|Year : 2012 | Volume
| Issue : 2 | Page : 123-128
Evaluation of the mutation of glutathione S-transferase T1 in childhood acute myeloid leukemia
Enas Swelam1, Abdel Baset Diab2
1 Department of Clinical Pathology, Zagazig University, Zagazig, Egypt
2 Department of Pediatric, Zagazig University, Zagazig, Egypt
|Date of Submission||28-Jan-2012|
|Date of Acceptance||20-Feb-2012|
|Date of Web Publication||23-Jun-2014|
Department of Clinical Pathology, Zagazig University, 44519 Zagazig
Source of Support: None, Conflict of Interest: None
Our aim is to determine the rate of glutathione S-transferase T1 (GSTT1) null genotypes in acute myeloid leukemia (AML) patients as a risk factor and analyze the prognostic significance of this gene polymorphism.
Patients and methods
We genotyped GSTT1 in two groups: the patient group included 30 children with AML who were receiving chemotherapy and the control group included 50 healthy children. PCR amplification was used to assign the GSTT1 genotype for the cases and the controls. The outcomes were compared in the patient group (those with and without GSTT1 genes).
The frequency of GSTT1 null was significantly increased in the AML cases compared with the controls (50 vs. 10%).
The GSTT1 null genotype is a significant risk factor for childhood AML. The frequency of early death was high in GSTT1-negative cases. Patients with the GSTT1-negative genotype had reduced survival compared with those with at least one GSTT1 allele (GSTT1 positive). The frequency of relapse from the end of induction did not show any significant difference in the GSTT1-negative and the GSTT1-positive cases. The GSTT1 genotype might be useful when deciding on appropriate chemotherapy regimens for children with AML.
Keywords: acute myeloid leukemia, children, glutathione S-transferase T1, polymerase chain reaction
|How to cite this article:|
Swelam E, Diab AB. Evaluation of the mutation of glutathione S-transferase T1 in childhood acute myeloid leukemia. Egypt J Haematol 2012;37:123-8
|How to cite this URL:|
Swelam E, Diab AB. Evaluation of the mutation of glutathione S-transferase T1 in childhood acute myeloid leukemia. Egypt J Haematol [serial online] 2012 [cited 2022 Jan 21];37:123-8. Available from: http://www.ehj.eg.net/text.asp?2012/37/2/123/135066
| Introduction|| |
The glutathione S-transferase (GST) family of metabolizing enzymes plays an important role in the metabolism and detoxification of mutagens and carcinogens. GST genes encode a family of enzymes that play major roles in catalyzing the conjugation of glutathione (GSH) to a wide variety of hydrophobic and electrophilic substrates and carcinogens such as benzpyrene and reactive oxygen species 1. GST levels can be induced by exposure to foreign substrates in vivo, suggesting that they form part of a system adaptive to chemical stress 2.
The gene family includes GST μ (GSTM1), &thgr; (GSTT1), and &pgr; (GSTP1). Independent gene deletions in GSTT1 or GSTM1 (null genotype) result in a lack of active protein. In vitro, the GSTT1 null status has been linked to an increased frequency of diepoxybutane-induced sister chromatid exchange in culture lymphocytes, whereas GSTM1 allele status has no effect on the DNA damage observed 3. GSTT1 gene polymorphism has significant clinical implications in younger patients with acute myeloid leukemia (AML) or intermediate-risk cytogenetics 4.
An increased frequency of GST-null genotypes has been associated with several malignancies, including lung cancer 5, stomach cancer 6, bladder cancer 7, colorectal cancer 8, astrocytoma 9, and esophageal squamous cell cancer 10. The influence of GST on susceptibility to cancer may be influenced by a variety of factors such as smoking, diet, and sex 11.
In hematological malignancies, an association has been shown between the GST-null genotype and an increased risk of developing acute leukemia, especially acute lymphoblastic leukemia (ALL) 2, AML 12, and myelodysplastic syndrome 13.
More studies are required to determine the effect of environmental factors in these malignancies, as it is possible that patients with malignancy who are more exposed to environmental carcinogens have a higher rate of GST-null genotypes than patients with less exposure to these agents. Although polymorphic loci have been identified in each class of GST gene families, most interest in the possible consequences of GST polymorphism has focused on the polymorphisms at the GSTT1 gene loci, which have been located on chromosome 22. GSTT1 is an attractive candidate gene as a susceptibility factor in cancer. It metabolizes various potential carcinogens such as monohalomethanes (e.g. methyl chloride) and ethylene oxide, present in cigarette smoke and ubiquitously used as methylating agents, pesticides, and solvents in industry 14. GSTP1-1 has received the most attention because it is usually overexpressed in cancer cells and has been associated with the development of tumor resistance to anticancer drugs. In its newly identified role, GSTP1-1 acts as a repressor of JNK and other protein kinases involved in stress response, cell proliferation, and apoptosis 15.
The incidence of the null genotype for GSTT1 is 10–20% in Caucasian 16 and 16.8–25.7% in other ethnic groups 17.
Genetic polymorphisms have been examined focusing on individual differences in pharmacodynamics, response, and the side-effects of drugs 18. However, it remains to be elucidated whether genetic polymorphisms influence the prognosis of leukemia after chemotherapy.
Because GSTs may be involved in the metabolism of chemotherapy drugs, we hypothesized that presence or absence of the genes may influence the outcome of treatment for childhood AML. The present study was carried out to determine the rate of GSTT1 null genotypes in AML patients as a risk factor and its importance in the prognosis of the disease.
| Patients and methods|| |
This is a prospective follow-up study that was carried out during the period from May 2006 to May 2009 at the Clinical Pathology Department and Haematology and Oncology Unit of Pediatric Departments of Zagazig University Hospitals. This study included 80 children, ranging in age from 2.5 to 15 years. They were divided into two groups: Group I cases: 30 children with proved AML by peripheral blood and bone marrow examination, cytochemistry, and immunophenotyping investigations. Group II controls: 50 apparently healthy children matched with the previous group for age and sex. Informed consent was obtained from all the patients according to our institutional guidelines.
All cases were subjected to full history taking including the following: present, past, and family history and general and systemic examination including vital signs, color, especially pallor, lymph node enlargement, skin for purpuric eruption and ecchymosis, and a thorough examination of organ systems, with a special focus on abdominal examination for palpation of the liver and the spleen.
For all participants, the following tests were carried out: complete blood count, peripheral blood smear, liver and kidney function tests, and serum electrolytes. For diagnosis of AML, bone marrow examination and immunophenotyping were carried out only for the cases only.
Specific investigation for the detection of the glutathione S-transferase T1 genotype
Genomic DNA used was extracted from mononuclear cells using the QIAamp DNA Mini isolation kit (catalogue number: 51304; Qiagen Inc., Valencia, California, USA). Then, DNA was stored at 2–8°C.
Polymerase chain reaction amplification
PCR amplification was performed on 25 ng of genomic DNA in a reaction mixture with the total volume of 50 μl that contained 0.5 μmol/l of each of the forward and reverse GSTT1 and β-globin primers (20 pmol/l), 200 μmol/l of each dNTPs, 2.0 mmol/l MgCl2, 10 mmol/l Tris-HCl (pH 8.3), and 50 mmol/l KCl; finally, 25 µl of GO-Taq green master mix (1×) was added.
The PCR program was as follows: the first step of denaturation was carried out at 94°C for 1 min, followed by the annealing step was at 62°C for 1 min, and finally, the extension step at 72°C for 1 min. The reaction was carried out using 30 cycles (see [Table 1].
|Table 1: Primer sequences for glutathione S-transferase multiplex polymerase chain reaction|
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Detection of gene bands by polymerase chain reaction electrophoresis
The PCR product was run on a 2% (w/v) agarose gel and the bands were visualized with ultraviolet light. DNA from patients with positive GSTT1 and β-globin alleles yielded 480 and 268 bp products, respectively, against DNA ladder 1000 bp (100 bp for each band).
The absence of GSTT1 (in the presence of a β-globin PCR product) indicates the respective null genotype. Samples positive for all PCR products were considered as normal expressions of the GSTT1 gene (two bands). Partial deletion of the GSTT1 gene was detected as two bands, but the band at 480 bp was thinner than normal. Coamplification of human β-globin served as a positive control, to ensure that a null genotype was attributed to the absence of the respective gene and not because of a PCR failure 19.
In this study, categorical data are presented as numbers and percentages (range) and continuous data as mean±SD. For the comparison of nonparametric (categorical) variables, the χ2-test or Fisher’s exact test was used (if a cell value was<5). The Kruskal–Wallis test was performed to compare the medians.
All tests were performed using the SPSS-15 evaluation program (SSPS Inc., Chicago, Illinois, USA). All statistical tests were considered significant at P less than 0.05.
| Results|| |
The current study included two groups: Group 1 included 30 children with de-novo AML. Their ages ranged from 2.5 to 15 years, with 15 males and 15 females. All of them were treated using the DCTER chemotherapy protocol 20. Group 2 included 50 apparently healthy children matched by age and sex to the control group.
Almost half of the AML patients had fever, pallor, hepatosplenomegaly, and lymphadenopathy, whereas bleeding occurred only in one-third of the patients. The median and the age range were 3.6 (2.5–15). The median count of white blood cells was 41.1×109/l, and the blast percentages were 66.9%. The median of the platelet count (43×103/µl) was found to be lower than that of the control group, whereas the lactate dehydrogenase values (945 U/l) were higher than normal. Twenty seven AML cases expressed myeloid markers in immunophenotyping (MPO, CD33, CD13, CD64, and/or CD14) and three were mixed lineage (myeloid and B-lymphatic markers such as CD79a, CD19, and CD10).
Out of 30 AML patients, patients 15, nine, and six carried the OO (null), TO (heterozygous), and TT (normal) genotype, respectively. In the control group (50 children), five, 10, and 35 carried the OO, TO, and TT genotype, respectively.
The prevalence of the OO genotype was significantly higher in cases compared with the controls as shown in [Table 2]. [Table 3] shows that the decrease in the T allele is significantly prevalent in cases. The T allele was present in 15 AML patients, nine of them with a heterozygous genotype (TO) and six with a normal genotype (TT), whereas the O allele was present in 24 AML patients, nine of them with a heterozygous genotype (TO) and 15 with a null genotype (OO). In contrast, the T allele was present in 45 children of the control group, 10 of them with a heterozygous genotype (TO) and 35 with a normal genotype (TT), whereas the O allele was present in 15 children of the control group, 10 of them with a heterozygous genotype (TO) and five with a null genotype (OO).
[Table 4] shows that there is no difference between the three genotypes in terms of age, sex, and weight.
[Table 5] shows that five cases that failed to achieve remission carried the null genotype. Two patients with a heterozygous genotype failed to achieve remission. Six out of six patients with a normal genotype achieved complete remission. Only two patients died during the induction therapy; they carried the null genotype.
[Table 6] shows that the patients with the null genotype had the lowest median survival time compared with the other genotypes. Significantly higher number of cases who died within the first month carried the null genotype.
The relation between relapse and genotype showed no significant difference between the three genotypic groups in terms of the outcome of the patients (P=0.238), although 21.7% of cases who had a relapse had the OO genotype [Figure 1] and [Figure 2].
|Figure 1: No significant difference between the three genotypic groups in the outcome of the patients (P=0.1324).|
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|Figure 2: Agarose gel electrophoresis of genomic PCR for GSTT1 and β-globin. M, high-molecular-weight marker. Positive GSTT1 and β-globin alleles yielded 480 and 268 bp products, respectively, against DNA ladder 100 bp (100 bp for each band). The absence of the 480 bp band indicates the GSTT1 null genotype (OO) (lanes 3 and 5). Thick 480 bp bands indicate the normal GSTT1 genotype (TT) (lanes 1, 6, and 7) and the presence of a thin band of 480 bp indicates the heterogeneous GSTT1 genotype (TO) (lanes 2 and 4). GSTT1, glutathione S-transferase T1.|
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| Discussion|| |
DNA damage in the hematopoietic precursor cell is an essential prerequisite for the development of AML. Such damage may result from the interaction of reactive species generated by environmental or endogenous metabolites. Humans vary in their ability to metabolize such reactive intermediates, which may explain the differences in the risk of leukemia as a result of the interplay of genetic susceptibility and exogenous exposure 21.
In our study, we aimed to investigate whether the GSTT1 null genotype can be considered as a risk factor in childhood AML and to determine its importance in the prognosis of the disease.
In this study, we found that the frequencies of the GSTT1 null genotype were significantly higher in patients with AML (50%) than those in the controls (10%).
Our data can be explained by a possible accumulation of reactive intermediates in individuals with the deletion of GST, increasing the risk of DNA damage and contributing to leukemogenesis 22. Previous reports on GST-null genotypes as a risk factor for AML have yielded heterogeneous results.
An Egyptian study has shown an increased risk of acute leukemia in adult Egyptian patients who carried the GSTT1 null genotype, particularly in AML cases. A significantly increased incidence of the GSTT1 null genotype was found in the patient group compared with the controls [34 vs. 15% P=0.03, odds ratio (OR)=2.98, 95% confidence interval 1.6–7.6] 23.
Another Chinese study showed that no correlation between the GSTT1 null genotype and childhood ALL 24.
A Spanish study found a higher incidence of del(GSTT1) in patients with AML than among the controls (25.6 vs. 13.7%, OR=2.2, P<0.001) 25.
A study from Britain has reported an association between GSTT1 null and GSTM1 null genotypes and the risk of AML (OR=1.32 and 1.24, respectively) 2; in addition, an epidemiological study from Japan has shown that individuals with the GSTT1 null genotype are at a 2.4-fold higher risk of developing therapy-related AML and AML with trilineage dysplasia 26. Other studies have failed to confirm this association 27.
In contrast to our results, a study from the USA found an increased risk for AML in children with the GSTM1 null genotype whereas the frequency of the GSTT1 null genotype was not statistically different from the controls 28.
The reasons for these discrepancies are unclear. The discrepancies between the results published on the association of the risk of leukemia and gene polymorphisms could have resulted from the differences between the populations of patients studied (different ethnic groups), as polymorphic variants might be associated with some of the patients’ characteristics.
According to the literature, the incidence of the GSTT1 null genotype in normal populations is 10–20% in Caucasian and 16.8–25.7% in other ethnic groups 17. Also, our results showed a 10% incidence of the null genotype among the healthy controls.
In the present study, all patients received the same chemotherapy. After starting the induction phase, many patients achieved remission but others failed to do so. We found that all cases who failed to achieve remission carried the null GSTT1 genotype. In agreement with our results, an Italian study on adults with AML showed that AML patients with deletions of GSTM1 or GSTT1 or both had a lower probability of achieving a complete remission on induction therapy as compared with patients with intact GST genes. The reasons underlying this finding are unclear. The lack of detoxification of electrophilic, DNA-damaging agents may contribute to the accumulation of genetic changes in the process of leukemogenesis. In this situation, the absence of GST enzymes might simply reflect a biologically distinct, more aggressive disease 22.
An alternative mechanism to explain the impact of GST genotypes on the outcome could be the putative role of these enzymes in the metabolism of several cytotoxic drugs, such as anthracyclines, used in induction chemotherapy for patients with AML. GSTs contribute to detoxification either by direct conjugation of the drug with GSH, increasing its secretion through bile and urine, or by neutralization of reactive compounds induced by the cytotoxic drug 29. This detoxification can protect cells from the injuries of chemotherapy. Expression of GST-null enzymes has been linked to in-vitro and in-vivo chemoresistance of tumor and leukemic cells 30.
We found a lower chemotherapy response rate and, consequently, a worse outcome in patients with AML and at least one GST-null genotype. In agreement with our findings, Howells et al. 31 found that the GST-null genotype was associated with reduced responsiveness to chemotherapy, shorter progression-free interval, and poorer survival in patients with ovarian cancer.
The deficiency of GST enzymes may cause higher levels of GSH because of the reduced consumption of GSH in GST-catalyzed reactions. Accordingly, in addition to its role in detoxification, intracellular GSH has also been implicated in the control of cell proliferation and apoptosis. By increasing GSH levels, the proliferation of T lymphocytes could be enhanced and apoptosis may be inhibited 32. This concept has been supported by data from a recent report in which high intracellular GSH levels in lymphoid blasts were correlated with a greater risk of relapse and reduced overall survival in childhood ALL 30. Interestingly, in the same study, there was no relationship between GSH levels and in-vitro drug sensitivity.
In contrast to our results, the data obtained by Naoe et al. 33 showed that complete remission was not significantly different between GSTT1-negative and GSTT1-positive groups. The rate of death among patients in remission was similar for the two genotypes.
The absence of GSTT1 may reduce or delay the metabolism of the chemotherapy drugs used for AML and might be expected to lead to increased toxicity. It is possible that the GSTT1 genotype influences the production or the excretion of drug metabolites that contribute to toxicity to a greater degree than it influences metabolites that exert an antileukemic effect 24.
The substrate specificity of GSTT1 remains unclear, making it difficult to determine which drug’s metabolism might be influenced by the GSTT1 genotype. An interaction between the GSTT1 genotype and sensitivity to the environmental carcinogen benzene has been reported. Similarly, a number of reports have described increased sensitivity to the genotoxic effects of the agent diepoxybutane in GSTT1-null individuals 34.
Naoe et al. 33 reported that the GSTT1 null genotype was associated with a worse prognosis than the GSTT1 genotype mainly because of increased early death after initial chemotherapy.
Notably, the rate of early death was higher for the GSTT1-null genotype than the GSTT1 genotype. As the GSTT1 enzyme potentially metabolizes chemotherapeutic agents, both increased responsiveness and toxicity might be expected in the GSTT1 (null) group.
It is unknown whether the GSTT1 enzyme is actually involved in the metabolism of chemotherapeutic agents used in AML patients. According to the literature, carcinogens such as methyl chloride, monoepoxybutane, and diepoxybutane are substrates for GSTT1. Lymphocytes with the GSTT1-negative genotype acquire chromosomal aberrations more sensitively than the GSTT1-positive genotype when exposed to specific mutagenic substrates 35.
The significance of the GST enzyme may be different in each malignancy and therapy. It is unknown whether the GSTT1 enzyme is actually involved in the metabolism of chemotherapeutic agents such as DNR, AraC, and BHAC used in AML patients. According to the literature, carcinogens such as methyl chloride, monoepoxybutane, and diepoxybutane are substrates for GSTT1. Lymphocytes with the GSTT1-negative genotype acquire chromosomal aberrations more sensitively than the GSTT1-positive genotype when exposed to specific mutagenic substrates 36.
In our study, it was found that patients with the GSTT1-negative genotype had reduced survival compared with those who had at least one GSTT1 allele. Further analysis showed that the frequency of death in remission was increased in the GSTT1-null cases. Also, relapse was nonsignificantly decreased in the GSTT1-null cases compared with cases with the GSTT1 genotype.
Davies et al. 28 found that the frequency of relapse from the end of induction was similar in GSTT1-negative and GSTT1-positive cases (38 vs. 35%, log rank P<0.5). This is in agreement with Naoe et al. 33, who found that the rate of relapse in the GSTT1-negative and the GSTT1-positive group was similar.
The prognostic importance of the GST genotype was studied by Voso et al. 22, where the GST genotype was an independent predictor for overall survival. In particular, GST genotyping could discriminate between a favorable and an unfavorable prognosis in the cytogenetically defined intermediate-risk group, which included the majority of AML patients.
In our analysis of the potential association of GSTT1 genotypes with additional factors that might influence the outcome of therapy for AML, such as age, weight, and sex, we found no significant difference in the distribution of genotypes within any of these categories.
Davies et al. 28 found that the GSTM1 null genotype is a significant risk factor for childhood AML, particularly French–American–British groups M3 and M4. This may indicate an important role for exogenous carcinogens in the etiology of childhood AML.
In the present study, there was no significant difference between different genotypes in terms of sex distribution; our data do not agree with those obtained by Bolufer et al. 25, who proved that men with NQO1*2hom and del(GSTT1) polymorphisms showed a higher risk than women of developing AML. Thus, sex might influence the risk of AML associated with these genetic polymorphisms.
From the previous data, we can conclude that the GSTT1 null genotype is a significant risk factor for childhood AML. Moreover, children who lacked GSTT1 had greater toxicity, early deaths, and reduced survival after chemotherapy for AML compared with children with at least one GSTT1 allele. The GSTT1 genotype did not affect the rate of relapse.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]