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Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia

  • RESEARCH ARTICLE
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Response to dexamethasone (DEXA), as a hallmark drug in the treatment of childhood acute lymphoblastic leukemia (ALL), is one of the pivotal prognostic factors in the prediction of outcome in ALL. Identification of predictive markers of chemoresistance is beneficial to selecting of the best therapeutic protocol with the lowest effect adverse. Hence, we aimed to find drug targets using the 2DE/MS proteomics study of a DEXA-resistant cell line (REH) as a model for poor DEXA responding patients before and after drug treatment. Using the proteomic methods, three differentially expressed proteins were detected, including voltage dependent anion channel 1 (VDAC1), sorting Nexin 3 (SNX3), and prefoldin subunit 6 (PFDN6). We observed low expression of three proteins after DEXA treatment in REH cells. We subsequently verified low expression of resulted proteins at the mRNA level using the quantitative PCR method. These proteins are promising proteins because of their important roles in drug resistance and regulation of apoptosis (VDAC1), protein trafficking (SNX3), and protein folding (PFDN6). Additionally, mRNA expression level of these proteins was assessed in 17 bone marrow samples from children with newly diagnosed ALL and 7 non-cancerous samples as controls. The results indicated that independent of the molecular subtypes of leukemia, mRNA expression of VDAC1, SNX3, and PFDN6 decreased in ALL samples compared with non-cancerous samples particularly in VDAC1 (p < 0.001). Additionally, mRNA expression of three proteins was also declined in high-risk samples compared with standard risk cases. These results demonstrated diagnostic and prognostic value of these proteins in childhood ALL. Furthermore, investigation of protein-protein interaction using STRING database indicated that these proteins involved in the signaling pathway of NR3C1 as dexamethasone target. In conclusion, our proteomic study in DEXA resistant leukemic cells revealed VDAC1, SNX3, and PFDN6 are promising proteins that might serve as potential biomarkers of prognosis and chemotherapy in childhood ALL.

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Abbreviations

ER:

ETV6/RUNX1

GC:

Glucocorticoid

ALL:

Acute lymphoblastic leukemia

DEXA:

Dexamethasone

VDAC1:

Voltage dependent anion channel 1

SNX3:

Sorting Nexin 3

PFDN6:

Prefoldin subunit 6

PPI:

Protein-protein interaction

2-DE:

Two-dimensional gel electrophoresis

MS:

Mass spectrometry

PIP3:

Phosphatidylinositol (3,4,5)-trisphosphate

FCM:

Flow cytometry

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Acknowledgments

The authors would like to thank the Shahid Beheshti University of Medical Sciences for supporting of this research and also Pasteur Institute of Iran for technical assistance.

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Authors and Affiliations

  1. Proteomics Research Center, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Nasrin Dehghan-Nayeri & Mostafa Rezaei-Tavirani

  2. Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mir Davood Omrani

  3. Department of Hematology and Blood Bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Ahmad Gharehbaghian

  4. Pediatric Congenital Hematologic Disorders Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Ahmad Gharehbaghian, Kourosh Goudarzi Pour & Peyman Eshghi

Authors
  1. Nasrin Dehghan-Nayeri
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  2. Mostafa Rezaei-Tavirani
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  3. Mir Davood Omrani
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  4. Ahmad Gharehbaghian
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  5. Kourosh Goudarzi Pour
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  6. Peyman Eshghi
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Corresponding authors

Correspondence to Ahmad Gharehbaghian or Kourosh Goudarzi Pour.

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The authors declare no competing financial interest.

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Informed consent was obtained from all individual participants included in the study.

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Dehghan-Nayeri, N., Rezaei-Tavirani, M., Omrani, M.D. et al. Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia. J. Cell Commun. Signal. 11, 137–145 (2017). https://doi.org/10.1007/s12079-016-0357-3

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  • DOI: https://doi.org/10.1007/s12079-016-0357-3

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