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Original Article

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Blood Res 2015; 50(4):

Published online December 31, 2015

https://doi.org/10.5045/br.2015.50.4.235

© The Korean Society of Hematology

The prognostic value of glucocorticoid receptors for adult acute lymphoblastic leukemia

Ahmed M. L. Bedewy1*, Shereen M. EL-Maghraby1, Noha S. Kandil2, and Waleed R. El-Bendary3

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1Hematology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.

2Chemical Pathology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.

3Department of Clinical Pathology, Medical Military Academy, Cairo, Egypt.

Correspondence to : Correspondence to Ahmed M. L. Bedewy, M.D. Hematology Department, Medical Research Institute, Alexandria University, 8 Mahmoud Younes Street, Smouha, 21615 Alexandria, Egypt. Tel: +201000040511, dr_ahmed_bedewy@yahoo.com

Received: July 20, 2015; Revised: November 19, 2015; Accepted: November 25, 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background

Therapeutic protocols used in adult acute lymphoblastic leukemia (ALL) are widely variable, and glucocorticoids (GCs) are essential components in ALL treatment. Therefore, this study aimed to evaluate the distribution of prominent glucocorticoid receptor (GR) gene polymorphic variants among adult ALL patients. We also investigated the association between GR messenger ribonucleic acid (mRNA) isoform expressions and the response to chemotherapy.

Methods

Fifty-two newly diagnosed Philadelphia-negative adult ALL patients and 30 healthy control subjects were enrolled in this study. Genotyping was carried out using a polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. GR mRNA isoform expressions were assayed by quantitative real-time PCR.

Results

ALL patients in this study had a median age of 34 years (range, 18-75). GRα expression was associated with complete remission (P=0.03), while GRγ mRNA expression was significantly higher in GC resistant patients (P=0.032) and in non-responders (P=0.019). However, there were no significant associations with GC resistance. The BclI polymorphic variant of the GR gene was the most frequent in adult ALL patients and was not associated with the GC response. Both higher GRα expression and lower GRγ expression were associated with achievement of complete remission, while higher GRγ expression was associated with GC-resistance.

Conclusion

Our data suggest that the level of GR isoform expression may be useful in predicting GC response, achievement of complete remission, and better event-free survival in ALL patients. However, further evaluation with a larger cohort of patients is warranted.

Keywords Glucocorticoid receptor, Genetic polymorphism, Acute lymphoblastic leukemia

Article

Original Article

Blood Res 2015; 50(4): 235-241

Published online December 31, 2015 https://doi.org/10.5045/br.2015.50.4.235

Copyright © The Korean Society of Hematology.

The prognostic value of glucocorticoid receptors for adult acute lymphoblastic leukemia

Ahmed M. L. Bedewy1*, Shereen M. EL-Maghraby1, Noha S. Kandil2, and Waleed R. El-Bendary3

1Hematology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.

2Chemical Pathology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.

3Department of Clinical Pathology, Medical Military Academy, Cairo, Egypt.

Correspondence to:Correspondence to Ahmed M. L. Bedewy, M.D. Hematology Department, Medical Research Institute, Alexandria University, 8 Mahmoud Younes Street, Smouha, 21615 Alexandria, Egypt. Tel: +201000040511, dr_ahmed_bedewy@yahoo.com

Received: July 20, 2015; Revised: November 19, 2015; Accepted: November 25, 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Therapeutic protocols used in adult acute lymphoblastic leukemia (ALL) are widely variable, and glucocorticoids (GCs) are essential components in ALL treatment. Therefore, this study aimed to evaluate the distribution of prominent glucocorticoid receptor (GR) gene polymorphic variants among adult ALL patients. We also investigated the association between GR messenger ribonucleic acid (mRNA) isoform expressions and the response to chemotherapy.

Methods

Fifty-two newly diagnosed Philadelphia-negative adult ALL patients and 30 healthy control subjects were enrolled in this study. Genotyping was carried out using a polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. GR mRNA isoform expressions were assayed by quantitative real-time PCR.

Results

ALL patients in this study had a median age of 34 years (range, 18-75). GRα expression was associated with complete remission (P=0.03), while GRγ mRNA expression was significantly higher in GC resistant patients (P=0.032) and in non-responders (P=0.019). However, there were no significant associations with GC resistance. The BclI polymorphic variant of the GR gene was the most frequent in adult ALL patients and was not associated with the GC response. Both higher GRα expression and lower GRγ expression were associated with achievement of complete remission, while higher GRγ expression was associated with GC-resistance.

Conclusion

Our data suggest that the level of GR isoform expression may be useful in predicting GC response, achievement of complete remission, and better event-free survival in ALL patients. However, further evaluation with a larger cohort of patients is warranted.

Keywords: Glucocorticoid receptor, Genetic polymorphism, Acute lymphoblastic leukemia

Fig 1.

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Figure 1.

(A) Lanes 1-4 represent polymerase chain reaction (PCR) products for BclI polymorphism from 4 acute lymphoblastic leukemia (ALL) patients (335 base pairs (bp)). (B) Restriction fragment length polymorphism-digested PCR products for BclI polymorphism from ALL patients. Lanes 1 and 2 represent restriction fragments of PCR products for ALL patients with the CC genotype (222, 117 bp). Lanes 3 and 4 represent restriction PCR products for ALL patients with the CG genotype (335, 222, 117 bp). (C) Lanes 1-4 represent PCR products for N363S polymorphism from ALL patients (248 bp). Lane M represents the 100 bp ladder marker.

Blood Research 2015; 50: 235-241https://doi.org/10.5045/br.2015.50.4.235

Fig 2.

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Figure 2.

Kaplan-Meier chart showing event-free survival for the BclI genotype (A), the N363S genotype (B), and the α/β isoform expression ratio (C).

Blood Research 2015; 50: 235-241https://doi.org/10.5045/br.2015.50.4.235
The primer sequences and restriction enzymes used for the PCR-RFLP.

Abbreviations: RE, restriction enzymes; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism..
Laboratory and clinical findings in adult ALL patients in relation to the response to induction chemotherapy.

a)P value of Fisher Exact test, b)P value of chi-square test..

Abbreviation: ALL, acute lymphoblastic leukemia..
Expression of GR mRNA isoforms and their relation to different demographic, laboratory, and clinical parameters.

Abbreviations: GR, glucocorticoid receptor; mRNA, messenger ribonucleic acid; Min, minimum; Max, maximum..
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