano C, Napoli C (2015) Epigenetic control of autoimmune diseases: from bench to bedside. Clin Immunol S1521–6616(15):00002–9Google Scholar
  141. 141.
    Li Z, Rana TM (2014) Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 13(8):622–38PubMedGoogle Scholar
  142. 142.
    Saba R, Sorensen DL, Booth SA (2014) MicroRNA-146a: a dominant, negative regulator of the innate immune response. Front Immunol 5:578PubMedCentralPubMedGoogle Scholar
  143. 143.
    Arruda LC, Lorenzi JC, Sousa AP, Zanette DL, Palma PV, Panepucci RA, Brum DS, Barreira AA, Covas DT, Simões BP, Silva WA Jr, Oliveira MC, Malmegrim KC (2014) Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients. Bone Marrow Transplant., in pressGoogle Scholar
  144. 144.
    Kaul V, Krams S (2015) MicroRNAs as master regulators of immune responses in transplant recipients. Curr Opin Organ Transplant 20(1):29–36PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Ciprian Tomuleasa
    • 1
    • 2
    Email author
  • Shigeo Fuji
    • 3
  • Andrei Cucuianu
    • 1
    • 2
  • Markus Kapp
    • 4
  • Valentina Pileczki
    • 1
  • Bobe Petrushev
    • 1
  • Sonia Selicean
    • 1
  • Alina Tanase
    • 5
  • Delia Dima
    • 2
  • Ioana Berindan-Neagoe
    • 1
    • 6
  • Alexandru Irimie
    • 1
    • 7
  • Hermann Einsele
    • 4
  1. 1.Iuliu Hatieganu University of Medicine and PharmacyCluj NapocaRomania
  2. 2.Department of HematologyIon Chiricuta Oncology InstituteCluj NapocaRomania
  3. 3.Division of Hematopoietic Stem Cell TransplantationNational Cancer Center HospitalTokyoJapan
  4. 4.Division of HematologyUniversitätsklinikum Würzburg Medizinische Klinik und Poliklinik IIWürzburgGermany
  5. 5.Department of Stem Cell TransplantationFundeni Clinical InstituteBucharestRomania
  6. 6.Department of Functional GenomicsIon Chiricuta Oncology InstituteCluj NapocaRomania
  7. 7.Department of SurgeryIon Chiricuta Oncology InstituteCluj NapocaRomania

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