Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

miR-139-5p controls translation in myeloid leukemia through EIF4G2

Oncogene volume 35, pages 1822–1831 (2016)Cite this article

Subjects

Abstract

MicroRNAs (miRNAs) are crucial components of homeostatic and developmental gene regulation. In turn, dysregulation of miRNA expression is a common feature of different types of cancer, which can be harnessed therapeutically. Here we identify miR-139-5p suppression across several cytogenetically defined acute myeloid leukemia (AML) subgroups. The promoter of mir-139 was transcriptionally silenced and could be reactivated by histone deacetylase inhibitors in a dose-dependent manner. Restoration of mir-139 expression in cell lines representing the major AML subgroups (t[8;21], inv[16], mixed lineage leukemia-rearranged and complex karyotype AML) caused cell cycle arrest and apoptosis in vitro and in xenograft mouse models in vivo. During normal hematopoiesis, mir-139 is exclusively expressed in terminally differentiated neutrophils and macrophages. Ectopic expression of mir-139 repressed proliferation of normal CD34+-hematopoietic stem and progenitor cells and perturbed myelomonocytic in vitro differentiation. Mechanistically, mir-139 exerts its effects by repressing the translation initiation factor EIF4G2, thereby reducing overall protein synthesis while specifically inducing the translation of cell cycle inhibitor p27Kip1. Knockdown of EIF4G2 recapitulated the effects of mir-139, whereas restoring EIF4G2 expression rescued the mir-139 phenotype. Moreover, elevated miR-139-5p expression is associated with a favorable outcome in a cohort of 165 pediatric patients with AML. Thus, mir-139 acts as a global tumor suppressor-miR in AML by controlling protein translation. As AML cells are dependent on high protein synthesis rates controlling the expression of mir-139 constitutes a novel path for the treatment of AML.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Sanders MA, Valk PJ . The evolving molecular genetic landscape in acute myeloid leukaemia. Curr Opin Hematol 2013; 20: 79–85.

    Article  CAS  PubMed  Google Scholar 

  2. Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S, de Bont E et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 2012, 10/18 120: 3187–3205.

    Article  CAS  PubMed  Google Scholar 

  3. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Wang Z, Hong Z, Gao F, Feng W . Upregulation of microRNA-375 is associated with poor prognosis in pediatric acute myeloid leukemia. Mol Cell Biochem 2013; 383: 59–65.

    Article  CAS  PubMed  Google Scholar 

  6. Lee DW, Futami M, Carroll M, Feng Y, Wang Z, Fernandez M et al. Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155. Oncogene 2012; 31: 4085–4094.

    Article  CAS  PubMed  Google Scholar 

  7. Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.

    Article  CAS  PubMed  Google Scholar 

  8. Berindan-Neagoe I, Monroig Pdel C, Pasculli B, Calin GA . MicroRNAome genome: a treasure for cancer diagnosis and therapy. CA Cancer J Clin 2014; 64: 311–336.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Wong CC, Wong CM, Tung EK, Au SL, Lee JM, Poon RT et al. The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology 2011; 140: 322–331.

    Article  CAS  PubMed  Google Scholar 

  11. Li Z, Huang H, Li Y, Jiang X, Chen P, Arnovitz S et al. 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 2012; 119: 2314–2324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Clemens MJ . Targets and mechanisms for the regulation of translation in malignant transformation. Oncogene 2004; 23: 3180–3188.

    Article  CAS  PubMed  Google Scholar 

  13. Lazaris-Karatzas A, Montine KS, Sonenberg N . Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature 1990; 345: 544–547.

    Article  CAS  PubMed  Google Scholar 

  14. Hinnebusch AG, Lorsch JR . The mechanism of eukaryotic translation initiation: new insights and challenges. Cold Spring Harb Perspect Biol 2012; 4: doi:10.1101/cshperspect.a011544.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 2004; 5: 553–563.

    Article  CAS  PubMed  Google Scholar 

  16. Fukuchi-Shimogori T, Ishii I, Kashiwagi K, Mashiba H, Ekimoto H, Igarashi K . Malignant transformation by overproduction of translation initiation factor eIF4G. Cancer Res 1997; 57: 5041–5044.

    CAS  PubMed  Google Scholar 

  17. Hariri F, Arguello M, Volpon L, Culjkovic-Kraljacic B, Nielsen TH, Hiscott J et al. The eukaryotic translation initiation factor eIF4E is a direct transcriptional target of NF-kappaB and is aberrantly regulated in acute myeloid leukemia. Leukemia 2013; 27: 2047–2055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tamburini J, Green AS, Chapuis N, Bardet V, Lacombe C, Mayeux P et al. Targeting translation in acute myeloid leukemia: a new paradigm for therapy? Cell Cycle 2009; 8: 3893–3899.

    Article  CAS  PubMed  Google Scholar 

  19. Gradi A, Imataka H, Svitkin YV, Rom E, Raught B, Morino S et al. A novel functional human eukaryotic translation initiation factor 4G. Mol Cell Biol 1998; 18: 334–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Imataka H, Gradi A, Sonenberg N . A newly identified N-terminal amino acid sequence of human eIF4G binds poly(A)-binding protein and functions in poly(A)-dependent translation. EMBO J 1998; 17: 7480–7489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qin H, Raught B, Sonenberg N, Goldstein EG, Edelman AM . Phosphorylation screening identifies translational initiation factor 4GII as an intracellular target of Ca(2+)/calmodulin-dependent protein kinase I. J Biol Chem 2003; 278: 48570–48579.

    Article  CAS  PubMed  Google Scholar 

  22. Caron S, Charon M, Cramer E, Sonenberg N, Dusanter-Fourt I . Selective modification of eukaryotic initiation factor 4F (eIF4F) at the onset of cell differentiation: recruitment of eIF4GII and long-lasting phosphorylation of eIF4E. Mol Cell Biol 2004; 24: 4920–4928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tu L, Liu Z, He X, He Y, Yang H, Jiang Q et al. Over-expression of eukaryotic translation initiation factor 4gamma 1 correlates with tumor progression and poor prognosis in nasopharyngeal carcinoma. Mol Cancer 2010; 9: 78 4598-9-78.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Solh M, Yohe S, Weisdorf D, Ustun C . Core-binding factor acute myeloid leukemia: Heterogeneity, monitoring, and therapy. Am J Hematol 2014; 89: 1121–1131.

    Article  PubMed  Google Scholar 

  25. Weber K, Bartsch U, Stocking C, Fehse B . A multicolor panel of novel lentiviral "gene ontology" (LeGO) vectors for functional gene analysis. Mol Ther 2008; 16: 698–706.

    Article  CAS  PubMed  Google Scholar 

  26. Cheng J, Guo S, Chen S, Mastriano SJ, Liu C, D'Alessio AC et al. An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis. Cell Rep 2013; 5: 471–481.

    Article  CAS  PubMed  Google Scholar 

  27. Masaki S, Ohtsuka R, Abe Y, Muta K, Umemura T . Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis. Biochem Biophys Res Commun 2007; 364: 509–514.

    Article  CAS  PubMed  Google Scholar 

  28. Shen K, Mao R, Ma L, Li Y, Qiu Y, Cui D et al. Post-transcriptional regulation of the tumor suppressor miR-139-5p and a network of miR-139-5p-mediated mRNA interactions in colorectal cancer. FEBS J 2014; 281: 3609–3624.

    Article  CAS  PubMed  Google Scholar 

  29. Bao W, Fu HJ, Xie QS, Wang L, Zhang R, Guo ZY et al. HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells. Gastroenterology 2011; 141: 2076–2087.e6.

    Article  CAS  PubMed  Google Scholar 

  30. Vinther J, Hedegaard MM, Gardner PP, Andersen JS, Arctander P . Identification of miRNA targets with stable isotope labeling by amino acids in cell culture. Nucleic Acids Res 2006; 34: e107.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature 2014; 513: 105–109.

    Article  CAS  PubMed  Google Scholar 

  32. Kar AN, MacGibeny MA, Gervasi NM, Gioio AE, Kaplan BB . Intra-axonal synthesis of eukaryotic translation initiation factors regulates local protein synthesis and axon growth in rat sympathetic neurons. J Neurosci 2013; 33: 7165–7174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Breinbauer R, Kohn M . Azide-alkyne coupling: a powerful reaction for bioconjugate chemistry. Chembiochem 2003; 4: 1147–1149.

    Article  CAS  PubMed  Google Scholar 

  34. Yanagisawa K, Horiuchi T, Fujita S . Establishment and characterization of a new human leukemia cell line derived from M4E0. Blood 1991; 78: 451–457.

    CAS  PubMed  Google Scholar 

  35. Lee SH, McCormick F . p97/DAP5 is a ribosome-associated factor that facilitates protein synthesis and cell proliferation by modulating the synthesis of cell cycle proteins. EMBO J 2006; 25: 4008–4019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen P, Price C, Li Z, Li Y, Cao D, Wiley A et al. miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia. Proc Natl Acad Sci USA 2013; 110: 11511–11516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dou L, Zheng D, Li J, Li Y, Gao L, Wang L et al. Methylation-mediated repression of microRNA-143 enhances MLL-AF4 oncogene expression. Oncogene 2012; 31: 507–517.

    Article  CAS  PubMed  Google Scholar 

  38. Luo HN, Wang ZH, Sheng Y, Zhang Q, Yan J, Hou J et al. MiR-139 targets CXCR4 and inhibits the proliferation and metastasis of laryngeal squamous carcinoma cells. Med Oncol 2014; 31: 789 ..

    Article  PubMed  Google Scholar 

  39. Krishnan K, Steptoe AL, Martin HC, Pattabiraman DR, Nones K, Waddell N et al. miR-139-5p is a regulator of metastatic pathways in breast cancer. RNA 2013; 19: 1767–1780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fan Q, He M, Deng X, Wu WK, Zhao L, Tang J et al. Derepression of c-Fos caused by microRNA-139 down-regulation contributes to the metastasis of human hepatocellular carcinoma. Cell Biochem Funct 2013; 31: 319–324.

    Article  CAS  PubMed  Google Scholar 

  41. Gu W, Li X, Wang J . miR-139 regulates the proliferation and invasion of hepatocellular carcinoma through the WNT/TCF-4 pathway. Oncol Rep 2014; 31: 397–404.

    Article  CAS  PubMed  Google Scholar 

  42. Li RY, Chen LC, Zhang HY, Du WZ, Feng Y, Wang HB et al. MiR-139 inhibits Mcl-1 expression and potentiates TMZ-induced apoptosis in glioma. CNS Neurosci Ther 2013; 19: 477–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang L, Dong Y, Zhu N, Tsoi H, Zhao Z, Wu CW et al. microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer. Mol Cancer 2014; 13: 124–4598-13-124.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Henis-Korenblit S, Shani G, Sines T, Marash L, Shohat G, Kimchi A . The caspase-cleaved DAP5 protein supports internal ribosome entry site-mediated translation of death proteins. Proc Natl Acad Sci USA 2002; 99: 5400–5405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nousch M, Reed V, Bryson-Richardson RJ, Currie PD, Preiss T . The eIF4G-homolog p97 can activate translation independent of caspase cleavage. RNA 2007; 13: 374–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mazan-Mamczarz K, Zhao XF, Dai B, Steinhardt JJ, Peroutka RJ, Berk KL et al. Down-regulation of eIF4GII by miR-520c-3p represses diffuse large B cell lymphoma development. PLoS Genet 2014; 10: e1004105.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Srivastava T, Fortin DA, Nygaard S, Kaech S, Sonenberg N, Edelman AM et al. Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII. J Neurosci 2012; 32: 5620–5630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Virgili G, Frank F, Feoktistova K, Sawicki M, Sonenberg N, Fraser CS et al. Structural analysis of the DAP5 MIF4G domain and its interaction with eIF4A. Structure 2013; 21: 517–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Marash L, Liberman N, Henis-Korenblit S, Sivan G, Reem E, Elroy-Stein O et al. DAP5 promotes cap-independent translation of Bcl-2 and CDK1 to facilitate cell survival during mitosis. Mol Cell 2008; 30: 447–459.

    Article  CAS  PubMed  Google Scholar 

  50. Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006; 20: 911–928.

    Article  CAS  PubMed  Google Scholar 

  51. Holcik M, Sonenberg N . Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 2005; 6: 318–327.

    Article  CAS  PubMed  Google Scholar 

  52. Alemdehy MF, Haanstra JR, de Looper HW, van Strien PM, Verhagen-Oldenampsen J, Caljouw Y et al. Interstrand cross-link induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation. Blood 2015.

  53. Jiang H, Shukla A, Wang X, Chen WY, Bernstein BE, Roeder RG . Role for Dpy-30 in ES cell-fate specification by regulation of H3K4 methylation within bivalent domains. Cell 2011; 144: 513–525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cheng YC, Lin TY, Shieh SY . Candidate tumor suppressor BTG3 maintains genomic stability by promoting Lys63-linked ubiquitination and activation of the checkpoint kinase CHK1. Proc Natl Acad Sci USA 2013; 110: 5993–5998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yu J, Zhang Y, Qi Z, Kurtycz D, Vacano G, Patterson D . Methylation-mediated downregulation of the B-cell translocation gene 3 (BTG3) in breast cancer cells. Gene Expr 2008; 14: 173–182.

    CAS  PubMed  Google Scholar 

  56. Deng B, Zhao Y, Gou W, Chen S, Mao X, Takano Y et al. Decreased expression of BTG3 was linked to carcinogenesis, aggressiveness, and prognosis of ovarian carcinoma. Tumour Biol 2013; 34: 2617–2624.

    Article  PubMed  Google Scholar 

  57. Lin TY, Cheng YC, Yang HC, Lin WC, Wang CC, Lai PL et al. Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis. Oncogene 2012; 31: 3287–3297.

    Article  CAS  PubMed  Google Scholar 

  58. Scheicher R, Hoelbl-Kovacic A, Bellutti F, Tigan AS, Prchal-Murphy M, Heller G et al. CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood 2014; 125: 90–101.

    Article  PubMed  Google Scholar 

  59. Placke T, Faber K, Nonami A, Putwain SL, Salih HR, Heidel FH et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 2014; 124: 13–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Stankov MV, El Khatib M, Kumar TB, Heitmann K, Panayotova-Dimitrova D, Schoening J et al. Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy. Leukemia 2014 03; 28: 577–588.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Drs K Weber, B Fehse and D Heckl for providing plasmids; Dr M Ballmaier for sorting. SE, FE and KH were supported by the Hannover Biomedical Research School. JEK-K was supported by the Children Cancer Free Foundation (KIKA, project 49). JHK is a fellow of the Emmy Noether-Programme from the German Research Foundation (DFG; KL-2374/2-1). A.O. was supported by KIKA project 109. This work was supported by grants to CMZ and MMvdH-E from the Children Cancer Free Foundation (KIKA, projects 49 and 109) and to JHK from the DFG (KL-2374/2-1).

Author information

Author notes

  1. S Emmrich and F Engeland: These authors equally contributed to this work.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    S Emmrich, F Engeland, M El-Khatib, K Henke, J Schöning & J H Klusmann

  2. Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children’s Hospital, Rotterdam, The Netherlands,

    A Obulkasim, J E Katsman-Kuipers, C Michel Zwaan, M Fornerod & M M van den Heuvel-Eibrink

  3. Institute for Toxicology, Hannover Medical School, Hannover, Germany

    A Pich

  4. Department of Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic

    J Stary

  5. Department of Hematology, Hopitaux universitaires Saint-Louis, St Louis Hospital, Paris, France

    A Baruchel

  6. Dutch Childhood Oncology Group (DCOG), Stichting Kinderoncologie Nederland (SKION), Hague, The Netherlands

    V de Haas

  7. Clinic for Pediatrics III, University Hospital Essen, Essen, Germany

    D Reinhardt

  8. Department of Biochemistry, Erasmus MC/Sophia Children’s Hospital, Rotterdam, The Netherlands

    M Fornerod

Authors
  1. S Emmrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Engeland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M El-Khatib
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Henke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Obulkasim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Schöning
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J E Katsman-Kuipers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Michel Zwaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Pich
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Stary
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Baruchel
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. V de Haas
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Reinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Fornerod
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M M van den Heuvel-Eibrink
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J H Klusmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J H Klusmann.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Emmrich, S., Engeland, F., El-Khatib, M. et al. miR-139-5p controls translation in myeloid leukemia through EIF4G2. Oncogene 35, 1822–1831 (2016). https://doi.org/10.1038/onc.2015.247

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.247

This article is cited by

Search

Advanced search

Quick links