Journal of Cancer Therapy, 2011, 2, 176-180
doi:10.4236/jct.2011.22022 Published Online June 2011 (http://www.SciRP.org/journal/jct)
Frequency of Bcr-Abl Fusion Oncogene Splice
Variants Associated with Chronic Myeloid
Leukemia (CML)
Zafar Iqbal1,2,3#, Fatima Manzoor1*, Mudassar Iqbal1,4, Shahid Ali5, Nadeem Sheikh6, Mahwish Khan1,3,
Aamer Aleem7, Tanveer Akhtar1
1Molecular Genetic Pathology (MGP) Unit, Department of Pathology, College of Medicine and King Khalid University Hospital,
King Saud University, Riyadh, Saudi Arabia; 2Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group,
Health Sciences Research Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab, Lahore,
Pakistan; 3Functional Molecular Biology/Hematology and Oncology Group, Centre for Research in Molecular Medicine and Institute
for Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan; 4Department of Medicine, Kyrgyz State
Medical Academy, Bishkek, Kyrgyzstan;5National Genetics Laboratory Lahore, Pakistan; 6Molecular Biology Laboratory, Depart-
ment of Zoology, University of the Punjab, Lahore, Pakistan; 7Division of Hematology and Oncology, Department of Medicine,
College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
Received April 9th, 2010; revised April 2nd, 2011; accepted April 15th, 2011.
ABSTRACT
BCR-ABL fusion oncogene originates from the reciprocal translocation of chromosome 9 and 22 t(9;22) (q34;q11). It
translates a chimeric protein, p210, characterized by constitutive activation of its tyrosine kinase, which triggers leu-
kemogenic pathways resulting in onset of chronic myeloid leukemia (CML). In CML, the classic fusion is b2a2 or b3a2
fusing exon 13 (b2) or exon 14 (b3) of BCR to exon 2 (a2) of ABL. The type of bcr/abl transcripts may be associated
with different prognosis and hence useful in therapeutic plan. This study was conducted to calculate the frequency of
these splice variants as the frequencies of different fusion oncogenes associated with leukaemia can vary in different
geographica l regions du e to interplay of genetic varia tion in different ethnic popu lation s, diverse environ men tal factors
and living style. A very sensitive nested RT-PCR wa s established to detect BCR-ABL splice variants in CML. Sensitivity
of RT-PCR assay was of the order of 10–6. Thirty CML patients were subjected to BCR-ABL analysis. Out of 30 Paki-
stani patients, 19 (64%) expressed b3a2 while 11 (36%) expressed b2a2 transcript. This shows that BCR-ABL splice
variants differ in their frequencies which may have an effect on biology and implications for prognosis and manage-
ment of BCR-ABL posi t i ve Le ukemias.
Keywords: BCR-ABL Positive Leukemia, Leukemia Cytogenetics , Philadelphia Chromosome, Chronic Myeloid
Leukemia, BCR-ABL Alternative Splicing, BCR-ABL Splice Variants, Leukemia Alternative Splicing,
Pharmacogenetics
1. Introduction
Cytogenetically chronic myeloid leukemia (CML) is
characterized by the presence of Philadelphia (Ph) chro-
mosome, the diagnostic hallmark of CML, which is pre-
sent in majority of CML patients. It originates from the
reciprocal translocation of chromosome 9 and 22 t(9;22)
(q34;q11) [1]. This reciprocal translocation gives rise to
BCR-ABL fusion oncogene, which translates a chimeric
protein, p210BCR-ABL that is characterized by constitu-
tive activation of its tyrosine kinase activity. In CML, the
classic fusion is b2a2 or b3a2 fusing exon 13 (b2) or
exon 14 (b3) of BCR to exon 2 (a2) of ABL [2,3]. Both
b3a2 and b2a2 transcripts can be formed as a result of
alternative splicing. These transcripts lead to the produc-
tion of an 8.5 kb transcript coding for a 210-KDa (p210)
chimeric protein [4,5]. This constitutively active cyto-
plasmic tyrosine kinase does not block differentiation,
but enhances proliferation and viability of myeloid line-
age cells and leads to development of CML [6].
*Authors contributed equally to this work and thus share first author-
ship.

Frequency of Bcr-Abl Fusion Oncogene Splice Variants Associated with Chronic Myeloid Leukemia (CML) 177
Genetic abnormalities lead to formation of fusion on-
cogenes and this phenomenon is driven by the environ-
mental factors and living style which differ in different
geographical regions, the frequencies of different fusion
oncogenes associated with leukaemia can vary in differ-
ent ethnic groups [7], which can have a significant effect
on the management and prognosis of this type of leuka-
emia [8,9]. This study was conducted to calculate the
frequency of BCR-ABL gene splice variants associated
with CML. RT-PCR (Reverse Transcriptase Polymerase
Chain Reaction) was chosen as the method of choice to
detect BCR-ABL gene as this technique is one of the
most sensitive methods for this purpose.
2. Materials and Methods
2.1. Sample Collection
Blood samples of 30 CML patients were collected from
different hospitals of Lahore. Clinical features of the pa-
tients are given in Table 1. Samples were collected in
EDTA vacutainer tubes as per manufacturer’s instruction
with patient number, age and time/date of collection
written on the tubes. Sample collection and processing
for analysis was always started within 24 hours to mini-
mize mRNA degradation [10]. All the samples were
stored at 20˚C. The procedure for isolation of RNA was
adapted from Chomczynski and Sacchi with slight modi-
fication [11,12].
2.2. RNA Extraction and cDNA Synthesis
Quantity of RNA was estimated spectrophotometrically
[13], while the quality of RNA was checked by native
Table 1. Clinical features of CML patients.
Characteristics Patient Number (n = 30)
Age (years) Mean = 35
Range = 12-70
Gender
Male
Female
21
9
Splenomegaly 26
Hemoglobin (< 10 g/dL) 16
WBC Count (/mm3)
50,000 - 100,000
> 100,000
5
25
Platelet Count (/mm3)
100,000 - 450,000
> 450,000
22
8
Mode of Diagnosis
Ph+
BCR-ABL+
30
30
agarose gel electrophoresis and formaldehyde denaturing
gel electrophoresis [14]. RNA was reverse-transcribed to
cDNA for using as template in PCR reaction. RT-reaction
protocol and other reaction conditions were adapted from
Van-Dongen [15]. Briefly, 10 µL of RNA was added to
10 µL of RT-reaction mixture containing 5X RT buffer
(20 mM Tris HCl, 50 mM KCl, pH 8.3, 10 mM DTT), 10
mM dNTPs, 10 mM random hexamer primers, RiboLockTM
RNase inhibitor (20 units), M-MuLV Reverse Transcrip-
tase (40 units) (Fermentas, USA) and DPCE-treated wa-
ter. Reaction was carried out by incubating at room tem-
perature for 10 min, 37˚C for 60 min, 99˚C for 3 min and
held at 4˚C in the last step in the PCR machine.
2.3. RT-PCR Amplifications
PCR primers and nested PCR protocols for the detection
of BCR-ABL fusion gene in CML patients were adopted
from Radich [16]. The sequences of primers are given in
Table 2.
The cDNA product was PCR amplified in two rounds
with 1 U/μL of Taq DNA Polymerase, 125 mM primers,
10x PCR buffer with KCl, 25 mM MgCl2 and 10 mM
dNTP Mix. Sterile water was used as negative control.
Thermal cycling conditions for nested PCR were: Pre-
liminary denaturation at 95˚C for 2 min followed by 35
cycles of denaturation of double stranded DNA at 95˚C
for 5 sec, annealing at 55˚C for 10 sec and extension at
72˚C for 15 sec, followed by a final extension at 72˚C for
3 minutes. Round 2 was carried out with the same condi-
tions. The PCR products were run on a 2% agarose gel
with ethidium bromide to analyze the size of the ampli-
cons.
3. Results
Primer combinations used in amplification allowed to
amplify both types of transcripts in a single reaction.
Quality of RNA was analyzed on formaldehyde gel elec-
trophoresis (Figure 1) and efficiency of cDNA synthesis
on agarose gel electrophoresis. Two types of PCR products
were detected as 305bp and 234bp for b3a2 and b2a2
respectively (Figure 2). The frequencies of both fusion
transcripts were found to be 63.33% and 36.66% for
b3a2 and b2a2 respectively. The sensitivity assay was
Table 2. Primers used for detec tion of fusion gene BCR- ABL
in CML by RT-PCR.
PCR
Round PrimerPrimer Sequence (5/-3/)
CML C5/-GAAGTGTTTCAGAAGClTCTCC-3/
1st RoundCML D5/- TGATTATAGCCTAAGACCCGGA-3/
CML A5/-TGGAGCTGCAGATGCTGACCAACTCG-3/
2nd RoundCML B5/-ATCTCCACTGGCCACAAAATCATACA-3/

Frequency of Bcr-Abl Fusion Oncogene Splice Variants Associated with Chronic Myeloid Leukemia (CML)
178
Figure 1. Formaldehyde gel showing bands of RNA from 3
different samples of CML patients.
Figure 2. 2% agarose gel containing Ethidium bromide
showing two types of characteristics BCR-ABL transcripts
b2a2 (1,4) and b3a2 (2,3,6) (234bp and 305bp respectively),
M: 50bp Ladder, NC: Negative Control.
also performed by generating 10-fold serial dilutions to
evaluate the sensitivity of RT-PCR for detection of these
fusion transcripts. Using these dilutions, detection limit
of the nested PCR was found upto 10–6 of cDNA for each
sample (Figure 3).
4. Discussion
RT-PCR is one of the most sensitive techniques to detect
BCR-ABL transcripts associated with CML [17]. Real
time quantitative PCR is increasingly used to assess
treatment response in patients with CML. When the level
of residual leukaemia falls below the level of detection
by bone marrow cytogenetic analysis, PCR based assays
like the real time quantitative PCR or nested reverse tran-
scriptase PCR are the methods of choice for further
monitoring [18]. In this study nested PCR was opted as
Figure 3. Amplification of BCR-ABL fusion transcript b3a2
(305 bp) from serial dilutions of cDNA (10–0 - 10–7) showing
a very good sensitivity of nested PCR for the detection of
this transcript. M; 50 bp ladder.
the method of choice due to its sensitivity to detect both
b3a2 and b2a2 fusion transcripts in a single reaction. In
the sensitivity assay of nested PCR, very high-quality
results were obtained and this technique showed sensi-
tivity upto 10–6.
In this study, the frequency of b3a2 and b2a2 was
found to be 63.33% and 36.66% respectively. The fre-
quency of b3a2 is two times higher than b2a2 with the
ratio of 2:1 in our population. The coexpression of tran-
scripts was not found in any of the patients. Spleen was
grossly enlarged in most of the patients and mildly
enlarged in some but without any correlation to transcript
type. Data has been published about the frequency of
different types of fusion oncogenes associated with acute
lymphocytic leukemia (ALL) in Pakistan [19]. The fre-
quency of BCR-ABL fusion oncogene in Pakistani child-
hood ALL patients was reported to be 49%, which is
higher as compared to other reports from around the
world [19]. Frequency of different fusion oncogenes in
Pakistani ALL patients is different from other geographic
regions [9]. The frequency of fusion oncogenes associ-
ated with different leukemia types was compared with
western populations and significant differences were
observed due to geographical, racial and ethnic differ-
ences [7]. In a study carried out by Verschraegen, the
frequencies of b2a2 and b3a2 transcripts were 30.2% and
67.9% respectively [20]. Reiter found the incidence of
b2a2 and b3a2 transcripts in CML patients to be 31.6%
and 68.4% respectively [21]. In Korean CML patients,
frequency of b2a2 and b3a2 was collectively found to be
98.18%, corresponding to 67.66% b3a2, and 32.34%
b2a2 transcripts [22] where the number of patients with
b3a2 was twice the number of patients with b2a2. Fre-
quencies of fusion transcripts in Iranian CML patients
were found to be 21% and 62% for b2a2 and b3a2 re-
spectively [23]. The frequency of b3a2 transcripts was
found to be almost three times higher than that of b2a2
[23].
Several authors have reported that CML patients with
b2a2 BCR-ABL splice variants have a better prognosis
and response to imatinib. De-Lemos et al. [24] reported
that statistically significant difference was found for the
levels of expression of transcripts b2a2 and b3a2 at six
months of imatinib treatment, which shows that b2a2
may have a better molecular response than b3a2. Verma
et al. [25] reported that rare variants like e1a2 have an
inferior response to imatinib. Sharma et al. [26] found
that 59% patients with b2a2 type achieved complete cy-
togenetic response (CGR) as compared to 28% patients
with b3a2 (p = 0.04) while in 24 patients with minor or
no CGR, 25% had b2a2 compared to 75% b3a2 type (p =
0.04). Moreover, expression of BCR-ABL/ABL% was
higher in b3a2 patients compared to b2a2 (p = 0.120).

Frequency of Bcr-Abl Fusion Oncogene Splice Variants Associated with Chronic Myeloid Leukemia (CML) 179
They also found that pre-treatment characteristics like
mean spleen size, mean hemoglobin, mean, and mean
platelets counts were not significantly different in the
b3a2 vs. b2a2 transcripts groups [26], which supports our
findings. These observations highlight the need for more
extensive studies in different ethnic groups on the role of
different BCR-ABL splice variants in biology [27] and
treatment response of the BCR-ABL positive leukemia
patients, as acquired BCR-ABL point mutations and
other factors associated with imatinib resistance do not
explain the reason of imatinib resistance in all BCR-ABL
positive patients [28-30]. Studies related to the differ-
rences in clinical features and response to treatment in
CML and philadelphia positive acute leukemia patients
are specially required with the advent and FDA approval
of other tyrosine kinase inhibitors (TKIs) like nilotinib
and dasatinib for front-line treatment of BCR-ABL posi-
tive CML and ALL.
In conclusion, frequencies of BCR-ABL splice vari-
ants can vary in different geographical regions due to
interplay of natural genetic variations in different ethnic
populations, diverse environmental factors and living
style. Moreover, the knowledge about the rate of occur-
rence of these transcripts associated with CML can be of
very significance as it can lend a hand to further under-
stand the pathobiology of t(9;22)-positive leukemic cells.
Moreover, it will also assist in prognosis, treatment and
management of these CML transcripts types.
5. Acknowledgements
This work was partially supported by the College of
Medicine Research Center, Deanship of Scientific Re-
search, King Saud University, Riyadh, Saudi Arabia,
Research funding provided by Higher Education Com-
mission Pakistan is also acknowledged.
6. Conflict of Interest Statement
The authors have no potential conflict of interest.
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