Advertisement

MicroRNAs: pivotal regulators in acute myeloid leukemia

  • 39 Accesses

Abstract

MicroRNAs are a class of small non-coding RNAs that are 19–22 nucleotides in length and regulate a variety of biological processes at the post-transcriptional level. MicroRNA dysregulation disrupts normal biological processes, resulting in tumorigenesis. Acute myeloid leukemia is an invasive hematological malignancy characterized by the abnormal proliferation and differentiation of immature myeloid cells. Due to the low 5-year survival rate, there is an urgent need to discover novel diagnostic markers and therapeutic targets. In recent years, microRNAs have been shown to play important roles in hematological malignancies by acting as tumor suppressors and oncogenes. MicroRNAs have the potential to be a breakthrough in the diagnosis and treatment of acute myeloid leukemia. In this review, we summarize the biology of microRNAs and discuss the relationships between microRNA dysregulation and acute myeloid leukemia in the following aspects: signaling pathways, the abnormal biological behavior of acute myeloid leukemia cells, the clinical application of microRNAs and competing endogenous RNA regulatory networks.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

ALL:

Acute lymphocytic leukemia

AML:

Acute myeloid leukemia

APL:

Acute promyelocytic leukemia

AUC:

Area under curve

B-ALL:

B cell acute lymphocytic leukemia

BM:

Bone marrow

CA-AL:

Cytogenetically abnormal acute leukemia

ceRNA:

Competing endogenous RNA

circRNAs:

Circular RNAs

CLL:

Chronic lymphoid leukemia

CN-AML:

Cytogenetically normal acute myeloid leukemia

CR:

Complete remission

DFS:

Disease-free survival

EFS:

Event-free survival

HOXA:

The homeobox transcription factor

HSPC:

The hematopoietic stem and progenitor cell

LFS:

Leukemia-free survival

LncRNAs:

Long non-coding RNAs

LSCs:

Leukemia stem cells

miRNAs:

MicroRNAs

MAPK:

Mitogen-activated protein kinase

MLL:

Mixed lineage leukemia

OS:

Overall survival

Pri-miRNAs:

Primary miRNA transcripts

PMNCs:

Peripheral blood mononuclear cells

RR:

Recurrence rate

T-ALL:

T cell acute lymphoblastic leukemia.

References

  1. 1.

    Estey EH (2018) Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol 93(10):1267–1291

  2. 2.

    Papayannidis C, Sartor C, Marconi G, Fontana MC, Nanni J, Cristiano G, Parisi S, Paolini S, Curti A (2019) Acute myeloid leukemia mutations: therapeutic implications. Int J Mol Sci 20:11

  3. 3.

    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233

  4. 4.

    Broughton JP, Lovci MT, Huang JL, Yeo GW, Pasquinelli AE (2016) Pairing beyond the seed supports microRNA targeting specificity. Mol Cell 64(2):320–333

  5. 5.

    Wallace JA, O'Connell RM (2017) MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts. Blood 130(11):1290–1301

  6. 6.

    Weiss CN, Ito K (2017) A macro view of microRNAs: the discovery of microRNAs and their role in hematopoiesis and hematologic disease. Int Rev Cell Mol Biol 334:99–175

  7. 7.

    Landskroner-Eiger S, Moneke I, Sessa WC (2013) miRNAs as modulators of angiogenesis. Cold Spring Harb Perspect Med 3(2):a006643

  8. 8.

    Trobaugh DW, Klimstra WB (2017) MicroRNA regulation of RNA virus replication and pathogenesis. Trends Mol Med 23(1):80–93

  9. 9.

    Kim J, Yao F, Xiao Z, Sun Y, Ma L (2018) MicroRNAs and metastasis: small RNAs play big roles. Cancer Metastasis Rev 37(1):5–15

  10. 10.

    Drobna M, Szarzynska-Zawadzka B, Dawidowska M (2018) T-cell acute lymphoblastic leukemia from miRNA perspective: basic concepts, experimental approaches, and potential biomarkers. Blood Rev

  11. 11.

    He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5(7):522–531

  12. 12.

    Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21(17):4663–4670

  13. 13.

    Ozsolak F, Poling LL, Wang Z, Liu H, Liu XS, Roeder RG, Zhang X, Song JS, Fisher DE (2008) Chromatin structure analyses identify miRNA promoters. Genes Dev 22(22):3172–3183

  14. 14.

    Monteys AM, Spengler RM, Wan J, Tecedor L, Lennox KA, Xing Y, Davidson BL (2010) Structure and activity of putative intronic miRNA promoters. RNA (New York, NY) 16(3):495–505

  15. 15.

    Borchert GM, Lanier W, Davidson BL (2006) RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13(12):1097–1101

  16. 16.

    Forstemann K, Horwich MD, Wee L, Tomari Y, Zamore PD (2007) Drosophila microRNAs are sorted into functionally distinct argonaute complexes after production by dicer-1. Cell 130(2):287–297

  17. 17.

    Schotte D, Pieters R, Den Boer ML (2012) MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia 26(1):1–12

  18. 18.

    Meister G (2013) Argonaute proteins: functional insights and emerging roles. Nat Rev Genet 14(7):447–459

  19. 19.

    Ruby JG, Jan CH, Bartel DP (2007) Intronic microRNA precursors that bypass Drosha processing. Nature 448(7149):83–86

  20. 20.

    Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130(1):89–100

  21. 21.

    Saraiya AA, Wang CC (2008) snoRNA, a novel precursor of microRNA in Giardia lamblia. PLoS Pathog 4(11):e1000224

  22. 22.

    Scott MS, Avolio F, Ono M, Lamond AI, Barton GJ (2009) Human miRNA precursors with box H/ACA snoRNA features. PLoS Comput Biol 5(9):e1000507

  23. 23.

    Titov II, Vorozheykin PS (2018) Comparing miRNA structure of mirtrons and non-mirtrons. BMC Genomics 19(Suppl 3):114

  24. 24.

    Westholm JO, Lai EC (2011) Mirtrons: microRNA biogenesis via splicing. Biochimie 93(11):1897–1904

  25. 25.

    Treiber T, Treiber N, Meister G (2019) Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat Rev Mol Cell Biol 20(1):5–20

  26. 26.

    Abdelfattah AM, Park C, Choi MY (2014) Update on non-canonical microRNAs. Biomolecular Concepts 5(4):275–287

  27. 27.

    Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11(9):597–610

  28. 28.

    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9(2):102–114

  29. 29.

    Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79:351–379

  30. 30.

    Hayes J, Peruzzi PP, Lawler S (2014) MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med 20(8):460–469

  31. 31.

    Chipman LB, Pasquinelli AE (2019) miRNA targeting: growing beyond the seed. Trends in Genetics: TIG 35(3):215–222

  32. 32.

    Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition. PLoS Biol 3(3):e85

  33. 33.

    Sun HL, Cui R, Zhou J, Teng KY, Hsiao YH, Nakanishi K, Fassan M, Luo Z, Shi G, Tili E, Kutay H, Lovat F, Vicentini C, Huang HL, Wang SW, Kim T, Zanesi N, Jeon YJ, Lee TJ, Guh JH, Hung MC, Ghoshal K, Teng CM, Peng Y, Croce CM (2016) ERK activation globally downregulates miRNAs through phosphorylating exportin-5. Cancer Cell 30(5):723–736

  34. 34.

    Braun T, Carvalho G, Fabre C, Grosjean J, Fenaux P, Kroemer G (2006) Targeting NF-kappaB in hematologic malignancies. Cell Death Differ 13(5):748–758

  35. 35.

    Karin M (2009) NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 1(5):a000141

  36. 36.

    Rushworth SA, Murray MY, Barrera LN, Heasman SA, Zaitseva L, Macewan DJ (2012) Understanding the role of miRNA in regulating NF-κB in blood cancer. Am J Cancer Res 2(1):65–74

  37. 37.

    Zhao JL, Rao DS, Boldin MP, Taganov KD, O'Connell RM, Baltimore D (2011) NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci U S A 108(22):9184–9189

  38. 38.

    Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, Hirst M, Hogge D, Marra M, Wells RA, Buckstein R, Lam W, Humphries RK, Karsan A (2010) Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nat Med 16(1):49–58

  39. 39.

    Fang J, Barker B, Bolanos L, Liu X, Jerez A, Makishima H, Christie S, Chen X, Rao DS, Grimes HL, Komurov K, Weirauch MT, Cancelas JA, Maciejewski JP, Starczynowski DT (2014) Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-kappaB gene network. Cell Rep 8(5):1328–1338

  40. 40.

    Li X, Xu L, Shen X, Cai J, Liu J, Yin T, Xiao F, Chen F, Zhong H (2018) Up-regulated miR-146a expression induced by G-CSF enhanced low dosage chemotherapy response in aged acute myeloid leukemia patients. Exp Hematol

  41. 41.

    Wang Y, Tang P, Chen Y, Chen J, Ma R, Sun L (2017) Overexpression of microRNA-125b inhibits human acute myeloid leukemia cells invasion, proliferation and promotes cells apoptosis by targeting NF-kappaB signaling pathway. Biochem Biophys Res Commun 488(1):60–66

  42. 42.

    Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26(22):3279–3290

  43. 43.

    Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22(2):153–183

  44. 44.

    Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiology and Molecular Biology Reviews: MMBR 75(1):50–83

  45. 45.

    Zaidi SK, Dowdy CR, van Wijnen AJ, Lian JB, Raza A, Stein JL, Croce CM, Stein GS (2009) Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network. Cancer Res 69(21):8249–8255

  46. 46.

    Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV, Sun Y, Koo S, Perera RJ, Jain R et al (2004) MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 279(50):52361–52365

  47. 47.

    Hartmann JU, Brauer-Hartmann D, Kardosova M, Wurm AA, Wilke F, Schodel C, Gerloff D, Katzerke C, Krakowsky R, Namasu CY et al (2018) MicroRNA-143 targets ERK5 in granulopoiesis and predicts outcome of patients with acute myeloid leukemia. Cell Death Dis 9(8):814

  48. 48.

    Bhayadia R, Krowiorz K, Haetscher N, Jammal R, Emmrich S, Obulkasim A, Fiedler J, Schwarzer A, Rouhi A, Heuser M, Wingert S, Bothur S, Döhner K, Mätzig T, Ng M, Reinhardt D, Döhner H, Zwaan CM, van den Heuvel Eibrink M, Heckl D, Fornerod M, Thum T, Humphries RK, Rieger MA, Kuchenbauer F, Klusmann JH (2018) Endogenous tumor suppressor microRNA-193b: therapeutic and prognostic value in acute myeloid leukemia. J Clin Oncol 36(10):1007–1016

  49. 49.

    Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27(41):5497–5510

  50. 50.

    Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8(8):627–644

  51. 51.

    Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M (2003) Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102(3):972–980

  52. 52.

    Kubota Y, Ohnishi H, Kitanaka A, Ishida T, Tanaka T (2004) Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells: direct evidence of PI3K activation. Leukemia 18(8):1438–1440

  53. 53.

    Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A, Saki N (2015) Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci 72(12):2337–2347

  54. 54.

    Xue H, Hua LM, Guo M, Luo JM (2014) SHIP1 is targeted by miR-155 in acute myeloid leukemia. Oncol Rep 32(5):2253–2259

  55. 55.

    Lechman ER, Gentner B, Ng SW, Schoof EM, van Galen P, Kennedy JA, Nucera S, Ciceri F, Kaufmann KB, Takayama N et al (2016) miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell 29(2):214–228

  56. 56.

    Deng L, Jiang L, Lin XH, Tseng KF, Liu Y, Zhang X, Dong RH, Lu ZG, Wang XJ (2017) The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia. Acta Pharmacol Sin 38(3):382–391

  57. 57.

    Emmrich S, Engeland F, El-Khatib M, Henke K, Obulkasim A, Schöning J, Katsman-Kuipers JE, Michel Zwaan C, Pich A, Stary J et al (2016) miR-139-5p controls translation in myeloid leukemia through EIF4G2. Oncogene 35(14):1822–1831

  58. 58.

    Alemdehy MF, Haanstra JR, de Looper HW, van Strien PM, Verhagen-Oldenampsen J, Caljouw Y, Sanders MA, Hoogenboezem R, de Ru AH, Janssen GM et al (2015) ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation. Blood 125(25):3937–3948

  59. 59.

    Zhang R, Tang P, Wang F, Xing Y, Jiang Z, Chen S, Meng X, Liu L, Cao W, Zhao H et al (2018) Tumor suppressor miR-139-5p targets Tspan3 and regulates the progression of acute myeloid leukemia through the PI3K/Akt pathway. J Cell Biochem

  60. 60.

    Favreau AJ, Sathyanarayana P (2012) miR-590-5p, miR-219-5p, miR-15b and miR-628-5p are commonly regulated by IL-3, GM-CSF and G-CSF in acute myeloid leukemia. Leuk Res 36(3):334–341

  61. 61.

    Chen L, Jiang X, Chen H, Han Q, Liu C, Sun M (2019) microRNA-628 inhibits the proliferation of acute myeloid leukemia cells by directly targeting IGF-1R. OncoTargets and Therapy 12:907–919

  62. 62.

    Zhou JD, Li XX, Zhang TJ, Xu ZJ, Zhang ZH, Gu Y, Wen XM, Zhang W, Ji RB, Deng ZQ et al (2019) Dysregulation predicts clinical outcome and facilitates leukemogenesis by activating PI3K/Akt signaling pathway in acute myeloid leukemia. Aging 11(10):3376–3391

  63. 63.

    Lento W, Congdon K, Voermans C, Kritzik M, Reya T (2013) Wnt signaling in normal and malignant hematopoiesis. Cold Spring Harb Perspect Biol 5(2)

  64. 64.

    Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI, Armstrong SA (2010) The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science (New York, NY) 327(5973):1650–1653

  65. 65.

    Simon M, Grandage VL, Linch DC, Khwaja A (2005) Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia. Oncogene 24(14):2410–2420

  66. 66.

    Emmrich S, Rasche M, Schöning J, Reimer C, Keihani S, Maroz A, Xie Y, Li Z, Schambach A, Reinhardt D et al (2014) miR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling. Genes Dev 28(8):858–874

  67. 67.

    Li G, Song Y, Zhang Y, Wang H, Xie J (2016) miR-34b targets HSF1 to suppress cell survival in acute myeloid leukemia. Oncol Res 24(2):109–116

  68. 68.

    Garzon R, Heaphy CEA, Havelange V, Fabbri M, Volinia S, Tsao T, Zanesi N, Kornblau SM, Marcucci G, Calin GA, Andreeff M, Croce CM (2009) MicroRNA 29b functions in acute myeloid leukemia. Blood 114(26):5331–5341

  69. 69.

    Liu B, Ma H, Liu Q, Xiao Y, Pan S, Zhou H, Jia L (2019) MiR-29b/Sp1/FUT4 axis modulates the malignancy of leukemia stem cells by regulating fucosylation via Wnt/β-catenin pathway in acute myeloid leukemia. J Exp Clin Cancer Res 38(1):200

  70. 70.

    Gerloff D, Grundler R, Wurm AA, Bräuer-Hartmann D, Katzerke C, Hartmann JU, Madan V, Müller-Tidow C, Duyster J, Tenen DG, Niederwieser D, Behre G (2015) NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia. Leukemia 29(3):535–547

  71. 71.

    Huang H, Jiang X, Wang J, Li Y, Song CX, Chen P, Li S, Gurbuxani S, Arnovitz S, Wang Y et al (2016) Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia. Cancer Lett 372(2):157–165

  72. 72.

    Jiang X, Hu C, Arnovitz S, Bugno J, Yu M, Zuo Z, Chen P, Huang H, Ulrich B, Gurbuxani S et al (2016) miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. Nat Commun 7:11452

  73. 73.

    Bi L, Zhou B, Li H, He L, Wang C, Wang Z, Zhu L, Chen M, Gao S (2018) A novel miR-375-HOXB3-CDCA3/DNMT3B regulatory circuitry contributes to leukemogenesis in acute myeloid leukemia. BMC Cancer 18(1):182

  74. 74.

    Mohr S, Doebele C, Comoglio F, Berg T, Beck J, Bohnenberger H, Alexe G, Corso J, Strobel P, Wachter A et al (2017) Hoxa9 and Meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia. Cancer Cell 31(4):549–562.e511

  75. 75.

    Zheng Z, Zheng X, Zhu Y, Gu X, Gu W, Xie X, Hu W, Jiang J (2019) miR-183-5p inhibits occurrence and progression of acute myeloid leukemia via targeting Erbin. Molecular Therapy: the Journal of the American Society of Gene Therapy 27(3):542–558

  76. 76.

    Marcucci G, Mrozek K, Radmacher MD, Garzon R, Bloomfield CD (2011) The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 117(4):1121–1129

  77. 77.

    Fleischmann KK, Pagel P, von Frowein J, Magg T, Roscher AA, Schmid I (2016) The leukemogenic fusion gene MLL-AF9 alters microRNA expression pattern and inhibits monoblastic differentiation via miR-511 repression. J Exp Clin Cancer Res 35:9

  78. 78.

    Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, Diverio D, Ammatuna E, Cimino G, Lo-Coco F, Grignani F, Nervi C (2007) Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12(5):457–466

  79. 79.

    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):3183–3189

  80. 80.

    Li Z, Huang H, Li Y, Jiang X, Chen P, Arnovitz S, Radmacher MD, Maharry K, Elkahloun A, Yang X, He C, He M, Zhang Z, Dohner K, Neilly MB, Price C, Lussier YA, Zhang Y, Larson RA, le Beau MM, Caligiuri MA, Bullinger L, Valk PJ, Delwel R, Lowenberg B, Liu PP, Marcucci G, Bloomfield CD, Rowley JD, Chen J (2012) Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML. Blood 119(10):2314–2324

  81. 81.

    Senyuk V, Zhang Y, Liu Y, Ming M, Premanand K, Zhou L, Chen P, Chen J, Rowley JD, Nucifora G, Qian Z (2013) Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis. Proc Natl Acad Sci U S A 110(14):5594–5599

  82. 82.

    Chen P, Price C, Li Z, Li Y, Cao D, Wiley A, He C, Gurbuxani S, Kunjamma RB, Huang H et al (2013) miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia. Proc Natl Acad Sci U S A 110(28):11511–11516

  83. 83.

    Emmrich S, Katsman-Kuipers JE, Henke K, Khatib ME, Jammal R, Engeland F, Dasci F, Zwaan CM, den Boer ML, Verboon L et al (2014) miR-9 is a tumor suppressor in pediatric AML with t(8;21). Leukemia 28(5):1022–1032

  84. 84.

    Yeh CH, Moles R, Nicot C (2016) Clinical significance of microRNAs in chronic and acute human leukemia. Mol Cancer 15(1):37

  85. 85.

    Zhang H, Luo X-Q, Feng D-D, Zhang X-J, Wu J, Zheng Y-S, Chen X, Xu L, Chen Y-Q (2011) Upregulation of microRNA-125b contributes to leukemogenesis and increases drug resistance in pediatric acute promyelocytic leukemia. Mol Cancer 10:108–108

  86. 86.

    Pelosi A, Careccia S, Lulli V, Romania P, Marziali G, Testa U, Lavorgna S, Lo-Coco F, Petti MC, Calabretta B et al (2013) miRNA let-7c promotes granulocytic differentiation in acute myeloid leukemia. Oncogene 32(31):3648–3654

  87. 87.

    Palma CA, Al Sheikha D, Lim TK, Bryant A, Vu TT, Jayaswal V, Ma DD (2014) MicroRNA-155 as an inducer of apoptosis and cell differentiation in acute myeloid leukaemia. Mol Cancer 13:79

  88. 88.

    De Luca L, Trino S, Laurenzana I, Tagliaferri D, Falco G, Grieco V, Bianchino G, Nozza F, Campia V, D’Alessio F et al (2017) Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia. Cell Death Dis 8(6):e2849

  89. 89.

    Hatzl S, Geiger O, Kuepper MK, Caraffini V, Seime T, Furlan T, Nussbaumer E, Wieser R, Pichler M, Scheideler M, Nowek K, Jongen-Lavrencic M, Quehenberger F, Wölfler A, Troppmair J, Sill H, Zebisch A (2016) Increased expression of miR-23a mediates a loss of expression in the RAF kinase inhibitor protein RKIP. Cancer Res 76(12):3644–3654

  90. 90.

    Zhang Y, Zhou SY, Yan HZ, Xu DD, Chen HX, Wang XY, Wang X, Liu YT, Zhang L, Wang S et al (2016) miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1. Sci Rep 6:19995

  91. 91.

    Wang H, He H, Yang C (2019) miR-342 suppresses the proliferation and invasion of acute myeloid leukemia by targeting Naa10p. Artificial Cells, Nanomedicine, and Biotechnology 47(1):3671–3676

  92. 92.

    Shaham L, Binder V, Gefen N, Borkhardt A, Izraeli S (2012) MiR-125 in normal and malignant hematopoiesis. Leukemia 26(9):2011–2018

  93. 93.

    Guo S, Lu J, Schlanger R, Zhang H, Wang JY, Fox MC, Purton LE, Fleming HH, Cobb B, Merkenschlager M et al (2010) MicroRNA miR-125a controls hematopoietic stem cell number. Proc Natl Acad Sci U S A 107(32):14229–14234

  94. 94.

    Ooi AG, Sahoo D, Adorno M, Wang Y, Weissman IL, Park CY (2010) MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets. Proc Natl Acad Sci U S A 107(50):21505–21510

  95. 95.

    Fayyad-Kazan H, Bitar N, Najar M, Lewalle P, Fayyad-Kazan M, Badran R, Hamade E, Daher A, Hussein N, ElDirani R et al (2013) Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia. J Transl Med 11:31–31

  96. 96.

    Trino S, Lamorte D, Caivano A, Laurenzana I, Tagliaferri D, Falco G, Del Vecchio L, Musto P, De Luca L (2018) MicroRNAs as new biomarkers for diagnosis and prognosis, and as potential therapeutic targets in acute myeloid leukemia. Int J Mol Sci:19(2)

  97. 97.

    Huang Y, Zou Y, Lin L, Ma X, Chen H (2018) Identification of serum miR-34a as a potential biomarker in acute myeloid leukemia. Cancer Biomarkers: Section A of Disease Markers 22(4):799–805

  98. 98.

    Hornick NI, Doron B, Abdelhamed S, Huan J, Harrington CA, Shen R, Cambronne XA, Chakkaramakkil Verghese S, Kurre P (2016) AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Science Signaling 9(444):ra88

  99. 99.

    Caivano A, La Rocca F, Simeon V, Girasole M, Dinarelli S, Laurenzana I, De Stradis A, De Luca L, Trino S, Traficante A et al (2017) MicroRNA-155 in serum-derived extracellular vesicles as a potential biomarker for hematologic malignancies—a short report. Cellular Oncology (Dordrecht) 40(1):97–103

  100. 100.

    Yamamoto H, Lu J, Oba S, Kawamata T, Yoshimi A, Kurosaki N, Yokoyama K, Matsushita H, Kurokawa M, Tojo A et al (2016) miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target. Sci Rep 6:19204

  101. 101.

    Dorrance AM, Neviani P, Ferenchak GJ, Huang X, Nicolet D, Maharry KS, Ozer HG, Hoellarbauer P, Khalife J, Hill EB et al (2015) Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia. Leukemia 29(11):2143–2153

  102. 102.

    Gao XN, Lin J, Li YH, Gao L, Wang XR, Wang W, Kang HY, Yan GT, Wang LL, Yu L (2011) MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia. Oncogene 30(31):3416–3428

  103. 103.

    Schwind S, Maharry K, Radmacher MD, Mrózek K, Holland KB, Margeson D, Whitman SP, Hickey C, Becker H, Metzeler KH et al (2010) Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 28(36):5257–5264

  104. 104.

    Diaz-Beya M, Brunet S, Nomdedeu J, Cordeiro A, Tormo M, Escoda L, Ribera JM, Arnan M, Heras I, Gallardo D et al (2015) The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. Blood Cancer Journal 5:e352

  105. 105.

    Butrym A, Rybka J, Baczyńska D, Tukiendorf A, Kuliczkowski K, Mazur G (2015) Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients. J Exp Clin Cancer Res 34:68

  106. 106.

    Zhang TJ, Wu DH, Zhou JD, Li XX, Zhang W, Guo H, Ma JC, Deng ZQ, Lin J, Qian J (2018) Overexpression of miR-216b: prognostic and predictive value in acute myeloid leukemia. J Cell Physiol 233(4):3274–3281

  107. 107.

    Fu L, Qi J, Gao X, Zhang N, Zhang H, Wang R, Xu L, Yao Y, Niu M, Xu K (2019) High expression of miR-338 is associated with poor prognosis in acute myeloid leukemia undergoing chemotherapy. J Cell Physiol 234(11):20704–20712

  108. 108.

    Madhavan D, Cuk K, Burwinkel B, Yang R (2013) Cancer diagnosis and prognosis decoded by blood-based circulating microRNA signatures. Front Genet 4:116

  109. 109.

    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105(30):10513–10518

  110. 110.

    Sheridan C (2016) Exosome cancer diagnostic reaches market. Nat Biotechnol 34(4):359–360

  111. 111.

    Boyiadzis M, Whiteside TL (2017) The emerging roles of tumor-derived exosomes in hematological malignancies. Leukemia 31(6):1259–1268

  112. 112.

    Takahashi RU, Prieto-Vila M, Hironaka A, Ochiya T (2017) The role of extracellular vesicle microRNAs in cancer biology. Clin Chem Lab Med 55(5):648–656

  113. 113.

    Hong CS, Muller L, Whiteside TL, Boyiadzis M (2014) Plasma exosomes as markers of therapeutic response in patients with acute myeloid leukemia. Front Immunol 5:160

  114. 114.

    Boyiadzis M, Whiteside TL (2016) Plasma-derived exosomes in acute myeloid leukemia for detection of minimal residual disease: are we ready? Expert Rev Mol Diagn 16(6):623–629

  115. 115.

    Whiteside TL (2015) The potential of tumor-derived exosomes for noninvasive cancer monitoring. Expert Rev Mol Diagn 15(10):1293–1310

  116. 116.

    Tomasetti M, Lee W, Santarelli L, Neuzil J (2017) Exosome-derived microRNAs in cancer metabolism: possible implications in cancer diagnostics and therapy. Exp Mol Med 49(1):e285

  117. 117.

    Hornick NI, Huan J, Doron B, Goloviznina NA, Lapidus J, Chang BH, Kurre P (2015) Serum exosome MicroRNA as a minimally-invasive early biomarker of AML. Sci Rep 5:11295

  118. 118.

    Pikman Y, Stegmaier K (2018) Targeted therapy for fusion-driven high-risk acute leukemia. Blood 132(12):1241–1247

  119. 119.

    Gabra MM, Salmena L (2017) microRNAs and acute myeloid leukemia chemoresistance: a mechanistic overview. Front Oncol 7:255

  120. 120.

    Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16(3):203–222

  121. 121.

    Bhagavathi S, Czader M (2010) MicroRNAs in benign and malignant hematopoiesis. Arch Pathol Lab Med 134(9):1276–1281

  122. 122.

    Yang N, Zhu S, Lv X, Qiao Y, Liu YJ, Chen J (2018) MicroRNAs: pleiotropic regulators in the tumor microenvironment. Front Immunol 9:2491

  123. 123.

    Carvalho de Oliveira J, Molinari Roberto G, Baroni M, Bezerra Salomao K, Alejandra Pezuk J, Sol Brassesco M (2018) MiRNA dysregulation in childhood hematological cancer. Int J Mol Sci 19(9)

  124. 124.

    Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I (2011) A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147(2):358–369

  125. 125.

    Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465(7301):1033–1038

  126. 126.

    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell 146(3):353–358

  127. 127.

    Huarte M (2015) The emerging role of lncRNAs in cancer. Nat Med 21(11):1253–1261

  128. 128.

    Garzon R, Volinia S, Papaioannou D, Nicolet D, Kohlschmidt J, Yan PS, Mrozek K, Bucci D, Carroll AJ, Baer MR et al (2014) Expression and prognostic impact of lncRNAs in acute myeloid leukemia. Proc Natl Acad Sci U S A 111(52):18679–18684

  129. 129.

    Chen L, Wang W, Cao L, Li Z, Wang X (2016) Long non-coding RNA CCAT1 acts as a competing endogenous RNA to regulate cell growth and differentiation in acute myeloid leukemia. Molecules and Cells 39(4):330–336

  130. 130.

    Zhao C, Wang S, Zhao Y, Du F, Wang W, Lv P, Qi L (2018) Long noncoding RNA NEAT1 modulates cell proliferation and apoptosis by regulating miR-23a-3p/SMC1A in acute myeloid leukemia. J Cell Physiol

  131. 131.

    Tian YJ, Wang YH, Xiao AJ, Li PL, Guo J, Wang TJ, Zhao DJ (2019) Long noncoding RNA SBF2-AS1 act as a ceRNA to modulate cell proliferation via binding with miR-188-5p in acute myeloid leukemia. Artificial Cells, Nanomedicine, and Biotechnology 47(1):1730–1737

  132. 132.

    Zhong Y, Du Y, Yang X, Mo Y, Fan C, Xiong F, Ren D, Ye X, Li C, Wang Y et al (2018) Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer 17(1):79–79

  133. 133.

    Cui X, Wang J, Guo Z, Li M, Li M, Liu S, Liu H, Li W, Yin X, Tao J, Xu W (2018) Emerging function and potential diagnostic value of circular RNAs in cancer. Mol Cancer 17(1):123–123

  134. 134.

    Liu Y, Cheng Z, Pang Y, Cui L, Qian T, Quan L, Zhao H, Shi J, Ke X, Fu L (2019) Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia. J Hematol Oncol 12(1):51

  135. 135.

    Li S, Ma Y, Tan Y, Ma X, Zhao M, Chen B, Zhang R, Chen Z, Wang K (2018) Profiling and functional analysis of circular RNAs in acute promyelocytic leukemia and their dynamic regulation during all-trans retinoic acid treatment. Cell Death Dis 9(6):651

  136. 136.

    Wu DM, Wen X, Han XR, Wang S, Wang YJ, Shen M, Fan SH, Zhang ZF, Shan Q, Li MQ et al: Role of circular RNA DLEU2 in human acute myeloid leukemia. Mol Cell Biol 2018, 38(20)

  137. 137.

    Haas G, Cetin S, Messmer M, Chane-Woon-Ming B, Terenzi O, Chicher J, Kuhn L, Hammann P, Pfeffer S (2016) Identification of factors involved in target RNA-directed microRNA degradation. Nucleic Acids Res 44(6):2873–2887

  138. 138.

    Shivarov V, Bullinger L (2014) Expression profiling of leukemia patients: key lessons and future directions. Exp Hematol 42(8):651–660

  139. 139.

    McDermott AM, Heneghan HM, Miller N, Kerin MJ (2011) The therapeutic potential of microRNAs: disease modulators and drug targets. Pharm Res 28(12):3016–3029

Download references

Author information

HZG provided direction and guidance throughout the preparation of this manuscript. MYL drafted the manuscript. HZG and XLC reviewed and made significant revisions to the manuscript. All authors have read and approved the final manuscript.

Correspondence to Hongzai Guan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, M., Cui, X. & Guan, H. MicroRNAs: pivotal regulators in acute myeloid leukemia. Ann Hematol (2020). https://doi.org/10.1007/s00277-019-03887-5

Download citation

Keywords

  • MicroRNAs
  • Acute myeloid leukemia
  • Leukemogenesis
  • Biomarkers
  • Therapeutic targets
  • ceRNA