miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities (original) (raw)

Leukemia volume 23, pages 1159–1163 (2009)Cite this article

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world and is characterized by a highly variable clinical course. CLL can be classified into two biological subtypes, according to the presence or absence of somatic mutations in the immunoglobulin heavy-chain variable region (IgVH). IgVH mutational status is of high-clinical relevance: cases with unmutated IgVH show a less favorable course with a rapid progression, whereas cases with mutated IgVH show a stable disease and longer survival. Unfavorable prognosis is also associated with the inactivation of an important tumor-suppressor p53; these patients harbor a deletion of 17p13 and this chromosomal abnormality is often accompanied by the mutation of the second TP53 allele, which leads to the complete elimination of p53 function. Moreover, a single mutation of one of the TP53 allele also occurs in a significant proportion of CLL cases. Patients with TP53 abnormalities typically do not respond to therapy and have a median survival of less than 3 years.

MicroRNAs (miRNAs) are short ∼22 nucleotide long RNA molecules that function as specific regulators of the gene expression with an essential role in cell proliferation, differentiation, apoptosis, chromosome structure and virus resistance. These highly conserved RNAs constitute more than 700 miR genes in the human genome and are supposed to regulate 20–30% of protein-coding genes. miRNAs are associated with RNA-induced silencing complex (RISC), which has been previously proven to repress the translation of the mRNA by an RNA interference mechanism. Many studies have shown that miRNAs are aberrantly expressed in cancer cells, suggesting that they might act as a novel class of oncogenes or tumor suppressors. The first evidence of the involvement of miRNAs in chronic lymphocytic leukemia came from molecular studies, which characterized the 13q14 deletion. Two miRNA genes (miR-15a and miR-16-1), which regulate Bcl2, are the candidate genes located in the 13q14.3 region.1 Several recent publications have defined the miRNA expression profiles in different CLL subtypes: mutated IgVH vs unmutated IgVH and ZAP-70+ vs ZAP-70− cases.1 Although, this data did indeed demonstrate the involvement of miRNAs in CLL pathogenesis, their role in aggressive CLL, bearing TP53 abnormalities, has not yet been clearly defined. Therefore, we have focused on the identification of miRNAs abnormally expressed in CLL cells, which harbor a deletion and/or mutation of the p53 gene (TP53).

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

Relevant articles

Open Access articles citing this article.

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

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

Additional access options:

References

  1. Nicoloso MS, Kipps TJ, Croce CM, Calin GA . MicroRNAs in the pathogeny of chronic lymphocytic leukaemia. Br J Haematol 2007; 139: 709–716.
    Article CAS Google Scholar
  2. Dijkstra MK, van Lom K, Tielemans D, Elstrodt F, Langerak AW, van 't Veer MB et al. 17p13/TP53 deletion in B-CLL patients is associated with microRNA-34a downregulation. Leukemia 2008, e-pub ahead of print.
  3. Zenz T, Mohr J, Eldering E, Kater AP, Bühler A, Kiele D et al. Mir-34a as part of the chemotherapy resistance network in chronic lymphocytic. Blood 2008, e-pub ahead of print.
  4. He L, He X, Lowe SW, Hannon GJ . microRNAs join the p53 network-another piece in the tumour-suppression puzzle. Nat Rev Cancer 2007; 7: 819–822.
    Article CAS Google Scholar
  5. Mott JL, Kobayashi S, Bronk SF, Gores GJ . mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 2007; 26: 6133–6140.
    Article CAS Google Scholar
  6. 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.
    Article CAS Google Scholar
  7. O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT . c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005; 435: 839–843.
    Article CAS Google Scholar
  8. Taguchi A, Yanagisawa K, Tanaka M, Cao K, Matsuyama Y, Goto H et al. Identification of hypoxia-inducible factor-1 alpha as a novel target for miR-17-92 microRNA cluster. Cancer Res 2008; 68: 5540–5545.
    Article CAS Google Scholar

Download references

Acknowledgements

We acknowledge Prof Ivo Slapak (Department of Paediatric Otorhinolaryngology) for providing control samples after tonsillectomy, Dr Hana Skuhrova Francova (Center of Molecular Biology and Gene Therapy) for performing IgVH status analysis and Professor Petr Kuglik (Department of Medical Genetics) for FISH data. This work was supported by Research Grant IGA MZ CR NR9293-3/2007 provided by the Internal Grant Agency of the Ministry of Health in the Czech Republic.

Author information

Authors and Affiliations

  1. Department of Internal Medicine–Hematooncology, Center of Molecular Biology and Gene Therapy, University Hospital Brno and Medical Faculty MU, Brno, Czech Republic
    M Mraz, K Malinova, J Kotaskova, S Pavlova, B Tichy, J Malcikova, K Stano Kozubik, Y Brychtova, M Doubek, M Trbusek, J Mayer & S Pospisilova
  2. Department of Pathology, University Hospital Brno, Brno, Czech Republic. E-mail: sarka.pospisilova@fnbrno.cz,
    J Smardova

Authors

  1. M Mraz
    You can also search for this author inPubMed Google Scholar
  2. K Malinova
    You can also search for this author inPubMed Google Scholar
  3. J Kotaskova
    You can also search for this author inPubMed Google Scholar
  4. S Pavlova
    You can also search for this author inPubMed Google Scholar
  5. B Tichy
    You can also search for this author inPubMed Google Scholar
  6. J Malcikova
    You can also search for this author inPubMed Google Scholar
  7. K Stano Kozubik
    You can also search for this author inPubMed Google Scholar
  8. J Smardova
    You can also search for this author inPubMed Google Scholar
  9. Y Brychtova
    You can also search for this author inPubMed Google Scholar
  10. M Doubek
    You can also search for this author inPubMed Google Scholar
  11. M Trbusek
    You can also search for this author inPubMed Google Scholar
  12. J Mayer
    You can also search for this author inPubMed Google Scholar
  13. S Pospisilova
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Mraz, M., Malinova, K., Kotaskova, J. et al. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities.Leukemia 23, 1159–1163 (2009). https://doi.org/10.1038/leu.2008.377

Download citation

This article is cited by