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MicroRNAs in B-cell lymphomas: how a complex biology gets more complex

Leukemia volume 29, pages 1004–1017 (2015)Cite this article

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Abstract

MicroRNAs (miRNAs) represent important regulators of gene expression besides transcriptional control. miRNA regulation can be involved in the cell developmental fate decisions, but can also have more subtle roles in buffering stochastic fluctuations in gene expression. They participate in pathways fundamental to B-cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell–cell interactions in immune niches, and the production and class-switching of immunoglobulins. miRNAs influence B-cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. In this review, we discuss miRNAs with essential functions in malignant B-cell development (such as miR-150, miR-155, miR-21, miR-34a, miR-17-92 and miR-15-16). We also put these miRNAs in the context of normal B-cell differentiation, as this is intimately connected to neoplastic B-cell development. We review miRNAs’ role in the most common B-cell malignancies, including chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). We focus on miR-contribution to the regulation of important signalling pathways (such as NF-κB, PI3K/AKT and TGF-β), BCR signalling and its modulators (such as PTEN, SHIP-1, ZAP-70, GAB1 and BTK), anti- and pro-apoptotic proteins (such as BCL2, MCL1, TCL1, BIM, p53 and SIRT1) and transcription factors (such as MYC, MYB, PU.1, FOXP1 and BCL6). We also discuss the association of miRNAs’ expression levels with the patients’ survival and response to therapy, summarizing their potential use as predictive and prognostic markers. Importantly, the targeting of miRNAs (like use of anti-miR-155 or miR-34a mimic) could provide a novel therapeutic approach as evidenced by tumour regression in xenograft mouse models and initial promising data from clinical trials.

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References

  1. Bartel DP . MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. O'Connell RM, Baltimore D . MicroRNAs and hematopoietic cell development. Curr Top Dev Biol 2012; 99: 145–174.

    CAS  PubMed  Google Scholar 

  3. Mraz M, Kipps TJ . MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia. Leuk Lymphoma 2013; 54: 1836–1839.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 2007; 27: 847–859.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, Kanellopoulou C et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 2008; 132: 860–874.

    CAS  PubMed  Google Scholar 

  6. Mraz M, Dolezalova D, Plevova K, Kozubik KS, Mayerova V, Cerna K et al. MicroRNA-650 expression is influenced by immunoglobulin gene rearrangement and affects the biology of chronic lymphocytic leukemia. Blood 2012; 119: 2110–2113.

    CAS  PubMed  Google Scholar 

  7. Ebert MS, Sharp PA . Roles for microRNAs in conferring robustness to biological processes. Cell 2012; 149: 515–524.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Akbari Moqadam F, Pieters R, den Boer ML . The hunting of targets: challenge in miRNA research. Leukemia 2013; 27: 16–23.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP . The impact of microRNAs on protein output. Nature 2008; 455: 64–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Friedman RC, Farh KK, Burge CB, Bartel DP . Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19: 92–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Dorsett Y, McBride KM, Jankovic M, Gazumyan A, Thai TH, Robbiani DF et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity 2008; 28: 630–638.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002; 99: 15524–15529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 2010; 17: 28–40.

    Article  CAS  PubMed  Google Scholar 

  15. Volinia S, Calin G, Liu C, Ambs S, Cimmino A, Petrocca F et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 2006; 103: 2257–2261.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S et al. A microRNA polycistron as a potential human oncogene. Nature 2005; 435: 828–833.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci USA 2006; 103: 7024–7029.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Costinean S, Sandhu S, Pedersen I, Tili E, Trotta R, Perrotti D et al. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice. Blood 2009; 114: 1374–1382.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Medina PP, Nolde M, Slack FJ . OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 2010; 467: 86–90.

    CAS  PubMed  Google Scholar 

  20. Sandhu SK, Fassan M, Volinia S, Lovat F, Balatti V, Pekarsky Y et al. B-cell malignancies in microRNA Emu-miR-17~92 transgenic mice. Proc Natl Acad Sci USA 2013; 110: 18208–18213.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Santanam U, Zanesi N, Efanov A, Costinean S, Palamarchuk A, Hagan JP et al. Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression. Proc Natl Acad Sci USA 2010; 107: 12210–12215.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cui B, Chen L, Zhang S, Mraz M, Fecteau JF, Yu J et al. MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood 2014; 124: 546–554.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mraz M, Chen L, Rassenti LZ, Ghia EM, Li H, Jepsen K et al. miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. Blood 2014; 124: 84–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lawrie C, Soneji S, Marafioti T, Cooper C, Palazzo S, Paterson J et al. MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer 2007; 121: 1156–1161.

    Article  CAS  PubMed  Google Scholar 

  25. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Brit J Haematol 2008; 141: 672–675.

    Google Scholar 

  26. Di Lisio L, Gomez-Lopez G, Sanchez-Beato M, Gomez-Abad C, Rodriguez ME, Villuendas R et al. Mantle cell lymphoma: transcriptional regulation by microRNAs. Leukemia 2010; 24: 1335–1342.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mraz M, Malinova K, Kotaskova J, Pavlova S, Tichy B, Malcikova J et al. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 2009; 23: 1159–1163.

    CAS  PubMed  Google Scholar 

  29. O'Carroll D, Mecklenbrauker I, Das PP, Santana A, Koenig U, Enright AJ et al. A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev 2007; 21: 1999–2004.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Seda V, Mraz M . B cell receptor (BCR) signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol 2014; e-pub ahead of print 1 August 2014 doi:10.1111/ejh.12427.

    PubMed  Google Scholar 

  31. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ et al. Targeted deletion reveals essential and overlapping functions of the miR-17∼92 family of miRNA clusters. Cell 2008; 132: 875–886.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 2008; 9: 405–414.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Belver L, de Yébenes VG, Ramiro AR . MicroRNAs prevent the generation of autoreactive antibodies. Immunity 2010; 33: 713–722.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Xu S, Guo K, Zeng Q, Huo J, Lam KP . The RNase III enzyme Dicer is essential for germinal center B-cell formation. Blood 2012; 119: 767–776.

    CAS  PubMed  Google Scholar 

  35. Rao DS, O'Connell RM, Chaudhuri AA, Garcia-Flores Y, Geiger TL, Baltimore D . MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1. Immunity 2010; 33: 48–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 2007; 131: 146–159.

    CAS  PubMed  Google Scholar 

  37. Zhou B, Wang S, Mayr C, Bartel DP, Lodish HF . miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci USA 2007; 104: 7080–7085.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. van den Berg A, Kroesen BJ, Kooistra K, de Jong D, Briggs J, Blokzijl T et al. High expression of B-cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma. Gene Chromosome Cancer 2003; 37: 20–28.

    CAS  Google Scholar 

  39. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR et al. Requirement of bic/microRNA-155 for normal immune function. Science 2007; 316: 608–611.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y et al. Regulation of the germinal center response by microRNA-155. Science 2007; 316: 604–608.

    CAS  PubMed  Google Scholar 

  41. Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 2008; 28: 621–629.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. de Yebenes VG, Belver L, Pisano DG, Gonzalez S, Villasante A, Croce C et al. miR-181b negatively regulates activation-induced cytidine deaminase in B cells. J Exp Med 2008; 205: 2199–2206.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Tan LP, Wang M, Robertus JL, Schakel RN, Gibcus JH, Diepstra A et al. miRNA profiling of B-cell subsets: specific miRNA profile for germinal center B cells with variation between centroblasts and centrocytes. Lab Invest 2009; 89: 708–716.

    CAS  PubMed  Google Scholar 

  44. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T . Identification of tissue-specific microRNAs from mouse. Curr Biol 2002; 12: 735–739.

    CAS  PubMed  Google Scholar 

  45. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T . Identification of novel genes coding for small expressed RNAs. Science 2001; 294: 853–858.

    CAS  PubMed  Google Scholar 

  46. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353: 1793–1801.

    CAS  PubMed  Google Scholar 

  47. Kminkova J, Mraz M, Zaprazna K, Navrkalova V, Tichy B, Plevova K et al. Identification of novel sequence variations in microRNAs in chronic lymphocytic leukemia. Carcinogenesis 2014; 35: 992–1002.

    CAS  PubMed  Google Scholar 

  48. Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M et al. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci USA 2008; 105: 5166–5171.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lia M, Carette A, Tang H, Shen Q, Mo T, Bhagat G et al. Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines. Blood 2012; 119: 2981–2990.

    CAS  PubMed  Google Scholar 

  50. Mraz M, Pospisilova S, Malinova K, Slapak I, Mayer J . MicroRNAs in chronic lymphocytic leukemia pathogenesis and disease subtypes. Leuk Lymphoma 2009; 50: 506–509.

    CAS  PubMed  Google Scholar 

  51. Mraz M, Pospisilova S . MicroRNAs in chronic lymphocytic leukemia: from causality to associations and back. Expert Rev Hematol 2012; 5: 579–581.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. Zenz T, Mohr J, Eldering E, Kater AP, BĂĽhler A, Kienle D et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood 2009; 113: 3801–3808.

    CAS  PubMed  Google Scholar 

  56. Asslaber D, Pinon JD, Seyfried I, Desch P, Stöcher M, Tinhofer I et al. microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia. Blood 2010; 115: 4191–4197.

    CAS  PubMed  Google Scholar 

  57. Trbusek M, Smardova J, Malcikova J, Sebejova L, Dobes P, Svitakova M et al. Missense mutations located in structural p53 DNA-binding motifs are associated with extremely poor survival in chronic lymphocytic leukemia. J Clin Oncol 2011; 29: 2703–2708.

    CAS  PubMed  Google Scholar 

  58. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y et al. A microRNA component of the p53 tumour suppressor network. Nature 2007; 447: 1130–1134.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Visone R, Veronese A, Rassenti LZ, Balatti V, Pearl DK, Acunzo M et al. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood 2011; 118: 3072–3079.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Tili E, Michaille JJ, Luo Z, Volinia S, Rassenti LZ, Kipps TJ et al. The downregulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state. Blood 2012; 120: 2631–2638.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Fabbri M, Bottoni A, Shimizu M, Spizzo R, Nicoloso MS, Rossi S et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA 2011; 305: 59–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Baer C, Claus R, Frenzel LP, Zucknick M, Park YJ, Gu L et al. Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microrna expression in chronic lymphocytic leukemia. Cancer Res 2012; 72: 3775–3785.

    CAS  PubMed  Google Scholar 

  63. Sampath D, Liu C, Vasan K, Sulda M, Puduvalli VK, Wierda WG et al. Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood 2012; 119: 1162–1172.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT . c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005; 435: 839–843.

    CAS  PubMed  Google Scholar 

  65. Mu P, Han YC, Betel D, Yao E, Squatrito M, Ogrodowski P et al. Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev 2009; 23: 2806–2811.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Olive V, Bennett MJ, Walker JC, Ma C, Jiang I, Cordon-Cardo C et al. miR-19 is a key oncogenic component of mir-17-92. Genes Dev 2009; 23: 2839–2849.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Olive V, Sabio E, Bennett MJ, De Jong CS, Biton A, McGann JC et al. A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis. Elife 2013; 2: e00822.

    PubMed  PubMed Central  Google Scholar 

  68. Rao E, Jiang C, Ji M, Huang X, Iqbal J, Lenz G et al. The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia 2012; 26: 1064–1072.

    CAS  PubMed  Google Scholar 

  69. Inomata M, Tagawa H, Guo YM, Kameoka Y, Takahashi N, Sawada K . MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes. Blood 2009; 113: 396–402.

    CAS  PubMed  Google Scholar 

  70. Lawrie CH, Chi JX, Taylor S, Tramonti D, Ballabio E, Palazzo S et al. Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma. J Cell Mol Med 2009; 13: 1248–1260.

    CAS  PubMed  Google Scholar 

  71. Fassina A, Marino F, Siri M, Zambello R, Ventura L, Fassan M et al. The miR-17-92 microRNA cluster: a novel diagnostic tool in large B-cell malignancies. Lab Invest 2012; 92: 1574–1582.

    CAS  PubMed  Google Scholar 

  72. Olive V, Li Q, He L . mir-17-92: a polycistronic oncomir with pleiotropic functions. Immunol Rev 2013; 253: 158–166.

    PubMed  PubMed Central  Google Scholar 

  73. Eis P, Tam W, Sun L, Chadburn A, Li Z, Gomez M et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 2005; 102: 3627–3632.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Roehle A, Hoefig K, Repsilber D, Thorns C, Ziepert M, Wesche K et al. MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas. Br J Haematol 2008; 142: 732–744.

    CAS  PubMed  Google Scholar 

  75. Vargova K, Curik N, Burda P, Basova P, Kulvait V, Pospisil V et al. MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia. Blood 2011; 117: 3816–3825.

    CAS  PubMed  Google Scholar 

  76. Malumbres R, Sarosiek KA, Cubedo E, Ruiz JW, Jiang X, Gascoyne RD et al. Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood 2009; 113: 3754–3764.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Alencar AJ, Malumbres R, Kozloski GA, Advani R, Talreja N, Chinichian S et al. MicroRNAs are independent predictors of outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. Clin Cancer Res 2011; 17: 4125–4135.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Thompson RC, Vardinogiannis I, Gilmore TD . Identification of an NF-kappaB p50/p65-responsive site in the human MIR155HG promoter. BMC Mol Biol 2013; 14: 24.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Gatto G, Rossi A, Rossi D, Kroening S, Bonatti S, Mallardo M . Epstein-Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-kappaB pathway. Nucleic Acids Res 2008; 36: 6608–6619.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Thompson RC, Herscovitch M, Zhao I, Ford TJ, Gilmore TD . NF-kappaB down-regulates expression of the B-lymphoma marker CD10 through a miR-155/PU.1 pathway. J Biol Chem 2011; 286: 1675–1682.

    CAS  PubMed  Google Scholar 

  81. Dagan LN, Jiang X, Bhatt S, Cubedo E, Rajewsky K, Lossos IS . miR-155 regulates HGAL expression and increases lymphoma cell motility. Blood 2012; 119: 513–520.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Rai D, Kim SW, McKeller MR, Dahia PL, Aguiar RC . Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis. Proc Natl Acad Sci USA 2010; 107: 3111–3116.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Babar IA, Cheng CJ, Booth CJ, Liang X, Weidhaas JB, Saltzman WM et al. Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci USA 2012; 109: E1695–E1704.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Vigorito E, Kohlhaas S, Lu D, Leyland R . miR-155: an ancient regulator of the immune system. Immunol Rev 2013; 253: 146–157.

    PubMed  Google Scholar 

  85. Thapa DR, Bhatia K, Bream JH, D'Souza G, Rinaldo CR, Wolinsky S et al. B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas. AIDS 2012; 26: 1177–1180.

    CAS  PubMed  Google Scholar 

  86. Rosato P, Anastasiadou E, Garg N, Lenze D, Boccellato F, Vincenti S et al. Differential regulation of miR-21 and miR-146a by Epstein-Barr virus-encoded EBNA2. Leukemia 2012; 26: 2343–2352.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ma X, Kumar M, Choudhury SN, Becker Buscaglia LE, Barker JR, Kanakamedala K et al. Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis. Proc Natl Acad Sci USA 2011; 108: 10144–10149.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Barnes NA, Stephenson S, Cocco M, Tooze RM, Doody GM . BLIMP-1 and STAT3 counterregulate microRNA-21 during plasma cell differentiation. J Immunol 2012; 189: 253–260.

    CAS  PubMed  Google Scholar 

  89. Bai H, Wei J, Deng C, Yang X, Wang C, Xu R . MicroRNA-21 regulates the sensitivity of diffuse large B-cell lymphoma cells to the CHOP chemotherapy regimen. Int J Hematol 2013; 97: 223–231.

    CAS  PubMed  Google Scholar 

  90. Yamanaka Y, Tagawa H, Takahashi N, Watanabe A, Guo YM, Iwamoto K et al. Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia. Blood 2009; 114: 3265–3275.

    CAS  PubMed  Google Scholar 

  91. Gu L, Song G, Chen L, Nie Z, He B, Pan Y et al. Inhibition of miR-21 induces biological and behavioral alterations in diffuse large B-cell lymphoma. Acta Haematol 2013; 130: 87–94.

    CAS  PubMed  Google Scholar 

  92. Rossi S, Shimizu M, Barbarotto E, Nicoloso MS, Dimitri F, Sampath D et al. microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival. Blood 2010; 116: 945–952.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R et al. Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system. Blood 2011; 117: 3140–3146.

    CAS  PubMed  Google Scholar 

  94. Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K . STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell 2010; 39: 493–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Navarro A, Clot G, Prieto M, Royo C, Vegliante MC, Amador V et al. microRNA expression profiles identify subtypes of mantle cell lymphoma with different clinicobiological characteristics. Clin Cancer Res 2013; 19: 3121–3129.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. He M, Gao L, Zhang S, Tao L, Wang J, Yang J et al. Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL. Gastric Cancer 2013; 17: 431–441.

    PubMed  Google Scholar 

  97. Zauli G, Voltan R, di Iasio MG, Bosco R, Melloni E, Sana ME et al. miR-34a induces the downregulation of both E2F1 and B-Myb oncogenes in leukemic cells. Clin Cancer Res 2011; 17: 2712–2724.

    CAS  PubMed  Google Scholar 

  98. Boysen J, Sinha S, Price-Troska T, Warner SL, Bearss DJ, Viswanatha D et al. The tumor suppressor axis p53/miR-34a regulates Axl expression in B-cell chronic lymphocytic leukemia: implications for therapy in p53-defective CLL patients. Leukemia 2014; 28: 451–455.

    CAS  PubMed  Google Scholar 

  99. Yamakuchi M, Ferlito M, Lowenstein CJ . miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA 2008; 105: 13421–13426.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Li L, Yuan L, Luo J, Gao J, Guo J, Xie X . MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin Exp Med 2013; 13: 109–117.

    PubMed  Google Scholar 

  101. Craig VJ, Cogliatti SB, Imig J, Renner C, Neuenschwander S, Rehrauer H et al. Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1. Blood 2011; 117: 6227–6236.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Rizzo M, Mariani L, Cavallini S, Simili M, Rainaldi G . The over-expression of miR-34a fails to block DoHH2 lymphoma cell proliferation by reducing p53 via c-MYC down-regulation. Nucleic Acid Ther 2012; 22: 283–288.

    CAS  PubMed  Google Scholar 

  103. Sotillo E, Laver T, Mellert H, Schelter JM, Cleary MA, McMahon S et al. Myc overexpression brings out unexpected antiapoptotic effects of miR-34a. Oncogene 2011; 30: 2587–2594.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Chen S, Wang Z, Dai X, Pan J, Ge J, Han X et al. Re-expression of microRNA-150 induces EBV-positive Burkitt lymphoma differentiation by modulating c-Myb in vitro. Cancer Sci 2013; 104: 826–834.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Thomas MD, Kremer CS, Ravichandran KS, Rajewsky K, Bender TP . c-Myb is critical for B cell development and maintenance of follicular B cells. Immunity 2005; 23: 275–286.

    CAS  PubMed  Google Scholar 

  106. Barrans SL, Fenton JA, Banham A, Owen RG, Jack AS . Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 2004; 104: 2933–2935.

    CAS  PubMed  Google Scholar 

  107. Brown P, Marafioti T, Kusec R, Banham AH . The FOXP1 transcription factor is expressed in the majority of follicular lymphomas but is rarely expressed in classical and lymphocyte predominant Hodgkin's lymphoma. J Mol Histol 2005; 36: 249–256.

    CAS  PubMed  Google Scholar 

  108. Sagaert X, de Paepe P, Libbrecht L, Vanhentenrijk V, Verhoef G, Thomas J et al. Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma. J Clin Oncol 2006; 24: 2490–2497.

    CAS  PubMed  Google Scholar 

  109. Tano N, Kim HW, Ashraf M . microRNA-150 regulates mobilization and migration of bone marrow-derived mononuclear cells by targeting Cxcr4. PLoS One 2011; 6: e23114.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Watanabe A, Tagawa H, Yamashita J, Teshima K, Nara M, Iwamoto K et al. The role of microRNA-150 as a tumor suppressor in malignant lymphoma. Leukemia 2011; 25: 1324–1334.

    CAS  PubMed  Google Scholar 

  111. Bryniarski K, Ptak W, Jayakumar A, Pullmann K, Caplan MJ, Chairoungdua A et al. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. J Allergy Clin Immunol 2013; 132: 170–181.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Jiang X, Huang H, Li Z, Li Y, Wang X, Gurbuxani S et al. Blockade of miR-150 maturation by MLL-fusion/MYC/LIN-28 is required for MLL-associated leukemia. Cancer Cell 2012; 22: 524–535.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004; 351: 2159–2169.

    CAS  PubMed  Google Scholar 

  114. Mraz M, Zent CS, Church AK, Jelinek DF, Wu X, Pospisilova S et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance. Br J Haematol 2011; 155: 53–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lin J, Lwin T, Zhao JJ, Tam W, Choi YS, Moscinski LC et al. Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas. Leukemia 2011; 25: 145–152.

    CAS  PubMed  Google Scholar 

  116. Lwin T, Lin J, Choi YS, Zhang X, Moscinski LC, Wright KL et al. Follicular dendritic cell-dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion-mediated Bim down-regulation through induction of microRNA-181a. Blood 2010; 116: 5228–5236.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Lwin T, Zhao X, Cheng F, Zhang X, Huang A, Shah B et al. A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. J Clin Invest 2013; 123: 4612–4626.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Psathas JN, Doonan PJ, Raman P, Freedman BD, Minn AJ, Thomas-Tikhonenko A . The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop. Blood 2013; 122: 4220–4229.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Li Z, Rana TM . Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 2014; 13: 622–638.

    CAS  PubMed  Google Scholar 

  120. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013; 368: 1685–1694.

    CAS  PubMed  Google Scholar 

  121. Bader AG . miR-34—a microRNA replacement therapy is headed to the clinic. Front Genet 2012; 3: 120.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Beg MBA, Sachdev J, Borad M, Cortes J, Tibes R, Kang Y et al. A Phase 1 study of first-in-class microRNA-34 mimic, MRX34, in patients with hepatocellular carcinoma or advanced cancer with liver metastasis (Late Breaking Abstract, 4LBA). 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics: Barcelona, Spain, 2014.

    Google Scholar 

  123. Craig VJ, Tzankov A, Flori M, Schmid CA, Bader AG, Muller A . Systemic microRNA-34a delivery induces apoptosis and abrogates growth of diffuse large B-cell lymphoma in vivo. Leukemia 2012; 26: 2421–2424.

    CAS  PubMed  Google Scholar 

  124. Di Martino MT, Leone E, Amodio N, Foresta U, Lionetti M, Pitari MR et al. Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. Clin Cancer Res 2012; 18: 6260–6270.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Salerno E, Scaglione BJ, Coffman FD, Brown BD, Baccarini A, Fernandes H et al. Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity. Mol Cancer Ther 2009; 8: 2684–2692.

    CAS  PubMed  Google Scholar 

  126. Arora S, Swaminathan SK, Kirtane A, Srivastava SK, Bhardwaj A, Singh S et al. Synthesis, characterization, and evaluation of poly (D,L-lactide-co-glycolide)-based nanoformulation of miRNA-150: potential implications for pancreatic cancer therapy. Int J Nanomedicine 2014; 9: 2933–2942.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Zhang Y, Roccaro AM, Rombaoa C, Flores L, Obad S, Fernandes SM et al. LNA-mediated anti-microRNA-155 silencing in low-grade B cell lymphomas. Blood 2012; 120: 1678–1686.

    CAS  PubMed  Google Scholar 

  128. Dereani S, Macor P, D'Agaro T, Mezzaroba N, Dal-Bo M, Capolla S et al. Potential therapeutic role of antagomiR17 for the treatment of chronic lymphocytic leukemia. J Hematol Oncol 2014; 7: 79.

    PubMed  PubMed Central  Google Scholar 

  129. Spierings DC, McGoldrick D, Hamilton-Easton AM, Neale G, Murchison EP, Hannon GJ et al. Ordered progression of stage-specific miRNA profiles in the mouse B2 B-cell lineage. Blood 2011; 117: 5340–5349.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Jima DD, Zhang J, Jacobs C, Richards KL, Dunphy CH, Choi WW et al. Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs. Blood 2010; 116: e118–e127.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Chen RW, Bemis LT, Amato CM, Myint H, Tran H, Birks DK et al. Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma. Blood 2008; 112: 822–829.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Stamatopoulos B, Meuleman N, Haibe-Kains B, Saussoy P, Van Den Neste E, Michaux L et al. microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification. Blood 2009; 113: 5237–5245.

    CAS  PubMed  Google Scholar 

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Acknowledgements

MM thanks Thomas J. Kipps (UCSD), Jiri Mayer (MU) and Sarka Pospisilova (MU) for inspiring discussions; however, TJK, JM and SP are not responsible for the content or presented ideas. This work was supported by SoMoPro II Programme—no. 4SGA8684 (co-financed by the EU and the South-Moravian Region), MUNI/A/0830/2013, MUNI/A/1180/2014, NGS-PTL (FP7-HEALTH-2012-INNOVATION-1, no. 306242), IGA MZ CR NT11218-6/2010, MH CZ-DRO (FNBr, 65269705), VaVPI project CEITEC – CZ.1.05/1.1.00/02.0068 and EHA Research Fellowship award granted by the European Hematology Association.

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KM and MM wrote the paper.

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  1. Central European Institute of Technology, Masaryk University, Brno, Czech Republic

    K Musilova & M Mraz

  2. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic

    M Mraz

  3. Faculty of Medicine, Masaryk University, Brno, Czech Republic

    M Mraz

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  1. K Musilova
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Musilova, K., Mraz, M. MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia 29, 1004–1017 (2015). https://doi.org/10.1038/leu.2014.351

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