Skip to main content
SpringerLink
Log in

MicroRNA as a prognostic biomarker for survival in childhood acute lymphoblastic leukemia: a systematic review

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Recent studies suggest abnormal microRNA (miRNA) expression may have potential prognostic value in childhood acute lymphoblastic leukemia (ALL). In this systematic review, we searched different databases (PubMed, ASH, ASCO, and SIOP) for studies published from 2008 to 2018 that evaluated the prognostic impact of miRNAs in childhood ALL. We also used DIANA-miRPath v3.0 to further characterize the functional role of the significant prognostic miRNAs identified in our systematic review. Here we evaluate 15 studies with a total of 38 different miRNAs and 1545 children with B-cell ALL (B-ALL) or T-cell ALL (T-ALL) recruited over approximately 3 decades (1984–2016) with different treatment protocols and ethnicities. Out of the 15 studies examined, 14 reported 32 dysregulated miRNAs with significant prognostic impact in pediatric ALL patients. Only one Brazilian study reported no significant prognostic effect of 7 miRNAs, while the seventh miRNA (miR-100) showed prognostic significance in a Chinese study. Using DIANA-TarBase v7.0 of DIANA-miRPath v3.0, pathway enrichment analysis revealed 25 miRNAs modulated 24 molecular pathways involved in cancer development. To remove the effect of salvage therapy, 9 studies carried out multivariate cox regression analysis for both relapse-free survival and disease-free survival to develop a panel of 23 miRNAs acting as independent prognostic biomarkers. To enhance the clinical application, utility, and validity of the miRNAs discussed here, their potential prognostic value should be confirmed in larger cohort studies within different ethnicities and different ALL protocols adjusted for other contemporary validated prognostic factors in childhood ALL.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kato, M., & Manabe, A. (2018). Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatrics International, 60(1), 4–12. https://doi.org/10.1111/ped.13457.

    Article  PubMed  Google Scholar 

  2. Hudson, M. M., Link, M. P., & Simone, J. V. (2014). Milestones in the curability of pediatric cancers. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 32(23), 2391–2397. https://doi.org/10.1200/JCO.2014.55.6571.

    Article  Google Scholar 

  3. Raetz, E. A., & Bhatla, T. (2012). Where do we stand in the treatment of relapsed acute lymphoblastic leukemia? Hematology. American Society of Hematology. Education Program, 2012, 129–136. https://doi.org/10.1182/asheducation-2012.1.129.

    Article  PubMed  Google Scholar 

  4. Hanna, J., Hossain, G. S., & Kocerha, J. (2019). The potential for microRNA therapeutics and clinical research. Frontiers in Genetics, 10, 478. https://doi.org/10.3389/fgene.2019.00478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Petrescu, G. E. D., Sabo, A. A., Torsin, L. I., Calin, G. A., & Dragomir, M. P. (2019). MicroRNA based theranostics for brain cancer: basic principles. Journal of Experimental & Clinical Cancer Research, 38(1), 231. https://doi.org/10.1186/s13046-019-1180-5.

    Article  CAS  Google Scholar 

  6. Fan, R., Xiao, C., Wan, X., Cha, W., Miao, Y., Zhou, Y., Qin, C., Cui, T., Su, F., & Shan, X. (2019). Small molecules with big roles in microRNA chemical biology and microRNA-targeted therapeutics. RNA Biology, 16(6), 707–718. https://doi.org/10.1080/15476286.2019.1593094.

    Article  PubMed  Google Scholar 

  7. Bonneau, E., Neveu, B., Kostantin, E., Tsongalis, G. J., & De Guire, V. (2019). How close are miRNAs from clinical practice? A perspective on the diagnostic and therapeutic market. EJIFCC, 30(2), 114–127. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/31263388

  8. Vlachos, I. S., Zagganas, K., Paraskevopoulou, M. D., Georgakilas, G., Karagkouni, D., Vergoulis, T., Dalamagas, T., & Hatzigeorgiou, A. G. (2015). DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Research, 43(W1), W460–W466. https://doi.org/10.1093/nar/gkv403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yan, J., Jiang, N., Huang, G., Tay, J. L.-S., Lin, B., Bi, C., et al. (2013). Deregulated MIR335 that targets MAPK1 is implicated in poor outcome of paediatric acute lymphoblastic leukaemia. British Journal of Haematology, 163(1), 93–103. https://doi.org/10.1111/bjh.12489.

    Article  CAS  PubMed  Google Scholar 

  10. Mosakhani, N., Sarhadi, V. K., Usvasalo, A., Karjalainen-Lindsberg, M.-L., Lahti, L., Tuononen, K., … Knuutila, S. (2012). MicroRNA profiling in pediatric acute lymphoblastic leukemia: novel prognostic tools. Leukemia & Lymphoma. England. doi:https://doi.org/10.3109/10428194.2012.685731

    Article  CAS  Google Scholar 

  11. Avigad, S., Verly, I. R. N., Lebel, A., Kordi, O., Shichrur, K., Ohali, A., et al. (2016). miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia. Genes, Chromosomes & Cancer, 55(4), 328–339. https://doi.org/10.1002/gcc.22334.

    Article  CAS  Google Scholar 

  12. Han, B.-W., Feng, D.-D., Li, Z.-G., Luo, X.-Q., Zhang, H., Li, X.-J., Zhang, X. J., Zheng, L. L., Zeng, C. W., Lin, K. Y., Zhang, P., Xu, L., & Chen, Y.-Q. (2011). A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL. Human Molecular Genetics, 20(24), 4903–4915. https://doi.org/10.1093/hmg/ddr428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schotte, D., de Menezes, R. X., Moqadam, F. A., Khankahdani, L. M., Lange-Turenhout, E., Chen, C., et al. (2011). MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia. Haematologica, 96(5), 703–711. https://doi.org/10.3324/haematol.2010.026138.

    Article  PubMed  PubMed Central  Google Scholar 

  14. de Oliveira, J. C., Scrideli, C. A., Brassesco, M. S., Morales, A. G., Pezuk, J. A., Queiroz, R. d. P., et al. (2012). Differential MiRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features. Leukemia Research, 36(3), 293–298. https://doi.org/10.1016/j.leukres.2011.10.005.

    Article  CAS  PubMed  Google Scholar 

  15. Organista-Nava, J., Gómez-Gómez, Y., Illades-Aguiar, B., Del Carmen Alarcón-Romero, L., Saavedra-Herrera, M. V., Rivera-Ramírez, A. B., et al. (2015). High miR-24 expression is associated with risk of relapse and poor survival in acute leukemia. Oncology Reports, 33(4), 1639–1649. https://doi.org/10.3892/or.2015.3787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li, X. J., Luo, X. Q., Han, B. W., Duan, F. T., Wei, P. P., & Chen, Y. Q. (2013). MicroRNA-100/99a, deregulated in acute lymphoblastic leukaemia, suppress proliferation and promote apoptosis by regulating the FKBP51 and IGF1R/mTOR signalling pathways. British Journal of Cancer, 109(8), 2189–2198. https://doi.org/10.1038/bjc.2013.562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Labib, H. A., Elantouny, N. G., Ibrahim, N. F., & Alnagar, A. A. (2017). Upregulation of microRNA-21 is a poor prognostic marker in patients with childhood B cell acute lymphoblastic leukemia. Hematology (Amsterdam, Netherlands), 22(7), 392–397. https://doi.org/10.1080/10245332.2017.1292204.

    Article  CAS  Google Scholar 

  18. Piatopoulou, D., Avgeris, M., Drakaki, I., Marmarinos, A., Xagorari, M., Baka, M., Pourtsidis, A., Kossiva, L., Gourgiotis, D., & Scorilas, A. (2018). Clinical utility of miR-143/miR-182 levels in prognosis and risk stratification specificity of BFM-treated childhood acute lymphoblastic leukemia. Annals of Hematology, 97(7), 1169–1182. https://doi.org/10.1007/s00277-018-3292-y.

    Article  CAS  PubMed  Google Scholar 

  19. Piatopoulou, D., Avgeris, M., Marmarinos, A., Xagorari, M., Baka, M., Doganis, D., Kossiva, L., Scorilas, A., & Gourgiotis, D. (2017). miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment. British Journal of Cancer, 117(6), 801–812. https://doi.org/10.1038/bjc.2017.256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaddar, T., Chien, W. W., Bertrand, Y., Pages, M. P., Rouault, J. P., Salles, G., et al. (2009). Prognostic value of miR-16 expression in childhood acute lymphoblastic leukemia relationships to normal and malignant lymphocyte proliferation. Leukemia Research, 33(9), 1217–1223. https://doi.org/10.1016/j.leukres.2008.12.015.

    Article  CAS  PubMed  Google Scholar 

  21. Agirre, X., Vilas-Zornoza, A., Jimenez-Velasco, A., Martin-Subero, J. I., Cordeu, L., Garate, L., et al. (2009). Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. Cancer Research, 69(10), 4443–4453. https://doi.org/10.1158/0008-5472.CAN-08-4025.

    Article  CAS  PubMed  Google Scholar 

  22. Sirugo, G., Williams, S. M., & Tishkoff, S. A. (2019). The missing diversity in human genetic studies. Cell, 177(1), 26–31. https://doi.org/10.1016/j.cell.2019.02.048.

    Article  CAS  PubMed  Google Scholar 

  23. Cooper, S. L., & Brown, P. A. (2015). Treatment of pediatric acute lymphoblastic leukemia. Pediatric Clinics of North America, 62(1), 61–73. https://doi.org/10.1016/j.pcl.2014.09.006.

    Article  PubMed  Google Scholar 

  24. Schmidt, S., Rainer, J., Ploner, C., Presul, E., Riml, S., & Kofler, R. (2004). Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death and Differentiation, 11(S1), S45–S55. https://doi.org/10.1038/sj.cdd.4401456.

    Article  CAS  PubMed  Google Scholar 

  25. Groninger, E., Meeuwsen-De Boer, G., De Graaf, S., Kamps, W., & De Bont, E. (2002). Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: a mitochondrial controlled pathway regulated by reactive oxygen species? International Journal of Oncology, 21(6), 1339–1345. https://doi.org/10.3892/ijo.21.6.1339.

    Article  CAS  PubMed  Google Scholar 

  26. Richardson, D. S., & Johnson, S. A. (1997). Anthracyclines in haematology: preclinical studies, toxicity and delivery systems. Blood Reviews, 11(4), 201–23. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9481450.

  27. Cimmino, A., Calin, G. A., Fabbri, M., Iorio, M. V., Ferracin, M., Shimizu, M., Wojcik, S. E., Aqeilan, R. I., Zupo, S., Dono, M., Rassenti, L., Alder, H., Volinia, S., Liu, C. G., Kipps, T. J., Negrini, M., & Croce, C. M. (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences, 102(39), 13944–13949. https://doi.org/10.1073/pnas.0506654102.

    Article  CAS  Google Scholar 

  28. Jing, D., Bhadri, V. A., Beck, D., Thoms, J. A. I., Yakob, N. A., Wong, J. W. H., et al. (2015). Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells. Blood, 125(2), 273–283. https://doi.org/10.1182/blood-2014-05-576470.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, H., Luo, X.-Q., Zhang, P., Huang, L.-B., Zheng, Y.-S., Wu, J., et al. (2009). MicroRNA patterns associated with clinical prognostic parameters and CNS relapse prediction in pediatric acute leukemia. PLoS One, 4(11), e7826. https://doi.org/10.1371/journal.pone.0007826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mei, Y., Gao, C., Wang, K., Cui, L., Li, W., Zhao, X., Liu, F., Wu, M., Deng, G., Ding, W., Jia, H., & Li, Z. (2014). Effect of microRNA-210 on prognosis and response to chemotherapeutic drugs in pediatric acute lymphoblastic leukemia. Cancer Science, 105(4), 463–472. https://doi.org/10.1111/cas.12370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mei, Y., Li, Z., Zhang, Y., Zhang, W., Hu, H., Zhang, P., Wu, M., & Huang, D. (2017). Low miR-210 and CASP8AP2 expression is associated with a poor outcome in pediatric acute lymphoblastic leukemia. Oncology Letters, 14(6), 8072–8077. https://doi.org/10.3892/ol.2017.7229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical Trials Unit, Clinical Research, Children’s Cancer Hospital Egypt-57357 (CCHE-57357), Cairo, Egypt

    Wafaa M. Rashed

  2. Biostatistics Unit, Clinical Research, Children’s Cancer Hospital Egypt-57357 (CCHE-57357), Cairo, Egypt

    Mahmoud M. Hamza

  3. Biochemistry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Marwa Matboli

  4. Cytogenetics Department, Children’s Cancer Hospital Egypt-57357 (CCHE-57357), Cairo, Egypt

    Sherin I. Salem

  5. National Cancer Institute, Cairo University, Giza, Egypt

    Sherin I. Salem

Authors
  1. Wafaa M. Rashed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud M. Hamza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marwa Matboli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sherin I. Salem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wafaa M. Rashed.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rashed, W.M., Hamza, M.M., Matboli, M. et al. MicroRNA as a prognostic biomarker for survival in childhood acute lymphoblastic leukemia: a systematic review. Cancer Metastasis Rev 38, 771–782 (2019). https://doi.org/10.1007/s10555-019-09826-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-019-09826-0

Keywords

Search

Navigation