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.

  • Original Article
  • Published:

Cytogenetics and Molecular Genetics

Identification of new microRNA genes and aberrant microRNA profiles in childhood acute lymphoblastic leukemia

Leukemia volume 23, pages 313–322 (2009)Cite this article

Abstract

MicroRNAs (miRNAs) control the expression of protein-coding genes in normal hematopoietic cells and, consequently, aberrant expression may contribute to leukemogenesis. To identify miRNAs relevant to pediatric acute lymphoblastic leukemia (ALL), we cloned 105 known and 8 new miRNA genes expressed in patients’ leukemia cells. Instead of known miRNA genes, new miRNA genes were not evolutionarily conserved. Quantification of 19 selected miRNA genes revealed an aberrant expression in ALL as compared with normal CD34+ cells (P⩽0.02); both upregulated (14/19) and downregulated (5/19) expressions were observed. Eight miRNAs were differentially expressed between MLL and non-MLL precursor B-ALL cases (P<0.05). Most remarkably, miR-708 was 250- up to 6500-fold higher expressed in 57 TEL-AML1, BCR-ABL, E2A-PBX1, hyperdiploid and B-other cases than in 20 MLL-rearranged and 15 T-ALL cases (0.0001< P<0.01), whereas the expression of miR-196b was 500-fold higher in MLL-rearranged and 800-fold higher in 5 of 15 T-ALL cases as compared with the expression level in the remaining precursor B-ALL cases (P<0.001). The expression did not correlate with the maturation status of leukemia cells based on immunoglobulin and T-cell receptor rearrangements, immunophenotype or MLL-fusion partner. In conclusion, we identified new miRNA genes and showed that miRNA expression profiles are ALL subtype-specific rather than linked to the differentiation stadium associated with these subtypes.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Ambros V . MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 2003; 113: 673–676.

    Article  CAS  Google Scholar 

  3. Chen CZ . MicroRNAs as oncogenes and tumor suppressors. N Engl J Med 2005; 353: 1768–1771.

    Article  CAS  Google Scholar 

  4. Available at http://www.sanger.ac.uk/Software/Rfam

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

    Article  CAS  Google Scholar 

  6. Bernstein E, Caudy AA, Hammond SM, Hannon GJ . Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 2001; 409: 363–366.

    Article  CAS  Google Scholar 

  7. Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD . A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 2001; 293: 834–838.

    Article  CAS  Google Scholar 

  8. Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH . Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. Elegans Genes Dev 2001; 15: 2654–2659.

    Article  CAS  Google Scholar 

  9. Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C elegans developmental timing cell. Genes Dev 2001; 106: 23–34.

    CAS  Google Scholar 

  10. Meister G . miRNAs get an early start on translational silencing. Cell 2007; 131: 25–28.

    Article  CAS  Google Scholar 

  11. Kim VN . MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 2005; 6: 376–385.

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  13. Chen K, Rajewsky N . The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet 2007; 8: 93–103.

    Article  CAS  Google Scholar 

  14. Olsen PH, Ambros V . The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev Biol 1999; 216: 671–680.

    Article  CAS  Google Scholar 

  15. Ambros V . The functions of animal microRNAs. Nature 2004; 431: 350–355.

    Article  CAS  Google Scholar 

  16. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004; 64: 3753–3756.

    Article  CAS  Google Scholar 

  17. Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz Jr LA, Sjoblom T et al The colorectal microRNAome. Proc Natl Acad Sci USA 2006; 103: 3687–3692.

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 2008; 111: 3183–3189.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–178.

    Article  CAS  Google Scholar 

  23. Stam RW, den Boer ML, Schneider P, Nollau P, Horstmann M, Beverloo HB et al. Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia. Blood 2005; 106: 2484–2490.

    Article  CAS  Google Scholar 

  24. Jansen MW, Corral L, van der Velden VH, Panzer-Grumayer R, Schrappe M, Schrauder A et al. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia 2007; 21: 633–641.

    Article  CAS  Google Scholar 

  25. Lau NC, Lim LP, Weinstein EG, Bartel DP . An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 2001; 294: 858–862.

    Article  CAS  Google Scholar 

  26. Available at http://www.tbi.univie.ac.at/~ivo/RNA

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

    Article  Google Scholar 

  28. Lim LP, Lau NC, Weinstein EG, Abdelhakim A, Yekta S, Rhoades MW et al. The microRNAs of Caenorhabditis elegans. Genes Dev 2003; 17: 991–1008.

    Article  CAS  Google Scholar 

  29. Guenther MG, Jenner RG, Chevalier B, Nakamura T, Croce CM, Canaani E et al. Global and Hox-specific roles for the MLL1 methyltransferase. Proc Natl Acad Sci USA 2005; 102: 8603–8608.

    Article  CAS  Google Scholar 

  30. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–764.

    Article  CAS  Google Scholar 

  31. van Zelm MC, van der Burg M, de Ridder D, Barendregt BH, de Haas EF, Reinders MJ et al. Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression. J Immunol 2005; 175: 5912–5922.

    Article  CAS  Google Scholar 

  32. Yu J, Wang F, Yang GH, Wang FL, Ma YN, Du ZW et al. Human microRNA clusters: genomic organization and expression profile in leukemia cell lines. Biochem Biophys Res Commun 2006; 349: 59–68.

    Article  CAS  Google Scholar 

  33. Baskerville S, Bartel DP . Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005; 11: 241–247.

    Article  CAS  Google Scholar 

  34. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 2007; 129: 1401–1414.

    Article  CAS  Google Scholar 

  35. Lui WO, Pourmand N, Patterson BK, Fire A . Patterns of known and novel small RNAs in human cervical cancer. Cancer Res 2007; 67: 6031–6043.

    Article  CAS  Google Scholar 

  36. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435: 834–838.

    Article  CAS  Google Scholar 

  37. 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.

    Article  CAS  Google Scholar 

  38. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475–482.

    Article  CAS  Google Scholar 

  39. Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 2007; 12: 457–466.

    Article  CAS  Google Scholar 

  40. Nervi C, Fazi F, Grignani F . Oncoproteins, heterochromatin silencing and microRNAs: a new link for leukemogenesis. Epigenetics 2008; 3: 1–4.

    Article  Google Scholar 

  41. Aboobaker AA, Tomancak P, Patel N, Rubin GM, Lai EC . Drosophila microRNAs exhibit diverse spatial expression patterns during embryonic development. Proc Natl Acad Sci USA 2005; 102: 18017–18022.

    Article  CAS  Google Scholar 

  42. Ason B, Darnell DK, Wittbrodt B, Berezikov E, Kloosterman WP, Wittbrodt J et al. Differences in vertebrate microRNA expression. Proc Natl Acad Sci USA 2006; 103: 14385–14389.

    Article  CAS  Google Scholar 

  43. Kloosterman WP, Wienholds E, de Bruijn E, Kauppinen S, Plasterk RH . In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes. Nat Methods 2006; 3: 27–29.

    Article  CAS  Google Scholar 

  44. Wienholds E, Kloosterman WP, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E et al. MicroRNA expression in zebrafish embryonic development. Science 2005; 309: 310–311.

    Article  CAS  Google Scholar 

  45. Pieters R, den Boer ML, Durian M, Janka G, Schmiegelow K, Kaspers GJ et al. Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia—implications for treatment of infants. Leukemia 1998; 12: 1344–1348.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  47. Yekta S, Shih IH, Bartel DP . MicroRNA-directed cleavage of HOXB8 mRNA. Science 2004; 304: 594–596.

    Article  CAS  Google Scholar 

  48. Available at www.microRNA.org.

  49. Available at http://pictar.bio.nyu.edu.

  50. Available at www.targetscan.org.

  51. Buske C, Humphries RK . Homeobox genes in leukemogenesis. Int J Hematol 2000; 71: 301–308.

    CAS  PubMed  Google Scholar 

  52. Molnar A, Georgopoulos K . The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol 1994; 14: 8292–8303.

    Article  CAS  Google Scholar 

  53. Perdomo J, Holmes M, Chong B, Crossley M . Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities. J Biol Chem 2000; 275: 38347–38354.

    Article  CAS  Google Scholar 

  54. Winandy S, Wu P, Georgopoulos K . A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 1995; 83: 289–299.

    Article  CAS  Google Scholar 

  55. Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM . Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA 1982; 79: 7824–7827.

    Article  CAS  Google Scholar 

  56. Sheer D, Hiorns LR, Stanley KF, Goodfellow PN, Swallow DM, Povey S et al. Genetic analysis of the 15;17 chromosome translocation associated with acute promyelocytic leukemia. Proc Natl Acad Sci USA 1983; 80: 5007–5011.

    Article  CAS  Google Scholar 

  57. Szczepanski T, van der Velden VH, van Dongen JJ . Classification systems for acute and chronic leukaemias. Best Pract Res Clin Haematol 2003; 16: 561–582.

    Article  Google Scholar 

Download references

Acknowledgements

We highly appreciate the contribution of CZ Chen (Department of Microbiology and Immunology, Stanford University, USA) for sharing knowledge and technologies to clone miRNAs, for performing computational analyses of miRNA structures as well as for discussing study results. We also thank the members of the COALL study group (headed by GE Janka-Schaub, Hamburg, Germany) and the Interfant study group (headed by R Pieters, Erasmus MC, Rotterdam, NL) for supporting this study with patient samples. We are grateful to MWJC Jansen (Department of Immunology, Erasmus MC, Rotterdam, NL) for providing the maturation status of MLL-rearranged cases. This study was financially supported by the Dutch Cancer Society (Program Grant EUR 2005-3662; MLdB/RP), The Netherlands Organization for Scientific Research (NWO-Vidi Grant; MLdB) and the Baxter foundation (Chen CZ).

Author information

Authors and Affiliations

  1. Department of Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands

    D Schotte, M J C Broekhuis, T C J M Peters, R Pieters & M L den Boer

  2. Department of Microbiology and Immunology, Baxter Laboratory of Genetic Pharmacology, Stanford University School of Medicine, Institute for Cancer, Stem Cell Biology and Medicine, Stanford, CA, USA

    J C K Chau, G Sylvester & G Liu

  3. Applied Biosystems, Foster City, CA, USA

    C Chen

  4. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    V H J van der Velden

  5. Interfant-99 Collaborative Study Group,

    R Pieters

Authors
  1. D Schotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J C K Chau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Sylvester
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V H J van der Velden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M J C Broekhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T C J M Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Pieters
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M L den Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M L den Boer.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schotte, D., Chau, J., Sylvester, G. et al. Identification of new microRNA genes and aberrant microRNA profiles in childhood acute lymphoblastic leukemia. Leukemia 23, 313–322 (2009). https://doi.org/10.1038/leu.2008.286

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.286

Keywords

This article is cited by

Search

Advanced search

Quick links