|Year : 2012 | Volume
| Issue : 4 | Page : 228-233
Detection of insulin-like growth factor type I receptor in adulthood acute lymphoblastic leukemia by a real-time polymerase chain reaction
Hebatallah Adel Sedky, Dina Adel Fouad, Deena Mohamed Mohamed Habashy, Nisreen Atef Abdel Ghaffar
Clinical Pathology Department, Hematology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||10-Jun-2012|
|Date of Acceptance||28-Jul-2012|
|Date of Web Publication||21-Jun-2014|
Deena Mohamed Mohamed Habashy
MD, Clinical Pathology Department, Hematology Unit, Faculty of Medicine, Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
Insulin-like growth factor I receptor (IGF-IR) is currently the focus of intensive research aimed at developing novel antitumor agents. It plays a documented novel role in the regulation of the MDM2/p53/p21 signaling pathway during DNA damage. The IGF system plays a critical role in tumor pathogenesis, progression, protection from apoptosis, and metastasis.
To detect the expression of IGF-IR in adult patients with acute lymphoblastic leukemia (ALL) in comparison with healthy controls, and to examine its prognostic impact on patients’ outcome, and its possible association with the known standard prognostic factors for ALL.
Participants and methods
Real-time polymerase chain reaction was applied to assess the expression of IGF-IR in 30 newly diagnosed adult patients with ALL and in 10 age-matched healthy controls.
The cycle threshold of IGF-IR expression in the patient group ranged from 20.21 to 30.18 (24.82±3.38), whereas it ranged from 30.21 to 37.98 (34.74±2.94) in the control group. The IGF-IR expression level in patients was statistically significantly higher (P=0.000) than those of the control group. Statistical analysis of IGF-IR expression in relation to standard prognostic factors and patient outcome showed no significance (P>0.05).
IGF-IR is significantly overexpressed in adult patients with ALL at diagnosis, indicating its possible role in pathogenesis. However, it is not valid as a prognostic marker in ALL. There was no significant association of IGF-IR with patient outcome. Considering its role in leukemogenesis, new therapeutic strategies directed against IGF-IR may be beneficial in arresting malignant cell proliferation and survival and blocking the progression of disease.
Keywords: acute lymphoblastic leukemia, insulin-like growth factor type I receptor, prognosis
|How to cite this article:|
Sedky HA, Fouad DA, Habashy DM, Abdel Ghaffar NA. Detection of insulin-like growth factor type I receptor in adulthood acute lymphoblastic leukemia by a real-time polymerase chain reaction. Egypt J Haematol 2012;37:228-33
|How to cite this URL:|
Sedky HA, Fouad DA, Habashy DM, Abdel Ghaffar NA. Detection of insulin-like growth factor type I receptor in adulthood acute lymphoblastic leukemia by a real-time polymerase chain reaction. Egypt J Haematol [serial online] 2012 [cited 2020 Apr 10];37:228-33. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/228/134969
| Introduction|| |
The insulin-like growth factor (IGF) pathway plays a critical role in acute lymphoblastic leukemia (ALL) pathogenesis, survival, and resistance to anticancer therapies 1. The Insulin-like growth factor type I receptor (IGF-IR) is the target of several investigational agents in clinical and preclinical development. Many reviews have focused on the rationale for targeting the IGF-IR and other components of the IGF-I system. In addition, others have examined the role of IGF-I signaling in resistance to clinically important cancer therapies 2.
The IGF-IR is a transmembrane heterotetramer that consists of two α and two β subunits. There is approximately 60% sequence homology between the IGF-IR and the insulin receptor 3. The IGF-IR, similar to the insulin receptor, possesses tyrosine kinase activity. It was linked to the RAS-RAF-MAPK and PI3K-PKB/AKT signal transduction cascades 2. IGF-IR was detected on human erythrocytes as well as monocytes, B lymphocytes, and a marginal number of T lymphocytes, playing an important role in the proliferation and differentiation of both normal and malignant hematopoietic cells 4. IGF-IR overexpression is recognized as a major promoter of tumor proliferation, progression, and blocking apoptosis 2.
The IGF-IR is a transmembrane tyrosine kinase that is known to functionally oppose apoptosis. It plays a documented novel role in the regulation of the MDM2/p53/p21 signaling pathway during DNA damage. Tumor suppressor gene p53 is a nuclear transcription factor that can block progression of the cell cycle, modulate DNA repair, and trigger apoptosis. IGF-I induces the exclusion of the p53 protein from the nucleus and leads to its degradation in the cytoplasm, and associated with an increase in MDM2, an upstream modulator of the half-life and activity of the p53 protein, and downregulation of p21 5.
The aim of the present work was to detect the expression of IGF-IR in adult patients with ALL in comparison with healthy controls, and to examine its prognostic impact on patients’ outcome, and its possible association with the known standard prognostic factors for ALL.
| Participants and methods|| |
This study was carried out on 30 newly diagnosed adult patients with ALL attending the Hematology Oncology Unit of Ain Shams University Hospitals. They ranged in age from 18 to 51 years, mean age 23.1±12.29 years. They were 18 men and 12 women, with a male to female ratio of 1.5 : 1. Immunophenotypic analysis classified them as follows: 22 (73.4%) B-cell precursor ALL, one (3.3%) mature B, and seven (23.3%) T-ALL. Ten healthy age- and sex-matched individuals were studied as controls. They ranged in age from 18 to 24 years, mean age 20.9±2.0 years. They were five men and five women, with a male to female ratio 1 : 1. Follow-up of patients was carried out for 12 months to detect the outcome of the disease. All participants were informed about the objectives and procedures of the study and provided written consent.
| Methods|| |
Two milliliters of peripheral blood (PB) was obtained on potassium EDTA for a complete blood count (CBC) and RNA extraction, amplification, and detection of IGF-IR expression by real-time polymerase chain reaction (PCR) (for both the patient group and the control group). Two milliliters of bone marrow (BM) aspirate was collected, 1 ml on sterile potassium EDTA for immunophenotyping. The remaining 1 ml of BM aspirate was collected in a sterile preservative-free heparin-coated vacutainer tube used for karyotyping.
Real-time polymerase chain reaction by TaqMan probes
TaqMan probes are linear oligonucleotides that are labeled with a reporter on the 5′-end and a quencher on the 3′-end [Figure 1]. When the reporter and quencher dyes are in close proximity in solution, the reporter signal is quenched. The efficiency of the quench is determined by the probe sequence, which in turn determines how efficiently the ends of the probe associate in solution. When the probe anneals to its complementary target sequence, the two dyes are maximally separated and the reporter signal is detected by the instrument 6.
Primer and probe design
TaqMan gene expression assay: Two unlabeled primers were used for amplifying the sequence of interest (IGF-IR) (final concentration of 900 nmol/l each) [Table 1].
The TaqMan minor groove binder (MGB) probes contain a reporter dye (6-FAM) linked to the 5′-end of the probe, a MGB, PCR master mix, and DNA polymerase.
Total RNA extraction
The RNA extraction was carried out on Magna pure (Roche Applied Science, Basel, Switzerland) according to the manufacturer’s instructions 8.
The synthesis of cDNA from total RNA samples is the first step in using TaqMan gene expression assays. Applied Biosystems recommends using the High-Capacity cDNA Archive Kit to obtain cDNA from total RNA samples.
Performing polymerase chain reaction amplification
Target amplification, using cDNA as the template, is the second step in using TaqMan gene expression assays. In this step, the DNA polymerase [from the TaqMan Universal PCR Master Mix (2×) or the TaqMan Fast Universal PCR Master Mix (2×), No AmpErase UNG] amplifies target cDNA synthesized from the RNA sample, using sequence-specific primers and a TaqMan MGB probe (6-FAM dye-labeled) from the TaqMan gene expression assay mix. The PCR reaction mix for each sample is shown in [Table 2].
Interpretation of results
The cDNA amount for IGF-IR in the target cDNA sample was calculated from the standard curve and the specific primer sets. To correct for both the quality and the quantity of RNA, cDNA amount values were adjusted with the reference gene glucose-6 phosphate dehydrogenase. Values between 30.18 and 30.22 cycle threshold (CT) represent the best cutoff between the control and the cases.
IBM SPSS statistics (V. 20.0, IBM Corp., Chicago, Illinois, USA, 2011) were used for data analysis. Data were expressed as mean±SD and range or as number (%) of cases. Comparison of proportions and means between two groups was carried out using the Student t-test. Comparison between more than two patient groups for parametric data was carried out using the analysis of variance test (F). Correlations between variables were determined using the ranked Spearman correlation test (r). The level P<0.05 was considered the cut-off value for significance.
| Results|| |
Real-time PCR analysis for the detection of IGF-IR expression was carried out successfully on 40 PB samples (30 patients and 10 controls). The CT of IGF-IR expression in the patient group ranged from 20.21 to 30.18 (24.82±3.38), whereas it ranged from 30.21 to 37.98 (34.74±2.94) in the control group. The difference between the patients and the controls in IGF-IR expression was highly statistically significant (P=0.000) [Table 3], [Figure 2]. No relation was found between IGF-IR expression and standard prognostic factors or outcome (P>0.05) [Table 4] and [Table 5].
|Table 3: Comparative study of IGF-IR expression between the patient group and the control group|
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|Table 4: Correlation between IGF-IR expression and age, laboratory parameters in patients with ALL|
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|Table 5: Relation between IGF-IR expression with standard prognostic markers and patients’ outcome in patients with ALL|
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Comparison of patients with a favorable prognosis with those with a poor prognosis showed a significant difference in age (P=0.01) as patients older than 30 years had poorer outcome. Total leukocytic count greater than 50×103/µl had a worse prognosis (P=0.03). CD33 expression was related to a poor outcome (P=0.01). A highly significant difference in PB blasts%, CD34 expression, and karyotyping was found between the two groups (P=0.004, 0.008, and 0.000, respectively). PB blast% greater than 19 and positivity of CD34 were higher in patients with a poor outcome. As for karyotypic analysis, the presence of t(9;22), t(8;14), t(1;19), del17p, and del(9p21) was associated with a poor prognosis [Table 6].
|Table 6: Comparison between patients with a good and a poor prognosis in standard prognostic parameters|
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| Discussion|| |
The IGF-IR and its associated signaling system have generated considerable interest over recent years as a novel therapeutic target in cancer 9. Design of specific IGF-IR inhibitors has shown promise in preclinical models of human cancer, and several agents are now in early phase clinical trials. It will be important to use data from preclinical and early clinical trials to establish the molecular correlates of sensitivity to IGF-IR blockade, and the optimum means of combining this new approach with standard treatment modalities 10.
In the current work, a significant difference in the relative measurement (CT) of IGF-IR expression by PCR analysis was found between the patient group and the control group. The IGF-IR expression in patients was statistically significantly higher (P=0.000) than those of the controls [Table 3], [Figure 2]. This has been discussed previously by Vorwerk et al. 1, who reported that malignant lymphoblasts of patients with ALL express components of the IGF system and therefore promote their own growth in an autocrine, paracrine, or endocrine manner, and these components may be useful as prognostic factors in the stratification of ALL treatment.
|Figure 2: Scatter diagram showing the distribution of cases in terms of insulin-like growth factor I receptor (IGF-IR) (the solid lines represent the mean values).|
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Medyouf et al. 11 also identified IGF-IR signaling as a critical initiator of growth and survival of the ALL malignant clone, and provided evidence that NOTCH may potentiate PI3K/Akt signaling by upregulating the expression of IGF-IR. Similarly, Whelan et al. 12 reported that HoxA9 overexpression induces IGF-IR expression and subsequently promotes leukemic cell growth in B-lineage ALL, identifying a crucial role of IGF-IR in ALL pathogenesis.
Interestingly, many reviews have focused on the rationale for targeting the IGF-IR as a key signaling component of the IGF system. Important therapies targeted at this pathway have been or are being developed, including monoclonal antibodies to the IGF-IR and small-molecule inhibitors of the tyrosine kinase function of this receptor. These investigational therapies are now being studied in clinical trials. Emerging data from trials are encouraging in terms of the safety of the monoclonal antibodies 13,14.
In addition, many strategies that have been applied to target IGF in cancer include reducing circulating ligand levels or bioactivity, blocking receptor function, using receptor-specific antibodies or small-molecule tyrosine kinase inhibitors, and activating AMP-activated protein kinase 2,15–18.
In the present study, no significant relation was found between IGF-IR expression and standard prognostic factors or patients’ outcome (P>0.05) [Table 4] and [Table 5]. No previous studies have been found correlating IGF-IR expression with prognosis in ALL. In acute myelogenous leukemia, Qi et al. 19 have reported previously that apoptosis occurs in IGF-IR-negative cells; they proposed that IGF-IR expression exerts a kind of protective effect for malignant cells that enhances resistance to therapy.
In the current work, statistical analysis of established prognostic factors with outcome identified that patients older than 30 years had poorer outcome (P=0.01) [Table 6]. It has been reported before that patients with ALL older than 30 years require more aggressive treatments and show a poor prognosis when compared with younger patients 20,21. The male predominance in patients with ALL was clear in the present study. This has been reported previously by Wu et al. 22, who found a male to female ratio of 3 : 1. This study did not find any statistical relationship between the sex and the outcome. In contrast, it has been reported before that male patients have an inferior outcome compared with female patients, possibly because of the impact of testicular relapse 23,24.
In the current work, the presence of hepatomegaly, splenomegaly, lymphadenopathy, or central nervous system (CNS) infiltration did not show any significant association with patient outcome. It has been reported previously that CNS disease at presentation did not appear to be an independent, poor prognostic factor because a favorable outcome in such patients could be achieved through aggressive systemic and CNS-directed therapy 23, 25, 26.
In terms of the laboratory criteria in the present work, 93.3% of our studied patients had hemoglobin level less than 10 g/dl, with no statistical significance with the outcome, as reported before 27–29. Also, no statistically significant relationship was found between the platelet count and the outcome, which has been reported by other investigators 25,30. Interestingly, other studies have used the platelet count as a recovery index, and not as a prognostic parameter; it has been reported that platelet recovery greater than 100×109/l is an essential component of complete remission (CR) in ALL and the time required for platelet recovery might be predictive of overall survival or disease-free survival in patients with ALL 31,32. Total leukocytic count was significantly higher in poor outcome (P=0.03) [Table 6] as proved previously 33,34.
In this study, PB blasts% was significantly higher in patients with a poor outcome (P=0.004) as reported by Pullarkat et al. 35. We found that CD33 aberrant expression was significantly higher with a poor prognosis (P=0.01); this has been confirmed previously by Yenerel et al. 36, who proved that these myeloid markers were the most significant factor that affected long-term survival in their patients. Also, we detected higher CD34 expression with poor outcome (P=0.008) [Table 6] as reported previously 21,37.
In terms of conventional cytogenetic analysis in this study, examination of the 23 cases with successful metaphases showed hyperdiploidy in only one patient, who achieved CR. Previous studies have reported that hyperdiploidy (>50 chromosomes) had a low incidence in adults (<10%) and excellent response to treatment 38–40. Structural abnormalities were found in this study in 11/23 patients (47.8%) in the form of t(9;22) in six patients characterized by a poor outcome (relapse and death). This has been confirmed previously by Moorman et al. 41, who reported that patients with t(9;22) typically had a lower frequency of CR and a shorter overall survival, and was considered one of the criteria that define high-risk ALL. t(8;14) was detected in one patient who failed to achieve CR; the same result has been reported by other investigators 35, 41, 42. Translocation (1;19) was detected in our work in one patient with a poor outcome, as shown before 21, 40, 43. Deletion 17p was found in one case and was associated with a poor outcome, in agreement with Okamoto et al. 44, who found significantly more 17p deletions in adult ALL as compared with the pediatric ALL, which are commonly associated with the loss of p53 function that would affect the normal mechanism of apoptosis and DNA repair in the adult ALL cells. Deletion (9p21) was found in one patient who failed to achieve remission; the same has been reported by previous studies 45–47.
In conclusion, adult patients with ALL showed overexpression of IGF-IR at diagnosis, indicating its role in leukemogenesis. Modified therapeutic strategies directed against IGF-IR may be beneficial in arresting malignant cell proliferation and survival and blocking the progression of disease. Reassessment of IGF-IR in relation to established prognostic factors after induction therapy is recommended to assess its role as an indicator for therapeutic response.
| Acknowledgements|| |
The facilities offered by Clinical Pathology Department - Hematology Unit - Faculty of Medicine- Ain Shams University that enabled us to carry out this work are greatly appreciated.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]