Association of MDR1 gene polymorphism

(G2677T) with imatinib response in Egyptian

chronic myeloid leukemia patients
Doaa M. Elghannam 1, Lamia Ibrahim1 , Mohamed A. Ebrahim1, Emad Azmy 2,3,
Hazem Hakem 4
1

Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Egypt, 2Medical Oncology,
Faculty of Medicine, Mansoura University, Egypt, 3Department of Clinical Hematology, Faculty of Medicine,
Mansoura University, Egypt, 4Internal Medicine, Faculty of Medicine, Mansoura University, Egypt
Background: Despite the excellent efficacy results of imatinib treatment in CML patients, resistance to
imatinib has emerged as a significant problem. Genetic variations in genes involved in drug transportation
might influence the pharmacokinetic and metabolism of imatinib. The genotype of a patient is increasingly
recognized in influencing the response to the treatment.
Aim: To investigate the genotype frequencies of single nucleotide polymorphisms (SNPs) G2677T in CML
patients undergoing imatinib treatment to determine whether different genotype pattern of these SNPs
have any influence in mediating response to imatinib.
Methods: A total of 96 CML and 90 control samples were analyzed for the human multidrug resistance gene 1
(MDR1) gene polymorphism (G2677T) using polymerase chain reaction-restriction fragment length
polymorphism technique.
Results: Genotype distribution revealed a significant lower frequency of TT genotype in CML patients and
non-significant difference in the GG, GT genotype frequencies between patients and controls (P = 0.004,
0.138, 0.210, respectively). GG genotype was significantly higher in chronic phase (P = 0.046), while GT
genotype was significantly higher in Blastic crisis phase (P = 0.002). There was a significant difference in
genotype frequency of G2677T among patients showing response and resistance to imatinib in chronic
phase (P = 0.02). TT genotype was associated with complete hematological response (P = 0.01),
complete cytogenetic response (P < 0.001), and better molecular response with a significant association
(P < 0.001). GT genotype was associated with partial hematological response (P = 0.01) and minor
cytogenetic response (P < 0.001). Optimal and suboptimal responses were observed for patients with
TT genotype (P = 0.003). Failure of drug response was associated with GT genotype (P = 0.02); however,
GG had no association with drug response. Multivariate analysis considered GT genotype as independent
risk factor for resistance (P = 0.037), while TT genotype as protective factor against resistance to imatinib
(P = 0.008).
Conclusion: Determination of MDR1 polymorphisms (G2677T) might be useful in response prediction to
therapy with imatinib in patients with CML.
Keywords: Chronic myeloid leukemia, Imatinib, MDR1 gene, Polymorphism

Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that comprises 14% of all leukemias.
Imatinib-mysylate, also known as Glivec or Gleevec,
is frontline therapy for Philadelphia positive (Ph+)
CML.1 It specially targets tyrosine kinase domain
of the BCR-ABL fusion protein, and blocks its phosphorylation, which is needed for kinase activation
Correspondence to: Departments of Clinical Pathology, Faculty of
Medicine, Mansoura University, 35511, Egypt.
Email: doaamahmoud1970@yahoo.com.

W. S. Maney & Son Ltd 2014

DOI 10.1179/1607845413Y.0000000102

and signal transduction.2 The treatment of CML

patients with imatinib has resulted in complete cytogenetic response (CCR) rates of 6585%.3 Despite of its
striking efficacy, however, resistance develops over
time in many patients. Resistance is more common
in patients who start imatinib in late chronic phase
and occurs in approximately 70% of patients treated
in myeloid blast crisis and in >90% of those in lymphoid blast crisis.2 Several molecular mechanisms
leading to imatinib resistance have been proposed;
amplification and overexpression of the BCR/ABL

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Association of MDR1 G2677T with imatinib response in Egyptian CML patients

gene, point mutations in the ATP-binding site with

kinase reactivation,4 or overexpression of the MDR1
gene.5 The human multidrug resistance gene
(MDR1, ABCB1) is located on the long arm of
seventh chromosome at q21.1 and consists of 28
exons,6 encodes for P-glycoprotein (P-gp) of 170KD,
an ATP-binding cassette transmembrane transporter.7
P-gp is well known to be overexpressed in human
tumor cells after cancer chemotherapy where it is associated with multidtug resistance and affect the pharmacokinetics of many drugs that are P-glycoprotein
substrates.8 Imatinib is a substrate of P-gp-mediated
efflux. The up-regulation of drug transporters
(ABCB1) is one of specific causes of imatinib resistance, since it can be effluxed through MDR1 transporters,9 resulting in enhanced clearance of drug from the
cell, reduced drug availability and drug resistance.2
MDR1 gene is polymorphic, and more than 1279
single nucleotide polymorphisms (SNPs) have been
identified.10 SNPs have the potential to affect the
expression and function of the P-gp,11,12 could also
influence the efficiency of absorption or elimination
of imatinib and could explain at least in part variable
responses to this drug.9,13 G2677T, is the most
common variants in the coding region of ABCB1.11
The G2677T polymorphism was significantly associated with increased or decreased plasma concentration
of P-gp substrates.14,15 Previous reports showed that
individuals who had the 2677 TT genotype had
lower P-gp messenger RNA expression than those
who had 2677 GG genotype.16 On the contrary,
some pharmacokinetic studies reported an opposite
effect of the 2677T mutant allele, i.e. an increase in
transport activity compared with that of 2677G
allele,17 whereas Tanabe et al. 18 reported a non-significant opposite trend for P-gp expression in placenta in
relation to the G2677T polymorphism. These contradictions might be due to the presence of different
amino acids at position 893, which might have different effects on different drugs. Identifying influential
SNPs may allow to predict the drug disposition,
response to imatinib, and may be helpful in dose
adjustments of imatinib, which should be effective in
case of imatinib resistant individuals.9,19

Patients and methods

Patients

A total of 96 Ph+ CML patients admitted to

Mansoura Oncology Center (OCMU) during 2012
were eligible in our study. They were treated regularly
with (400600 mg)imatinib. Sixty-six (68.75%) patients were in chronic phase, 18 (18.75%) in accelerated
phase, and 12 (12.5%) patients in blastic crises. They
were 54 (56.25%) males and 42 (43.75%) females
with mean age of 44.44 12.37 years. In addition,
90 healthy subjects with matched age and sex

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without history of cancer were randomly selected as

a control group. A written informed consent was
obtained from all subjects prior to their enrollment
in this study.
Chronic-phase CML was defined by the presence of
less than 10% blasts, less than 20% basophils, and less
than 30% blasts plus promyelocytes in peripheral
blood or bone marrow and a platelet count of at
least 100 000/cmm, with no extramedullary involvement. Accelerated phase was characterized by a
proportion of blasts of 1030%, or blasts and
promyelocytes < 30%, basophils > 20%, platelets
>100 109/l unrelated to therapy, or chromosomal
abnormalities other than the Philadelphia chromosome, or progressive splenomegaly. Blast crisis was
defined as the presence of >30% blasts in peripheral
blood or bone marrow or as evidence for an extramedullary blast infiltration (except liver, spleen, or lymph
nodes).3
The evaluation of the response is based on blood
counts and differential (hematologic response, HR),
on the examination of marrow cell metaphases
(cytogenetic response, CgR) and on a quantitative
assessment of BCR-ABL transcripts level (molecular
response, MolR).20 HR was defined as normalized
peripheral blood cell counts (WBC <10 109/l and
platelet count <450 109/l) without evidence of peripheral blasts, promyelocytes, or myelocytes, and
without evidence of extramedullary disease including
disappearance of palpable splenomegaly lasting for
at least 4 weeks. Cytogenetic responses were categorized as complete (CCyR; 0% Ph+ cells in marrow
by conventional cytogenetics or fluorescence in situ
hybridization), partial (135% Ph+ cells in marrow),
minor (3665% Ph+ cells in marrow), minimal
(6695% Ph+ cells in marrow), and none (>95% Ph+
cells in marrow). A major cytogenetic response was
defined as the sum of CCyR and partial cytogenetic
response (035% Ph+ cells in marrow). Complete molecular response was defined by non-detectable, nonquantifiable BCR/ABL mRNA. Major MolR was
defined as ratio of BCR-ABL to ABL (or other housekeeping genes) 0.1% on the international scale.20,21
An optimal response to imatinib is defined by complete HR and at least minimal CgR (Ph+ <95%) at
3 months, at least partial CgR (Ph+ <35%) at
6 months, complete CgR at 12 months and major
MolR (BCR-ABL: ABL 0.1%) at 18 months.
Failure is defined by incomplete HR at 3 months, no
CgR (Ph+ > 95%) at 6 months, less than partial CgR
(Ph+ > 35%) at 12 months, less than complete CgR
at 18 months and loss of a complete HR or a complete
CgR. In any other situation, the response is defined
suboptimal.20
Patients were regularly monitored on an outpatient
basis; biweekly physical examinations, blood counts,

Elghannam et al.

Association of MDR1 G2677T with imatinib response in Egyptian CML patients

and biochemistry were obtained during the first month

of imatinib therapy and then monthly until a cytogenetic response was achieved, and then every 3
months thereafter until a CCR was confirmed, bone
marrow evaluation was performed every 3 months.

Methods
Cytogenetic analysis
Pretreatment cytogenetic analyses of bone marrow or
peripheral blood for Philadelphia chromosome was
done; metaphase chromosomes were banded by
G-banding technique and Karyotyped according to
the International System for Human Cytogenetic
Nomenclature. A minimum of 20 metaphases was
required to be examined for a patient to be classified
as having normal cytogenetics.22

Real-time quantitative polymerase chain

reaction
To assess molecular responses, total RNA was
extracted from peripheral or bone marrow blood
cells. BCR-ABL and internal control transcript levels
were quantified using real-time polymerase chain reaction (PCR) analysis (TaqMan) on an ABI prism 7000
sequence detection system (Applied Biosystems, Foster
City, CA, USA). Specific PCR products were amplified and detected using dual-fluorescent non-extendable probes labeled with 6-carboxy-fluorescein
(FAM), reporter and 6-carboxytetramethylrhodamine
(TAMRA), quencher at 5 -end and 3 -end, respectively. The relative mRNA expression of BCR-ABL
transcript was calculated using the comparative cycle
threshold (Ct) method.23

Analysis of G2677T polymorphism

DNA from the peripheral blood of the study subjects
were extracted using QIAamp DNA blood mini kit
(Qiagen, Hilden, Germany) following the manufacturers protocol. The G2677T polymorphism was analyzed using a set of primers F5 -TGC AGG CTATAG
GTT CCA GG-3 and R5 -TTT AGTTTG ACT CAC
CTT CCC G-3 to amplify 224-bp fragment. PCRs
were performed in a final volume of 25 l with
0.5 M of each of the primers (Sigma-Aldrich, St
Louis, MO, USA), 400 M of each dNTPs, 10 mM
Tris-HCL, 1.5 mM MgCl2, 50 mM KCl ( pH 8.3),
and 1 U Taq polymerase (Roche Diagnostics,
Mannheim, Germany). PCR amplification consisted

Figure 1 Electrophoretic pattern for MDR1 (G2677T)

polymorphism by polymerase chain reaction-restriction
fragment length polymorphism. Lane 150 bp ladder; lanes 2,
3, 4, 5, 8, 9, 11, 13-GG (198 bp); lanes 6, 7, 12-GT (198, 224 bp);
lane 10-TT (224 bp).

of an initial denaturation for 5 minutes at 95C followed by 40 cycles of denaturation at 95C for 30
seconds, annealing at 56C for 30 seconds, and extension at 72C for 1 minute. The terminal elongation was
performed at 72C for 20 minutes. The amplified PCR
products were digestedwith Ban I restriction enzyme
(New England, Biolabs) for 1 hour at 37C. After
digestion, the products were electrophoresed on a 2%
agarose gel for genotyping. 2677G allele creates site
for Ban I enzyme and produces two fragments of
198 and 26 bp whereas 2677T allele was identified by
single fragment of 224 bp (Fig. 1).

Statistical analysis
All the statistical analyses were performed with
Statistical Package for the Social Sciences (SPSS)
16.0. Mean (SD) values were used for quantitative
data, numbers and percentages were used for qualitative data. Chi-square test was calculated to test the significance of qualitative variables. One-way analysis of
variance test were calculated to test for quantitative
variables. Multivariate analysis was performed by
unconditional logistic regression analysis. The risk
associated with a genetic variant was expressed as
odds ratio (with a 95% confidence interval). All the
P values were two-sided and the level of significance
was taken as P < 0.05.

Results
This study comprised 96 CML patients and 90 control
subjects. The overall frequencies of the MDR-1 2677
GG, GT, TT, genotypes were 34.4, 46.9, and 18.8%,
respectively. There was no significant difference in
the GG, GT genotype frequencies, and a significant
lower frequency of TT genotype between patients
and controls (P = 0.13, 0.21, 0.004, respectively)
(Table 1). No significant association of G2677T

Table 1 Distribution of MDR1 G2677T polymorphism in CML patients and control

Genotype

Cases
Control
P value

P value

Total

GG

GT

TT

96 (100%)
90 (100%)

33 (34.4%)
22 (24.4%)
0.138

45 (46.9%)
34 (37.8%)
0.210

18 (18.8%)
34 (37.8%)
0.004

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Table 2

Association of MDR1 G2677T with imatinib response in Egyptian CML patients

Patients characteristics according to MDR G2677T polymorphisms

Genotype

Age (years)
P
Males
Females
P
Chronic
Accelerated
Blastic
Blastic/Accelerated
P*
Complete
Partial
P
Complete
Partial
Minor
Minimal+ None
P
Complete
Major
Not achieved
P#

Sex

Phases

Hematological response

Cytogenetic response

Molecular response

Total
n = 96

GG
n = 33

GT
n = 45

TT
n = 18

44.44 12.37

41.64 13.96

45.53 11.145
0.259
24 (44.4%)
21 (50.0%)
0.556
24 (36.4%)
9 (50.0%)
12 (100.0%)
23 (76.7)
0.002
16 (35.6%)
29 (64.4%)
0.010
16 (35.6%)
10 (22.2%)
14 (31.1%)
5 (11.1%)
<0.001
8 (17.8%)
3 (6.7%)
34 (75.6%)
<0.001

46.83 11.947

54 (100%)
42 (100%)

21 (38.9%)
12 (28.6%)

66 (68.8%)
18 (18.8%)
12 (12.5%)
30 (31.3%)
47 (49.0%)
49 (51.0%)

27 (40.9%)
6 (33.3%)
0 (0%)
6 (20.0)
0.046
17 (51.5%)
16 (48.5%)

44 (45.8%)
17 (17.7%)
17 (17.7%)
18 (18.8%)

15 (45.5%)
4 (12.1%)
1 (3.0%)
13 (39.4%)

25 (26.0%)
18 (18.75%)
53 (55.2)

9 (27.3%)
7 (21.2%)
17 (51.5%)

9 (16.7%)
9 (21.4%)
15 (22.7%)
3 (16.7%)
0 (0%)
3 (10.0)
0.168
14 (77.8%)
4 (22.2%)
13 (72.2%)
3 (16.7%)
2 (11.1%)
0 (0%)
8 (44.4%)
8 (44.4%)
2 (11.1%)

P *, Significance between combined blastic/accelerated phases and chronic phase.

P#, Significance between combined complete and major molecular response versus molecular response not achieved.

polymorphism was observed with respect to age and

sex (P = 0.25, 0.55). When the association of G2677T
polymorphisms with clinical phase was considered,
GG genotype was significantly higher in chronic
phase (27; 40.9%) compared to accelerated/blast
crisis (6; 20%) (P = 0.046). Hetrozygous GT genotype
was more frequent in blastic crisis (12; 100%) than
other phases (P = 0.002). With respect to drug response
status, complete hematological response was achieved
in 49% of all cases, with significant association with
TT genotype (77.8%), while partial hematological response was achieved in 51% of all cases, with significant
association with GT genotype (64.4%) (P = 0.010).
Cytogenetic response varied significantly between
GG, GT, and TT genotypes (P < 0.001). CCR was
achieved in 45.8% of all cases, with significantly
higher incidence of TT genotype (72.2%), minor cytogenetic response was achieved in 17.7% of all cases
with higher incidence of GT genotype (31.1%).
Molecular response was achieved completely in
26%. A better molecular response was observed for
patients with TT genotype with a significant association (P < 0.001) (Table 2).

Table 3

Out of 96 CML patients, 50 (52.1%) were responsive

(36 in chronic phase and 14 in accelerated/blast crisis)
and 46 (47.9%) were resistant (30 in chronic phase and
16 in accelerated/blast crisis) to imatinib with a significant difference in the distribution of G2677T genotypes among sensitive and resistance groups in
chronic phase (P = 0.002) (Table 3), where TT genotype was associated with optimal and suboptimal
response to imatinib (P = 0.003), meanwhile GT was
associated with response failure to imatinib (60%;
P = 0.026). GG had no association with drug response
(P = 0.93) (Table 4).
The relationship between G2677T polymorphism
and risk of imatinib resistance in CML patients was
assessed by means of multivariate analysis that considered GT genotype as independent risk factor for
resistance (P = 0.037, odds ratio, OR: 2.519, 95% confidence interval, CI: 1.0595.990), meanwhile TT
genotype as protective factor against resistance to
imatinib (P = 0.008, OR: 0.166, 95% CI: 0.044
0.627). However, accelerated/blastic phases were not
predictors for imatinib resistance (P = 0.777, OR:
1.139, 95% CI: 0.4622.811).

Response to Imatinib according to MDR G2677T polymorphisms various in CML phases

Chronic phase (n = 66)
Response (n = 36)

Resistance (n = 30)

Response (n = 14)

Resistance (n = 16)

16 (44.4%)
7 (19.4%)
13 (36.1%)

11 (36.7%)
17 (56.7%)
2 (6.7%)

0.002

1 (7.1%)
11 (78.6%)
2 (14.3%)

5 (31.3%)
10 (62.5%)
1 (6.3%)

0.231

GG (n = 33)
GT (n = 45)
TT (n = 18)

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Table 4 Response to imatinib according to MDR G2677T polymorphisms

Genotype
Response to Imatinib
Optimal (n = 27)
Suboptimal (n = 23)
Optimal + suboptimal (n = 50)
Failure (n = 46)
P
P*
OR* (95% CI)

GG
n = 33

GT
n = 45

TT
n = 18

9 (27.3%)
8 (24.2%)
17 (51.5%)
16 (48.5%)
0.991
0.936
1.035 (0.4462.405)

10 (22.2%)
8 (17.8%)
18 (40.0%)
27 (60.0%)
0.083
0.026
2.526 (1.1095.755)

8 (44.4%)
7 (38.9%)
15 (83.3%)
3 (16.7%)
0.013
0.003
0.163 (0.0030.608)

P, Significance between optimal, suboptimal, and failure for each genotype.

P*,Significance between response (combined optimal, suboptimal) versus failure for each genotype.
OR*, Odds ratio for response (combined optimal, suboptimal) and failure for each genotype.

Discussion
It is well known that different patients may respond
differently to the same drug. The MDR1 polymorphisms might alter P-gp expression and activity toward
specific anticancer agents, thereby influencing their
therapeutic efficacy; the functional consequences of
the changes at positions 2677 is still controversial.24
The SNP G2677T in exon 21 (893 codon) results
in the substitution of alanine to serine/threonine
in such a manner that the lipophilic residue (Ala)
is changed to hydrophilic residue (Ser, Thr) conferring higher resistance to various drugs such as
adriamycin and vinblastine.25,26 The frequency of
G2677Tgenotypes in this study was similar to that previously reported by Dulucq et al.,19 and dissimilar to
Ni et al.,27 and Sailaja et al. 2 Interethnic differences
in the frequencies of several SNPs have been reported.
In particular, G2677T SNPs have been found to differ
significantly among different ethnic groups.24 GG
genotype was significantly higher in chronic phase.
While GT was higher in blast crisis, likewise reported
by Sailaja et al. 2, who reported that heterozygous
2677GT genotype frequency was increased in blast
crisis compared to other phases. GT genotype frequency was associated with partial hematological
and minor cytogenetic response, while the frequency
of GG genotype was elevated in minimal cytogenetic
response in consistent with Sailaja et al. 2 TT genotype
was associated with CCR. However Ni et al. 27
reported a better CCR with GT genotype. A better
molecular response was observed for patients with
TT genotype with a significant association. Dulucq
et al. 19 reported a better major molecular response
(MMR) for patients with TT genotype. Another
study conducted by Kim et al. 28, on CML patients,
did not find an association between G2677T polymorphism and MMR. We observed a significant
difference in the distribution of G2677T genotypes
among sensitive and resistance groups in chronic
phase likewise reported by Ni et al. 27 TT was significantly associated optimal and suboptimal imatinib

response that also confirmed by multivariate analysis.

However, the study of Gurney et al. 9, showed that
patients with 2677T homozygotes had higher estimated imatinib clearance compared with other genotypes. Another study on AML patients reported that
2677T allele was associated significantly with shorter
relapse time and survival rates compared to heterozygotes.29 In some other studies, haplotype of 2677TT
and 3435TT was associated with highest risk of drug
resistance in lymphoproliferative diseases.30 These
results are surprising in light of impressive report
demonstrating an association between decreased Pgp mRNA and 2677T allele.16 Failure of imatinib
response was significantly higher with GT genotype
that considered as independent risk factor for imatinib
resistance by multivariate analysis. This may indicates
that 2677 G allele carriers might be at risk for drug
resistance. In consistent with our results, Dulucq
et al. 19 reported that the G allele at 2677 position
was significantly associated with worse response in
CML patients who were on imatinib therapy. The G
allele was reported to have enhanced P-gp expression
and was observed to be associated with increased
efflux of P-gp substrates. Since imatinib is one of the
P-gp substrate, hence G allele was associated with
poor response to imatinib in CML patients.2 In line
with previous data, studies on G2677T polymorphism have yielded contradictory results, possibly due
to small sample sizes and the different ethnic
groups.24,31 In conclusion, the results of our study
demonstrated a significant association of the SNPs
polymorphisms with imatinib efficacy. Hence, genotyping of MDR1 gene polymorphism (G2677T)
might be helpful in planning the individualized
therapy based on the genotype. Further genotype
analysis of other ABCB1 polymorphisms in patients
treated with imatinib may be used as a basis for
studies on the relationship between ABCB1 genotypes and drug efficacy and may provide some
insight into who is likely to respond optimally to
imatinib.

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