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

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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.

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Fig. 1: Analysis of miR-143/miR-182 expression in childhood ALL patients and correlation with clinicopathological parameters.
Fig. 2: Overexpression of miR-143 and/or miR-182 at the EoI of BFM protocol (day 33) correlates with patients’ poor treatment outcome.
Fig. 3: Childhood ALL patients overexpressing miR-143 and/or miR-182 at the EoI of the BFM protocol (day 33) are at significant higher risk for disease short-term relapse and poor survival outcome.
Fig. 4: Evaluation of miR-143/miR-182 levels at the EoI (day 33) strengthens the prognostic value of the established and clinically used disease markers.
Fig. 5: Evaluation of miR-143/miR-182 levels at the EoI (day 33) improves significantly the specificity BFM risk group stratification.

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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.

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Authors and Affiliations

  1. Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, Medical School, “P. & A. Kyriakou” Children’s Hospital, National and Kapodistrian University of Athens, Levadias 13 Str., 11527, Athens, Greece

    Despina Piatopoulou, Ioanna Drakaki, Antonios Marmarinos, Marieta Xagorari & Dimitrios Gourgiotis

  2. Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701, Athens, Greece

    Margaritis Avgeris & Andreas Scorilas

  3. Department of Pediatric Oncology, “P. & A. Kyriakou” Children’s Hospital, Thivon & Levadias Str., 11527, Athens, Greece

    Margarita Baka & Apostolos Pourtsidis

  4. Second Department of Pediatrics, Medical School, “P. & A. Kyriakou” Children’s Hospital, National and Kapodistrian University of Athens, Levadias 13 Str., 11527, Athens, Greece

    Lydia Kossiva

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  1. Despina Piatopoulou
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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

Corresponding author

Correspondence to Andreas Scorilas.

Ethics declarations

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.

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Piatopoulou, D., Avgeris, M., Drakaki, I. et al. Clinical utility of miR-143/miR-182 levels in prognosis and risk stratification specificity of BFM-treated childhood acute lymphoblastic leukemia. Ann Hematol 97, 1169–1182 (2018). https://doi.org/10.1007/s00277-018-3292-y

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