The translational expression of ABCA2 and ABCA3 is a strong prognostic biomarker for multidrug resistance in pediatric acute lymphoblastic leukemia
Received 26 April 2017
Accepted for publication 1 June 2017
Published 10 July 2017 Volume 2017:10 Pages 3373—3380
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 3
Editor who approved publication: Dr Carlos E Vigil
Narges Aberuyi,1 Soheila Rahgozar,1 Zohreh Khosravi Dehaghi,1 Alireza Moafi,2 Andrea Masotti,3,* Alessandro Paolini3,*
1Department of Biology, Faculty of Science, University of Isfahan, 2Department of Pediatric-Hematology-Oncology, Sayed-ol-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran; 3Gene Expression – Microarrays Laboratory, Bambino Gesù Children’s Hospital-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
*These authors contributed equally to the manuscript
Purpose: The aim of this work was to study the correlation between the expressions of the ABCA2 and ABCA3 genes at the mRNA and protein levels in children with acute lymphoblastic leukemia (ALL) and the effects of this association on multidrug resistance (MDR).
Materials and methods: Sixty-nine children with de novo ALL and 25 controls were enrolled in the study. Mononuclear cells were isolated from the bone marrow. The mRNA levels of ABCA2 and ABCA3 were measured by real-time polymerase chain reaction (PCR). Samples with high mRNA levels were assessed for respective protein levels by Western blotting. Following the first year of treatment, persistent monoclonality of T-cell gamma receptors or immunoglobulin H (IgH) gene rearrangement was assessed and considered as the MDR. The tertiary structure of ABCA2 was predicted using Phyre2 and I-TASSER web systems and compared to that of ABCA3, which has been previously reported. Molecular docking was performed using DOCK 6.7.
Results: Real-time quantitative PCR (qRT-PCR) showed high levels of ABCA2 and ABCA3 mRNAs in 13 and 17 samples, respectively. Among them, five and eight individuals demonstrated high levels of ABCA2 and ABCA3, respectively. Response to chemotherapy was significantly decreased (P=0.001) when the mRNA and protein of both genes were overexpressed compared to individuals with high transcriptional levels of either ABCA2 or ABCA3 alone. Close similarity between ABCA2 and ABCA3 structures was revealed by protein tertiary structure prediction, whereas molecular docking analysis suggested similar binding of chemotherapy drugs and therefore a potentially similar role in determining the MDR.
Conclusion: Our findings suggested, for the first time, that quantification of the protein level of ABCA2 and ABCA3 transporters had a prognostic impact on pediatric ALL MDR. Furthermore, the tertiary structure of ABCA2 was predicted for the first time, and docking analysis revealed a possible compensatory effect between ABCA2 and ABCA3 transporters, which may contribute to the efflux of cytotoxic drugs and, ultimately, to chemoresistance.
Keywords: ABCA2 transporter, ABCA3 transporter, multidrug resistance, childhood acute lymphoblastic leukemia, molecular docking, tertiary structure
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