|Year : 2012 | Volume
| Issue : 4 | Page : 274-280
Expression of matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 in childhood acute lymphoblastic leukemia
Mohamed A. Mekawy1, Sahar S. Abdel Maksoud1, Doaa G. Eissa1, Abeer A. Abdelmaksoud2, Iman A. Ragab2, Mahmoud T. Sallam3, Adam A. Yousef1
1 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
3 National Research Center, Cairo, Egypt
|Date of Submission||21-Jun-2012|
|Date of Acceptance||15-Jul-2012|
|Date of Web Publication||21-Jun-2014|
Doaa G. Eissa
MD, Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, 11535 Cairo
Source of Support: None, Conflict of Interest: None
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate the turnover of the extracellular matrix and may modulate the biology of hematopoietic cells. They are key players in many physiological and pathological processes such as development, angiogenesis, connective tissue remodeling, as well as tumor invasion and metastasis.
Estimate marrow MMP-9 expression and detect the levels of TIMP-1 in patients with acute lymphoblastic leukemia (ALL) and correlate these results to the clinical characteristics and survival studies of the patients.
Materials and methods
Thirty newly diagnosed patients with childhood ALL and 10 healthy control children were studied using real-time PCR for the measurement of mRNA expression of the MMP-9 gene and using the flow cytometric technique for the detection of intracytoplasmic protein levels of TIMP-1.
MMP-9 expression was significantly lower in patients compared with the control group, whereas TIMP-1 expression showed no significant difference between both the groups. No significant difference was observed between patients with a high MMP-9 expression and low MMP-9 expression in terms of clinical and laboratory data, except for the platelet count, which was higher in patients with a high MMP-9 expression. Besides CD34 expression, TIMP-1 expression was not significantly related to clinical and laboratory data of the patients studied. The median TIMP-1 expression, but not MMP-9, was significantly associated with the initial response to therapy. However, neither MMP-9 nor TIMP-1 expression was significantly associated with the relapse rate, overall survival, or event-free survival.
The clinical importance of MMP-9 and TIMP-1 expression in childhood ALL is still unclear. Further larger studies with a longer follow-up period are recommended to confirm the prognostic value of MMP-9 and TIMP-1 expression in pediatric ALL patients.
Keywords: matrix metalloproteinase-9, pediatric acute lymphoblastic leukemia, tissue inhibitors of metalloproteinases-1
|How to cite this article:|
Mekawy MA, Maksoud SA, Eissa DG, Abdelmaksoud AA, Ragab IA, Sallam MT, Yousef AA. Expression of matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 in childhood acute lymphoblastic leukemia. Egypt J Haematol 2012;37:274-80
|How to cite this URL:|
Mekawy MA, Maksoud SA, Eissa DG, Abdelmaksoud AA, Ragab IA, Sallam MT, Yousef AA. Expression of matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 in childhood acute lymphoblastic leukemia. Egypt J Haematol [serial online] 2012 [cited 2020 Mar 28];37:274-80. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/274/134977
| Introduction|| |
The extracellular microenvironment is a dynamic entity that governs the destiny of the cell by providing regulatory signals that affect important cellular processes. Changes in these function may lead the cells to acquire tumorigenic properties, with matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) being their major regulators 1.
MMPs participate in the turnover of extracellular matrix (ECM) in the hematopoietic microenvironment, regulating the release of hematopoietic stem cells and mature leukocytes from the bone marrow (BM) to peripheral blood (PB) 2, ECM proteolysis, and growth factor/cytokine release, which are central to progression of leukemia 3.
The proteolytic activity of MMPs in the extracellular space is controlled by a series of natural endogenous inhibitors, with TIMPs representing the major group of proteins involved in this inhibition. Four types of TIMPs (TIMP1–4) have been described 4. TIMP-1 forms a 1 : 1 complex with the latent form of MMP-9, whereas TIMP-2 binds with the highest affinity to the latent and active forms of MMP-2. TIMP-1 promotes the growth of K-562 erythroleukemia cells and may act on this cell line as an autocrine growth factor. The importance of these data is further supported by the fact that the first MMP inhibitor drugs are in clinical trials 5. This study was carried out to estimate marrow MMP-9 expression and TIMP-1 in acute lymphoblastic leukemia (ALL) patients and to correlate these results to clinical and biological variables in an attempt to clarify their role as useful markers for disease monitoring and/or potential prognostic factors.
| Patients and methods|| |
This study was carried out on 30 newly diagnosed childhood ALL patients attending the Oncology Unit, Ain Shams University, Pediatric Hospital in the period from January 2009 through October 2011. The diagnosis of ALL was made by cytomorphological and cytochemical examination of blood and BM smears at the local institution. For the diagnosis of ALL, at least 25% blasts in the BM was mandatory. Immunological markers were considered positive if expressed in at least 20% of the malignant cells. A leukemia was classified as precursor B-ALL if the malignant cells were positive for TdT, CD19, and HLA-DR (pro-B ALL), or for TdT, CD10, CD19, and HLA-DR (common ALL), or for TdT, CD10, CD19, HLA-DR, and CyIg (pre-B-ALL). A T-ALL was defined by positivity for TdT, CD2, cytoplasmic CD3 (CyCD3), and/or CD7. Patients were considered in CR if BM blasts were less than 5% by day 28 of induction. Patients were considered to be in relapse if more than 25% blasts of marrow nucleated cells were detected.
The duration of follow-up of patients ranged from 12 to 33 months. Ten age-matched and sex-matched individuals with a nonhematological malignancy were included as controls to verify the results of the PCR technique. Informed consent for inclusion in this study was provided by the patients’ parents.
Risk stratification was made on the basis of clinical data, morphological, and immunological studies, day 14 BM response as well as conventional cytogenetics. The standard-risk ALL group involved patients 1–9.99 years of age, white blood cells count less than 50×109/l, and a pre-B immunophenotype. The high-risk standard arm group included patients with T-ALL and/or age at least 10 years and/or white blood cell count more than 50×109/l. The high-risk augmented arm group included patients with central nervous system (CNS) disease and/or BM blast day 14 more than 5% (slow early responders) and/or adverse cytogenetics, if performed, including hypodiploidy less than 45 chromosomes, t9,22, 11q23 rearrangements, t1,19 until BMT is performed. All the patients studied received chemotherapy according to the CCG 1991 protocol for standard-risk patients 6 and CCG 1961 for high-risk patients 7.
All studied patients were subjected to a detailed assessment of history, thorough clinical examination, with an emphasis on the presence of hepatomegaly, splenomegaly, lymphadenopathy, fever, CNS, and testes infiltrations. Laboratory investigations were carried out, including complete blood count using a coulter Gen S system 2 (Beckman Coulter, Miami, Florida, USA) with an examination of Leishman-stained PB films, BM aspiration, and examination of Leishman-stained BM smears, cytochemical studies using myeloperoxidase stain, and immunophenotyping of BM or PB samples using Beckman Coulter Epics XL (Flowcytometer, Brea, California, USA) to determine the WHO category using the acute leukemia panel.
Detection of MMP-9 gene expression by real-time PCR; detection of TIMP-1 expression by EPICS XL coulter flow cytometry, and estimation of serum LDH level were carried out.
Detection of TIMP-1
The principle of this test depends on using conjugated monoclonal antibodies to identify and quantify cells expressing cytoplasmic forms of the protein TIMP-1. BM cells were fixed with a fixative reagent obtained from Beckman Coulter (Brea, California, USA) (paraformaldehyde to 100 ml PBS), and then the conjugated antibody was allowed to penetrate and bind to its target within the cell using a permeabilizing reagent obtained from Beckman Coulter.
Fifty microliters of diluted BM sample was placed in each of two test tubes. 1.5 ml lyse solution (NH4Cl buffered with KHCO3 at PH 7.2) was added to each tube, and then vortexed. The tubes were incubated for 5–10 min at room temperature in the dark, then centrifuged, and the supernatant was discarded. Tubes were washed with PBS, and then centrifuged at 3000 rpm for another 5 min and the supernatant was discarded. One hundred microliters of the fixative reagent was added to each tube. The mixture was vortexed and then incubated for 15 min in the dark, washed with cold PBS, and centrifuged at 3000 rpm for 5 min, and then the supernatant was discarded. One hundred microliters of permeabilizing reagent was added to each tube. Five microliters of isotypic control was added to the control tube and 5 μl of TIMP-1-fluorescein mouse monoclonal Ab (IgG2B) obtained from R and D systems Inc. (California, USA), was added to the test tube. The mixture was vortexed and then incubated for 15 min in the dark, washed with PBS, and centrifuged at 3000 rpm for 5 min; then, the supernatant was discarded. Lymphoblast cells were gated on the basis of forward and sideward scatter characteristics, lymphoblasts were chosen by their CD45 positivity, and the fluorescence of this population was expressed on a log-scale as TIMP-1 (%) and TIMP-1 (MFI).
Interpretation of results
Results were expressed as the TIMP-1 percentage (%) and MFI [Figure 1] and [Figure 2].
Real-time PCR for MMP-9 detection
RNA was extracted from BM samples automatically using a MagNA pure LC Instrument and the MagNA Pure LC RNA Isolation Kit I (Roche applied Science, Mannheim, Germany). The RNA of each sample was stored at −80°C until use.
Reverse transcription and amplification by one-step RT-PCR
This system allows reverse transcription using DNA polymerase and PCR amplification in one step using SYBR Green I PCR Master Mix supplied by Roche applied Science. GAPDH was used as a housekeeping gene as a control with the MMP-9 gene and performed for each set of PCR reactions. The master mix was prepared as follows for each sample: 10 µl of RNA-direct TM SYBR Green Real-time PCR Master Mix (Roche applied Science, Mannheim, Germany), 0.5 µl of forward primer, 0.5 µl of the reverse primer, 1 μl Mn(OAc), 2 and 8 µl of the PCR grade water. Then, the PCR mix was prepared by multiplying the number of the samples required, plus an additional one (excess volume for pipetting). The PCR reaction was performed in glass capillary tubes in 20 µl final volume using 15 µl of the PCR mix and 5 µl of each RNA sample was added to each corresponding capillary tube, 5 µl of PCR water grade was added to the negative control capillary tube, and the same volume of the serial standard dilution was added to the six standard capillary tubes. The PCR program involved denaturation at 90°C for 30 min, reverse transcription at 61°C for 20 min, and predenaturation at 95°C for 1 min. Amplification comprised 45 cycles of denaturation at 95°C for 15 s, annealing at 55°C for 15 s, and elongation at 74°C for 45 s.
Interpretation of results
The MMP-9 gene expression was assessed in the form of an amplification curve that shows the amount of fluorescence during the PCR cycles. Quantification of the PCR target was calculated using the standard curve method in which; the amount of target gene in the sample and control gene was determined from the appropriate standard curve. The target amount was subsequently divided by the control gene amount to obtain a normalized target value.
The sequences of MMP-9 and GAPDH primers (forward and reverse) were as follows: MMP-9 primer(F): 5′ACT GTC CAC CCC TCA GAG C-3′, MMP-9 primer(R): 5′-CCA CTT GTC GGC GAT AAG G-3′, GAPDH(F): 5′-CAC CAT CTT CCA GGA GCG AG-3′, GAPDH(R): 5′-GCA GGA GGC ATT GCT GAT-3′, respectively.
The data collected were analyzed using the statistical package for the social sciences software, version 15 (IBM, New York, USA), with the Windows XP operating system. Quantitative variables were described as mean, SD, and range. Qualitative variables were described as number and percent. Student’s t-test and the Mann–Whitney U-test were used to compare the parametric and the nonparametric quantitative variables, respectively. The χ2-test and Fisher exact test were used for the comparison of qualitative data. P values less than 0.05 and less than 0.01 were considered significant and highly significant, respectively. Survival analyses were carried out using the Kaplan– Meier curve, which compares the survival rates of the groups.
| Results|| |
The patients studied included 17 males (56.7%) and 13 females (43.3%), with an M : F ratio 1.3 : 1. Their age ranged from 0.25 to 16 years, with a mean of 7.6±4.8 years. The age of the patients in the control group ranged from 1 to 16 years, with a mean age of 7.5±5 years. There were six males and four females, with a male to female ratio of 1.5 : 1. The clinical characteristics and laboratory findings are shown in [Table 1]. Of the 30 ALL patients studied, CNS involvement at diagnosis was observed in four patients (13.3%). Extramedullary infiltration defined as the presence of splenomegaly (spleen enlargement >2 cm under the left costal margin) was observed in 23 (76.7%) patients, hepatomegaly (liver enlargement >2.5 cm under the right costal margin) in 20 (66.7%) patients, and lymphadenopathy (lymph node enlargement with a diameter >1.5 cm) in 11 patients (36.7%). Immunophenotypically, 23 (76.7%) patients had B-derived ALL and seven (23.3%) had T cell-derived ALL.
The means of MMP-9 and TIMP-1 in patients were 0.6±1.8 and 9.71 ±12.5, respectively. MMP-9 expression was significantly lower in the patient group (0.68±1.8) compared with the control group (19.5±11.8) (P<0.001); TIMP-1 expression was higher in the patient group (9.72±1) compared with the control group (3.5±0.7); yet, this did not reach a statistically significant difference (P=0.14).
MMP-9 expression and TIMP-1 expression in association with clinical and laboratory findings
Patients expressing MMP-9 were classified according to the median MMP-9 value (0.07) into two groups: group A with a low expression level and group B with a high expression level. Comparison of both groups showed no statistically significant difference in the clinical and laboratory data, except for the platelet count, which was higher in group B (P=0.01) [Table 2]. An insignificant statistical difference was observed between TIMP-1 expression and clinical or laboratory data, except for CD34 expression (P=0.042) [Table 3].
|Table 2: Relation between MMP-9 expression and laboratory data in the ALL patients studied|
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|Table 3: Relation between TIMP-1 expression and clinical data of the ALL patients studied|
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Treatment and response to therapy
During the follow-up period, four patients were missed; therefore, they were excluded from the survival studies. Overall survival (OS) was estimated from the time of diagnosis to the date of death or the last follow-up. The mean OS in ALL patients was 20.8±9.8 months, with a range of 1–33 months [Table 1]. Of the remaining 26 patients, 19 (73%) patients were alive by the end of the study and seven (27%) patients were dead. Event-free survival (EFS) was estimated from the time of first diagnosis to relapse or death or the last follow-up. The mean EFS in ALL patients was 15.5.±11.1 months, with a range of 0–33 months [Table 1]. The 26 patients who completed the follow-up were categorized according to the response rate into good responders 17 (65.4%) and poor responders nine (34.6%). In terms of the relapse rate, 10 patients (38.5%) suffered from relapse by the end of this study [Table 4].
|Table 4: Comparison between MMP-9 expression status in the response and relapse rates|
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MMP-9 and TIMP-1 expression in relation to the response and relapse rates
No significant difference in MMP-9 expression was found between the groups of good responders and poor responders (P=1.00). However, good responders had a significantly higher median level of TIMP-1 expression than the poor responders (P=0.014). In terms of the relapse rate, there was no significant difference in MMP-9 expression and TIMP-1 expression (P=0.1 and 0.3, respectively) [Table 4] and [Table 5].
|Table 5: Comparison between TIMP-1 expression in the response and relapse rates|
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Impact of MMP-9 and TIMP-1 expression on OS and EFS
TIMP-1 expression was classified into low and high expression according to the median value (4.6). Our results showed a lower mean survival time in patients with a high MMP-9 expression than patients with a lower expression (24.4±2.9 and 25.6±3.6 months, respectively) and a lower mean survival time in patients with a high TIMP-1 expression than patients with a lower expression (23.7±3.9 and 26.3±2.4 months, respectively); however, these results failed to show a statistically significant difference in terms of OS (P=0.98 and 0.53, respectively). In addition, the EFS time was lower in group B (high MMP-9 expression) than in group A (low MMP-9 expression) (14.5±2.7 and 22.1±4.4, respectively) and lower in the high TIMP-1 than in the low TIMP-1 expression group (14.7±4.11 and 20.1±2.6, respectively). Also, these results showed a nonsignificant difference in EFS (P=0.24 and 0.20, respectively).
| Discussion|| |
An increase in MMP-9 has been described as a characteristic of many malignant tumors, being associated with tumor invasion and metastases 8. High TIMP-1 expression has been associated classically with a reduction in tumor size and metastases in cell lines and in human tumors 8,9. However, several clinical studies have reported that high TIMP-1 levels are associated with an unfavorable prognosis and with tumor progression, suggesting a double influence of these genes on cancer development 10.
In the current study, MMP-9 expression was significantly lower in patients compared with the control group. Similarly Lin et al. 11 found that the MMP-9 levels in the patients with ALL were paradoxically lower than those in the controls and as the average marrow cellularity of the patients with ALL was around 90%, the lower MMP-9 levels in the ALL patients were not because of insufficient marrow cells secreting MMPs; furthermore, MMP-9 levels were in the same range as the controls at the time of complete remission.
In contrast, TIMP-1 expression was higher in the patient group, than the control group, a result that is in agreement with a previous study 12. The elevated levels of TIMP-1 in ALL patients’ raise the possibility that TIMP-1 may function in a capacity other than as MMP inhibitors in acute leukemias 11.
Levels of MMP-9 or TIMP-1 expression did not show any difference in peripheral organ infiltration (hepatomegaly, splenomegaly, lymphadenopathy). This was similar to other studies carried out by Suminoe et al. 9 and Kuittinen et al. 13. In contrast, the percentage of lymphoblasts containing intracytoplasmic MMP-9 was significantly higher in patients with peripheral infiltration in one study, Schneider et al. 14, and lower in another, Scrideli et al. 15. This huge discrepancy between different studies could be attributed to the variable sensitivity of MMP-9 expression detection methods and number of patients studied or differences in the groups studied. Suminoe et al. 9 suggested that the balance between MMP and TIMP (MMP-9/TIMP-1 ratios) and not the separate expression of each gene may be associated with the dissemination and extramedullary invasion in ALL in infants. However, others showed no significant association between the MMP-9/TIMP-1 ratios and survival or a higher risk of infiltrative disease in children older than one year, suggesting that this finding may be specific for infant leukemias, which have a different clinical behavior 15.
CNS disease showed no significant difference between low and high MMP-9 or TIMP-1 expression. Suminoe et al. 9 and Scrideli et al. 15 found that MMP-9 mRNA was not associated with CNS infiltration in infant ALL patients.
Laboratory parameters such as the total leukocytic count and HB level showed no significant difference with low and high MMP-9 expression or TIMP-1 expression. This has been documented by several previous studies 9, 14, 15. However, a significant difference in the platelet count was found between high and low MMP-9 expression, where the platelet count was higher in high MMP-9 expression than low expression. This was similar to a study carried out by Aref et al. 12.
MMP-9 and TIMP-1 expression showed no significant difference between B-ALL and T-ALL. This is in agreement with Scrideli et al. 15. However, other reports have found that MMP-9 expression was correlated with childhood and adult T-ALL 13,16.
MMP-9 expression showed no difference between good responders and poor responders in our work. This is in agreement with Scrideli et al. 15, whereas good responders had a statistically significant higher median TIMP-1 expression compared with poor responders. These findings were obtained by Scrideli et al. 15, but were not statistically significant. By the end of the follow-up, MMP-9 and TIMP-1 expression showed no significant difference in terms of the relapse rate. This result was similar to that of Scrideli et al. 15 and was confirmed by Schneider et al. 14, who found no significant difference; however, MMP-9 expression was higher in relapsed patients than patients not in relapse. Again, this discrepancy between different studies could be attributed to the variable sensitivity in detection methods. RT-PCR in our study and Scrideli et al. 15 versus flow cytometry in Schneider et al. 14 who measured it as protein levels.
The impact of MMP-9 expression on OS showed no significant difference in our study, although the mean survival time was shorter in high MMP-9 expression. Previous studies 11,13 have shown that the expression of MMP-9 in childhood ALL was not correlated to the OS time; the mean EFS was shorter in patients with high MMP-9 expression than patients with low expression, but the P value did not reach a statistically significant difference. This was similar to the study of Scrideli et al. 15, in which no significant difference was found in EFS of the MMP-9 expression gene and MMP-9/TIMP-1 ratios. Moreover, the mean EFS showed no significant difference in TIMP-1 expression in our results. These results have been confirmed previously by Scrideli et al. 15, who reported that TIMP-1 expression above the median range was significantly associated with lower EFS and with a higher risk of unfavorable events in ALL children. The failure to detect significance in our work may be because of the small number of patients and the relatively short follow-up period compared with the study of Scrideli et al. 15, in which follow-up was over 5 years.
TIMPs have been associated with a protective effect against the development of metastases by MMP inhibition and regulation of ECM turnover. Several experiments using animal models have been designed in order to show the beneficial influence of TIMP-1 on malignant neoplasias 10,17. New evidence, however, has indicated greater complexity of the TIMPs action during tumor progression and has suggested other activities of these genes in addition to MMP inhibition. TIMP expression has been associated with cancer development and progression through processes such as apoptosis inhibition, promotion of tumor growth, and angiogenesis 18.
Rust et al. 19 have provided evidence in functional studies using human erythroleukemic and anaplastic large lymphoma cell lines, that TIMP-1 activates the FAK/Akt axis and the Bcl-2 survival signaling pathway, thereby inhibiting apoptosis.
| Conclusion|| |
The median TIMP-1 expression but not MMP-9 expression was significantly associated with response to therapy. However, neither MMP-9 nor TIMP-1 expression was significantly associated with the relapse rate, OS, and EFS. Further studies in a larger number of patients with a longer follow-up period are recommended to confirm the prognostic values of MMP-9 and TIMP-1 expression in pediatric ALL patients, in addition to assessment of the role of the MMP-9/TIMP-1 ratio not separate genes for a better understanding of these mechanisms in childhood leukemia.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]