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Annals of Hematology

, Volume 97, Issue 7, pp 1169–1182 | Cite as

Clinical utility of miR-143/miR-182 levels in prognosis and risk stratification specificity of BFM-treated childhood acute lymphoblastic leukemia

  • Despina Piatopoulou
  • Margaritis Avgeris
  • Ioanna Drakaki
  • Antonios Marmarinos
  • Marieta Xagorari
  • Margarita Baka
  • Apostolos Pourtsidis
  • Lydia Kossiva
  • Dimitrios Gourgiotis
  • Andreas Scorilas
Original Article

Abstract

Although childhood acute lymphoblastic leukemia (ALL) is characterized by high remission rates, there are still patients who experience poor response to therapy or toxic effects due to intensive treatment. In the present study, we examined the expression profile of miR-143 and miR-182 in childhood ALL and evaluated their clinical significance for patients receiving Berlin–Frankfurt–Münster (BFM) protocol. Bone marrow specimens from 125 childhood ALL patients upon diagnosis and the end-of-induction (EoI; day 33), as well as from 64 healthy control children undergone RNA extraction, polyadenylation, and reverse transcription. Expression levels of miRNAs were quantified by qPCR analysis. Patients’ cytogenetic, immunohistotype and MRD evaluation was performed according to international guidelines. Median follow-up time was 86.0 months (95% CI 74.0–98.0), while patients’ mean DFS and OS intervals were 112.0 months (95% CI 104.2–119.8) and 109.2 months (95% CI 101.2–117.3), respectively. Bone marrow levels of miR-143/miR-182 were significantly decreased in childhood ALL patients at diagnosis and increased in more than 90% of patients at the EoI. Patients’ survival analysis highlighted that children overexpressing miR-143/miR-182 at the EoI presented significantly higher risk for short-term relapse (log-rank test: p = 0.021; Cox regression: HR = 4.911, p = 0.038) and death (log-rank test: p = 0.028; Cox regression: HR = 4.590, p = 0.046). Finally, the evaluation of the miR-143/miR-182 EoI levels along with the established disease prognostic markers resulted to improved prediction of BFM-treated patients’ survival outcome and response to therapy and additionally to superior BFM risk stratification specificity. Concluding, miR-143 and miR-182 could serve as novel prognostic molecular markers for pediatric ALL treated with BFM chemotherapy.

Keywords

ALL Childhood ALL miRNA Non-coding RNA ALL IC-BFM Berlin–Frankfurt–Münster protocol 

Notes

Acknowledgments

We wish to sincerely thank Dr. M. Varvoutsi, Dr. D. Doganis, and Dr. M. Servitzoglou for their valuable professional assistance in the characterization and collection of our samples. We would also like to thank the nursing staff of the Department of Pediatric Oncology, “P. & A. Kyriakou” Children’s Hospital, for their expert help with the collection of samples.

Authors’ contributions

Conception and design: D. Gourgiotis, A. Scorilas, M. Avgeris

Development of methodology: M. Avgeris, D. Piatopoulou, M. Xagorari

Acquisition of data: D. Piatopoulou, M. Avgeris, I. Drakaki, A. Marmarinos, M. Xagorari, M. Baka, A. Pourtsidis, L. Kossiva

Analysis and interpretation of data: M. Avgeris, D. Piatopoulou

Acquired and managed patients: M. Baka, A. Pourtsidis, L. Kossiva

Drafting of the manuscript: D. Piatopoulou, M. Avgeris, I. Drakaki, A. Marmarinos, M. Xagorari

Critical revision of the manuscript: M. Avgeris, A. Marmarinos, M. Baka, A. Pourtsidis, L. Kossiva, D. Gourgiotis, A. Scorilas

Administrative, technical, or material support: D. Gourgiotis, A. Scorilas, M. Baka, A. Pourtsidis, L. Kossiva

Study supervision: A. Scorilas, D. Gourgiotis

Approval of the submitted and final version: all authors

Compliance with ethical standards

The study was approved by the Ethics Committee of “P. & A. Kyriakou” Children’s Hospital, Athens, Greece, and performed with respect to the ethical standards of the Declaration of Helsinki, as revised in 2008. Informed consent was obtained from all parents and legal guardians of the participating patients.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Despina Piatopoulou
    • 1
  • Margaritis Avgeris
    • 2
  • Ioanna Drakaki
    • 1
  • Antonios Marmarinos
    • 1
  • Marieta Xagorari
    • 1
  • Margarita Baka
    • 3
  • Apostolos Pourtsidis
    • 3
  • Lydia Kossiva
    • 4
  • Dimitrios Gourgiotis
    • 1
  • Andreas Scorilas
    • 2
  1. 1.Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, Medical School, “P. & A. Kyriakou” Children’s HospitalNational and Kapodistrian University of AthensAthensGreece
  2. 2.Department of Biochemistry and Molecular Biology, Faculty of BiologyNational and Kapodistrian University of AthensAthensGreece
  3. 3.Department of Pediatric Oncology“P. & A. Kyriakou” Children’s HospitalAthensGreece
  4. 4.Second Department of Pediatrics, Medical School, “P. & A. Kyriakou” Children’s HospitalNational and Kapodistrian University of AthensAthensGreece

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