|Year : 2016 | Volume
| Issue : 4 | Page : 187-193
Significance of neuropilin-1 mRNA expression in chronic myeloid leukemia
Hany A Labib MD, PhD 1, Rasha M Hagag2, Sheren Elshorbagy2, Ahmed A Alnagar2, Neveen G Elantonuy3
1 Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||08-Jun-2016|
|Date of Acceptance||30-Aug-2016|
|Date of Web Publication||20-Jan-2017|
Hany A Labib
Clinical Pathology Department, Faculty of Medicine, Zagazig University, 9 Taleat Harb Street, Zagazig 44155
Source of Support: None, Conflict of Interest: None
Background Neuropilins (NRPs) are transmembrane glycoproteins that act as receptors for vascular endothelial growth factors and are involved in the process of tumor angiogenesis.
Patients and methods We analyzed the significance of NRP-1 RNA expression level in 63 newly diagnosed chronic myeloid leukemia (CML) patients and 40 healthy controls using real-time PCR.
Results NRP-1 was significantly highly expressed in CML patients than in controls and in patients in the accelerated phase than in those in the chronic phase. Its levels were significantly positively correlated with total leucocytic count (TLC), platelets count, and percentage of blast, whereas it was negatively correlated with progression-free survival. NRP-1 expression level revealed a statistically significant difference as regards response to imatinib therapy: it was significantly higher in those who did not achieve complete molecular response. During the follow-up period, the NRP-1 levels in patients still in remission were significantly lower than those who showed progression to accelerated or blastic phase; the median time of progression-free survival in patients with high NRP-1 was significantly shorter than those who had normal level.
Conclusion We conclude that NRP-1 expression is significantly associated with CML and that its level might serve as an indicator for disease severity and progression.
Keywords: chronic myeloid leukemia, neuropilins, real-time PCR
|How to cite this article:|
Labib HA, Hagag RM, Elshorbagy S, Alnagar AA, Elantonuy NG. Significance of neuropilin-1 mRNA expression in chronic myeloid leukemia. Egypt J Haematol 2016;41:187-93
|How to cite this URL:|
Labib HA, Hagag RM, Elshorbagy S, Alnagar AA, Elantonuy NG. Significance of neuropilin-1 mRNA expression in chronic myeloid leukemia. Egypt J Haematol [serial online] 2016 [cited 2020 Feb 18];41:187-93. Available from: http://www.ehj.eg.net/text.asp?2016/41/4/187/198647
| Introduction|| |
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of the Philadelphia chromosome (Ph+). Increased angiogenesis, the process of new blood vessel formation from endothelial precursors, which is an important requirement for the development and progression of many hematological malignancies such as leukemias and lymphomas, has also been reported to be associated with the progression of CML .
Neuropilins (NRPs) are transmembrane glycoprotein receptors that play an important role in various biological processes. Two NRP genes, NRP-1 and NRP-2, have been identified. NRP-1 was originally identified as a receptor for class III semaphorins (SEMA3s) mediating neuronal guidance and axonal growth ; thereafter, it was subsequently found to be a coreceptor for the specific isoform of vascular endothelial growth factor (VEGF), and it was expressed by endothelial cells and several types of tumor cells. VEGF, as a key factor for angiogenesis and tumor growth, exerts its functions mainly through activation of two tyrosine kinase receptors: VEGFR-1 (Flt 1) and VEGFR-2 (KDR). Unlike Flt 1 and KDR, NRP-1 does not possess intrinsic tyrosine kinase activity and thus forms a complex with KDR to transmit signals of VEGF. When coexpressed with KDR on endothelial cells, NRP-1 promotes the binding of VEGF to KDR and enhances VEGF-mediated mitogenic and chemotactic activity .
The importance of NRP-1 in hematological malignancies such as leukemias remains to be elucidated. Some studies determined increased NRP-1 expression in newly diagnosed untreated leukemias , and others correlated poor survival with high versus low NRP-1 levels .
In CML, blast crisis is fundamentally different from chronic phase in many aspects. The main obvious functional changes that occur with progression of CML are marked changes in proliferation, differentiation, apoptosis, neovascularization, and adhesion. These functional changes accompanying progression are accompanied by profound changes in treatment response as well .
Imatinib is currently thought to be the most effective therapy in CML, but many patients on imatinib show disease progression after variable duration. The dilemma is predicting who will go into advanced disease and when antiangiogenic therapy might have a role as an adjuvant therapy in such patients. Studies aiming to explore the detailed angiogenic profile of CML may help in developing new therapeutic strategies for this myeloproliferative disorder .
The clinical relevance of NPR-1 expression on CML outcome is not clear as, to the best of our knowledge, no data are available concerning the significant of NRP-1 level in CML patients. Therefore, the current study aimed to analyze the expression level of NRP-1 mRNA in newly diagnosed CML patients using a quantitative real-time PCR trying to find a link between this gene expression and disease severity, progression, and response to therapy.
| Patients and methods|| |
Sixty-three Egyptian patients with CML were included in this study. They were recruited from Zagazig University Hospital, Clinical Pathology and Medical Oncology Departments. They were 38 male and 25 female patients with a mean age of 39 years; 45 of them were in chronic phase and 18 were in accelerated phase. The definitions of chronic-phase, AP, and BC are the same as those used in previously published studies ,. Forty healthy, age-matched and sex-matched volunteers were recruited as a control group. All samples were obtained under protocols approved by the Internal Review Ethics Board of the University and with the patient’s written informed consent.
Patients were subjected to full history taking, proper clinical examination, and complete blood count.
NRP-1 gene was analyzed in patients and controls using real-time quantitative reverse transcriptase PCR (RTQ-PCR) to study its mRNA expression levels.
Complete molecular response (CMR) was defined as a point when BCR-ABL mRNA was undetectable by real-time quantitative RT-PCR. Patients were treated with a standard dose of imatinib (400 mg/day) and were regularly monitored on an outpatient basis: weekly during the first month of IM therapy and then monthly until a cytogenetic response was achieved, and then every 3 months for CMR; time-to-treatment failure was defined as the interval between the initiation of IM therapy and the occurrence of events.
Those who had CMR were followed up for 30 months. The quantification of peripheral blood BCR/ABL fusion gene transcripts by real-time quantitative PCR was repeated every 3 months. Time to progression to accelerated phase (AP) or blastic crisis (BC) was defined as the interval between the date of any confirmed response and the date at which the criteria for response were no longer met.
RNA isolation and real-time quantitative RT-PCR for neuropilin-1
Total RNA was extracted from the blood specimens using column spin silica-gel membrane adsorption technique (Jena Bioscience, Germany) according to the manufacturer’s instructions. The total RNA was transcripted to cDNA and amplified using the fluorescent DNA stain EvaGreen Real Time PCR master mix (Jena Bioscience). This system allows for two-step real-time PCR, including first reverse transcription step using oligo-dT primer followed by PCR using a 2× MasterMix. Two micrograms of total RNA was reverse-transcribed into cDNA, and the PCR components of the 20-µl total volume included template DNA, 10 µl of EvaGreen master mix, and 0.25 µmol/l of each primer.
The sequences of the forward and reverse primers for NRP-1 were AAG ACC TTC TGC CAC TGG GAA CAT and AGT TGC CAT CTC CTG TGT GAT CCT, respectively . The thermal cycler program was performed using LG AdvanSure SLAN (LG Life Science, South Korea). For reverse transcription, the program was incubation at 42°C for 10 min followed by 50°C for 30 min. For real-time PCR, the program was initial denaturation at 95°C for 2 min, followed by 45 PCR cycles of 95°C for 15 s, 60°C for 15 s, and 74°C for 45 s. The housekeeping β-actin gene was used for normalization. The forward and reverse primer sequences for β-actin were CCA AGC CCA ACC GTG AGA AGA T and CAA CGT TCC GTG AGG ATC TTC A, respectively.
The expression levels of NRP-1 gene in tested samples were expressed in the form of cycle threshold (CT) level; next, normalized copy number (relative quantification) was calculated using the ΔΔCT equation as follows: ΔΔCT=ΔCT of case−ΔCT of control; the normalized copy number (relative quantitation)=2−ΔΔCT. A negative control without template was included in each experiment. Expression level of NRP-1 mRNA was correlated with the clinical and laboratory features of the studied patients at diagnosis and after therapy.
Data were entered, checked, and analyzed using SPSS program package version 15 (Chicago, USA) for Windows. Comparison of quantitative nonparametric variables between the studied groups was performed using Kruskal–Wallis and Mann–Whitney tests. Correlation analysis was performed with Spearman’s correlation test. A probability P value of less than 0.05 was considered statistically significant. A normal reference of NRP-1 expression level was calculated on the values of the healthy controls adjusting for age; the 90th percentile was chosen as the cutoff point. Survival curves were constructed using the Kaplan–Meier method, and the log-rank test was used to compare progression-free survival (PFS) between patient groups.
| Results|| |
The median value of the NRP-1 mRNA expression level in patients in chronic and accelerated phase was 47.7 and 76.8, respectively, whereas the median level was 22.3 in the control group. There was a statistically significant increase in patients in the accelerated phase compared with those in the chronic phase and control group ([Table 1]).
|Table 1 Kruskal–Wallis test: comparison of median relative expression level of NRP-1 in patient groups and in controls|
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In the CML patient group, a positive significant correlation was found between NRP-1 RNA level and TLC (P=0.004), platelet count (P=0.021), and blast % (P<0.001) ([Figure 1],[Figure 2],[Figure 3]), but a negative significant correlation was found with PFS (P=0.017) ([Figure 4]), whereas there was no significant correlation between NRP-1 RNA level and age, Hb concentration, and size of spleen (not shown).
|Figure 1 Significant positive correlation between NRP-1 expression and TLC (×109/l) (P=0.004).|
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|Figure 2 Significant positive correlation between NRP-1 expression and platelet count (×109/l) (P=0.021).|
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|Figure 3 Significant positive correlation between NRP-1 expression and blast cell % (P<0.001).|
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|Figure 4 Significant negative correlation between NRP-1 expression and progression-free survival (PFS) (months) (P=0.017).|
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Our results showed a significantly higher level of NRP-1 at diagnosis in patients who do not respond to therapy compared with those who achieved molecular response later on in both chronic-phase and accelerated-phase patient groups (P=0.004 and P<0.001, respectively). Re-evaluation of relative expression level of NRP-1 in patients after 1 year of therapy revealed a statistically significant difference between those who showed CMR and not reached complete molecular response (P=0.002) ([Table 2]).
|Table 2 Mann–Whitney: comparison of NRP-1 relative expression level as regards response to therapy in patients at diagnosis and after 1 year and its relation to diseases outcome during 2 years of follow-up|
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During the follow-up period, the difference of NRP-1 relative expression level between patients still in remission and those who showed progression was highly significant (P<0.001), with the level being higher in those cases who showed progression to accelerated or blastic phase ([Table 2]).
The 90th percentile of NRP-1 expression values was used for the normal control group; 62.3 was used as the cutoff value for the analyses. According to this cutoff point, patients with higher values were distinguishable from patients with normal values. The Kaplan–Meier estimate of the PFS was significantly shorter in patients with high NRP-1 expression compared with those with normal level (median 12.5, 18 months, P<0.01) ([Figure 5]).
|Figure 5 Kaplan–Meier estimates of progression-free survival (PFS) (months) of patients according to NRP-1 expression (P<0.001).|
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| Discussion|| |
The identification of prognostic markers in CML patients is important for the development of new molecular therapies and might also allow improvement of risk-adapted treatment stratification for these patients .
Angiogenesis is the formation of new blood vessels from an existing vasculature . In addition to its role in vascularization during ovulation, placentation, and embryogenesis, angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors ,,.
The mechanism responsible for the angiogenic process and its clinical relevance needs to be fully defined in CML, as angiogenesis-dependent growth pathway has been shown to be important in leukemogenesis. VEGF stimulates growth of the vascular endothelium, thereby providing blood supply to feed growing leukemic cells .
In the present study, we measured NRP-1 RNA expression level in 63 newly diagnosed CML patients compared with 40 healthy controls by RT PCR. We found that NRP-1 level is significantly higher in patients compared with controls and in patients in the accelerated phase compared with those in the chronic phase.
The relation between NRP-1 and CML is not surprising because of the growing evidence that solid tumors, as well as hematological malignancies, are dependent on neovascularization . Increased microvessel density has been documented in the bone marrow (BM) of patients with many hematologic cancers, including CML. VEGF has also been shown to be significantly higher in CML patients compared with normal controls ,. Furthermore, transfection of the BCR/ABL fusion oncogenes into hematopoietic cell lines resulted in the induction of VEGF , which implies that BCR/ABL fusion protein augments angiogenesis process either in a direct way or through microenvironmental factors in the marrow .
BM cells are recruited to the sites of neoangiogenesis through the NRP-1 receptor also, they are essential for the maturation of the activated endothelium and the formation of arteries making NRP-1 isoform named VEGF 165 receptor . The 165-aa isoform of VEGF, which activates the endothelium and recruits NRP-1-expressing myeloid cells, is a powerful arteriogenic agent .
In our study, the level of NRP-1 was significantly correlated with higher TLC, BM blast percentage, and higher platelet count at diagnosis. Lundberg et al.  reported that the number of VEGFR1-expressing BM cells was significantly higher in samples from CML patients than in normal controls and that it was significantly correlated with BM vascularity.
Lu et al.  examined mRNA expression of NRP-1 in leukemic cells and found that it was increased in AML patients compared with healthy controls. NRP-1 expression was directly correlated with myeloblast percentage, suggesting that NRP-1 correlates with tumor load and disease activity.
The expression of NRP-1 can be stimulated in response to tissue injury or hypoxia . These indicate that NRP-1 is not markedly expressed by any type of leukocyte but rather may be generally expressed in leukemic BM, perhaps as a response to hypoxic microenvironment, which may also explain its association with higher platelet count as a consequence of increasing Epo .
The ectopic overexpression of NRP-1 results in inappropriate VEGF-165 activity, leading to aberrant angiogenesis. In addition, it has been proposed that NRP-1 may store or sequester VEGF-165 and attract endothelial cells toward the tumor, contributing to angiogenesis through paracrine mechanisms allowing prolonged signal activation . This is why NRP-1 is usually associated with a bad prognosis because of its role in tumor angiogenesis and migration .
In the present work, we did not find any significant association between NRP-1 expression and splenic size, but Murphy et al.  showed a significant correlation between splenomegaly and increased VEGF serum levels in polycythemia vera patients. Therefore, NRP-1 is the receptor of VEGF and the increase in splenic size was reported to be primarily due to increased splenic vasculature.
We found a significant difference in response to imatinib therapy as regards NRP-1 level – the higher the NRP-1 level, the more the response failure; therefore, it could be a surrogate to predict the response to imatinib therapy.
Other studies indicated that imatinib, with selective activity against BCR/ABL fusion tyrosine kinase, could decrease BM angiogenesis through reverse phosphorylation of VEGFR2/KDR and decrease the plasma concentration of VEGF in CML patients; therefore, it is probable that blockade of the angiogenesis pathway would be an alternative action mechanism of imatinib .
VEGF-dependent pathway was shown to protect leukemic cells from chemotherapy-induced apoptosis by upregulating MCL-1 . In addition, VEGF inhibits DC differentiation, which are important targets for tumor escape mechanisms . This may give additional explanation for why patients with higher NRP-1 level are more resistant to therapy.
Failure to remain in CR and high percentage of blast cells are both features suggestive of more active/progressive disease. On studying the impact of NRP-1 level on disease progression, we found that there was a significant negative correlation between NRP-1 level and time of disease progression during the follow-up period; in addition, PFS was significantly shorter in patients with high NRP-1 expression compared with those with normal level. In support of this finding, Verstovsek et al.  reported that chronic-phase CML patients with increased VEGFR2 levels had significantly inferior survival than patients without elevated VEGFR2 and indicated VEGFR2 overexpression as an independent prognostic indicator in CML patients
In addition, regarding other hematological malignancies, many studies confirmed this poor prognostic impaction of NRP-1 expression on AML  and ALL patients ,; those with higher NRP-1 expression had significantly shorter overall survival and disease-free survival. They found that higher NRP-1 expression levels are correlated with disease severity and biologic progression, and they also examined NRP-1 as a detector of minimal-residual disease rather than a prognostic marker only.
Tumor angiogenesis promotes cancer progression by increasing tumor growth and providing a conduit for metastasis . Thus, antiangiogenic therapies are now a common component of cancer therapies for multiple tumor types. In 2004, bevacizumab (anti-VEGF) became the first antiangiogenic drug approved. Antibodies to NRP-1 in combination with anti-VEGF enhanced the ability of anti-VEGF to block tumor growth, as both inhibition of VEGF and its functional receptor effectively inhibit tumor growth ; in addition, silencing of the NRP-1 gene results in a significant decrease of VEGF-induced cell proliferation and migration, and therefore the blocking of NRP-1 signaling may represent a novel therapeutic approach ,.
| Conclusion|| |
NRP-1 expression level is significantly higher in CML patients compared with controls, and its high level is an indicator for more disease severity and less response to therapy.
The authors thank all participating subjects for cooperation and support to this study. They also acknowledge Professor Amal Hanna for her assistance and guidance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]