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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 40  |  Issue : 1  |  Page : 17-23

Estimation of plasma concentrations of hepatocyte growth factor in acute leukemia in Upper Egypt


1 Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt
2 Department of Public Health and Community Medicine, Faculty of Medicine, South Valley University, Qena, Egypt
3 Department of Internal Medicine, Faculty of Medicine, South Valley University, Qena, Egypt
4 Department of Clinical Pathology, Faculty of Medicine, South Valley University, Qena, Egypt

Date of Submission21-Aug-2014
Date of Acceptance21-Nov-2014
Date of Web Publication24-Apr-2015

Correspondence Address:
Ahmed E Ahmed
Lecturer of Pediatrics, Pediatric Department, Qena Faculty of Medicine, South Valley University, Qena
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.155789

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  Abstract 

Background Angiogenesis is a fundamental element during malignant transformation. The induction of angiogenesis has been proposed to be through angiogenic factors such as hepatocyte growth factor (HGF).
Objective The aim of the study was to assess plasma concentrations of HGF in acute leukemia in Upper Egypt.
Patients and Methods We performed a cross-sectional study of 90 participants and divided them into three groups: group I included 30 newly diagnosed acute lymphoblastic leukemia patients; group II included 30 patients with newly diagnosed acute myeloid leukemia; and group III included 30 apparently healthy individuals who served as controls. Plasma HGF concentration was measured using the ELISA technique.
Results Statistical comparison between the mean values of plasma HGF in the three studied groups on using the F test, followed by the least significant difference, showed a significant difference (F = 77, P = 0.001) between acute lymphoblastic leukemia patients and controls and between acute myeloid leukemia patients and controls.
Conclusion The results of the present study suggest that high plasma HGF may play a significant role in leukemia process and contribute to the leukemic cell dissemination. The clinical significance of the increased level of HGF in acute leukemia needs further investigation and may suggest a novel therapeutic approach in this disease.

Keywords: acute leukemia, angiogenesis, hepatocyte growth factor


How to cite this article:
Ahmed AE, Zytoun SS, Alsenbesy MA, Elsaid AEA. Estimation of plasma concentrations of hepatocyte growth factor in acute leukemia in Upper Egypt. Egypt J Haematol 2015;40:17-23

How to cite this URL:
Ahmed AE, Zytoun SS, Alsenbesy MA, Elsaid AEA. Estimation of plasma concentrations of hepatocyte growth factor in acute leukemia in Upper Egypt. Egypt J Haematol [serial online] 2015 [cited 2019 Dec 9];40:17-23. Available from: http://www.ehj.eg.net/text.asp?2015/40/1/17/155789


  Introduction Top


Acute leukemia is a heterogenous group of malignant disorders arising from hematopoietic progenitor cell at different stages of maturation. It is characterized by the appearance of immature cells (blasts) in the bone marrow cells, resulting in anemia, thrombocytopenia, and an outpouring of the neoplastic blasts into the peripheral blood. They may infiltrate other parenchymatous organs such as the liver, spleen, and lymph nodes. The blasts have common characteristics, which include rapid proliferation, immaturity, and poor responsiveness to regulatory mechanisms [1],[2] . There are two types of leukemia: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). ALL is characterized by the proliferation of lymphoblasts originating in lymphocyte progenitor cells of the bone marrow [2] , whereas AML originates from myeloid hematopoietic cells, which include myeloblasts, monoblasts, erythroid precursors, and megakaryoblasts [3] .

AML is a relatively rare cancer. There are ~10 500 new cases each year in the USA, and the incidence rate has remained stable from 1995 through 2005. AML accounts for 1.2% of all cancer deaths in the USA [4] .

The incidence of AML increases with age, and the median age at diagnosis is 63 years. AML accounts for about 90% of all acute leukemia in adults but is rare in children [1] . The rate of therapy-related AML (i.e. AML caused by previous chemotherapy) is rising; therapy-related disease currently accounts for about 10-20% of all cases of AML. AML is slightly more common in men, with a male-to-female ratio of 1.3: 1 [5] .

There are many risk factors for acute leukemia:

  1. Environmental factors: Three well-documented environmental factors have been established as causal agents increasing the risk of AML: exposure to a high dose of external radiation, chronic benzene exposure, and chemotherapeutic agents such as alkylating agents [5] . Pesticide exposure (occupational or home use) and parental cigarette smoking before or during pregnancy have been suggested as causes of childhood ALL. Other proposed causes of childhood ALL include neonatal administration of vitamin K and maternal alcohol consumption during pregnancy [6] .
  2. Acquired disease (evolution from a chronic clonal hemopathy): AML may develop from progression of other clonal disorders of hematopoietic stem cells, including chronic myeloid leukemia, polycythemia vera, idiopathic myelofibrosis, and primary thrombocythemia [7] .
  3. Inherited conditions: such as Down's syndrome [8] , Fanconi syndrome [9] , and Bloom syndrome [9] . Children with Down's syndrome have a 10-30-fold increase risk of leukemia. AML predominates in patients younger than 3 years and ALL in the older age group.


The term angiogenesis, first used by Hertig in 1935 to describe the growth of blood vessels in the placenta, was reintroduced by Folkman [10] in 1972 to describe neovascularization accompanying solid tumor growth. Angiogenesis is the process by which new capillaries sprout and differentiate from pre-existing blood vessels. This process results in newly developed microvessels, most of which resemble capillaries (diameter of 5-8 μm). This process is distinct from vasculogenesis, which occurs during embryonic development and involves the formation of larger blood vessels from stem cells of mesenchymal origin called angioblasts [11] . In normal mature adults, angiogenesis is a rare event that occurs only in certain specialized situations such as during the female reproductive and menstrual cycle. Microvascular blood vessels are extremely long lived. The endothelial cells that line the microvasculature have a half-life ranging from months to years [12] . Abnormal or pathologic angiogenesis can be seen in diseases such as rheumatoid arthritis, diabetic retinopathy, infantile hemangiomas, psoriasis, and cancer [11] . Hepatocyte growth factor (HGF)/scatter factor was initially identified in 1984 [13] and molecularly cloned as a potent mitogen of primary cultured hepatocytes [14] . It has multiple activities (multifunctional cytokine) in a variety of tissues during the course of development and also in various disease states. It is named scatter factor as it affects the increase in local motility and causes a scattering of contiguous sheets of cells. This factor might be involved in epithelial migration such as occurs in embryogenesis and wound healing [15] . Molecular cloning revealed that HGF is a heterodimeric molecule composed of a 69 kDa α-chain and a 34 kDa β-chain. The α-chain contains an N-terminal hairpin domain and subsequent four-kringle domains. The β-chain contains a serine-protease-like domain with no enzymatic activity [16] . The α-subunit and the β-subunit have a length of 440 and 234 amino acids, respectively [17] . HGF is synthesized and secreted as a biologically inactive single-chain precursor form and further processed by serine protease into the two-chain form. Serine proteases responsible for the activation of HGF include HGF activator or HGF converting enzyme and urokinase-type plasminogen activator [18] . The receptor for HGF was identified as c-Met proto-oncogene product. The c-Met receptor is composed of a 50 kDa α-chain and a 145 kDa β-chain. The α-chain is exposed extracellularly, whereas the β-chain is a transmembrane subunit containing an intracellular tyrosine kinase domain [19] . Binding of HGF to the c-Met receptor induces activation of tyrosine kinase, an event that results in the subsequent phosphorylation of c-terminally cultured tyrosine residues. Although HGF was initially identified as a potent mitogen for hepatocytes, considerable evidence indicates that intracellular signaling pathways driven by HGF and c-Met receptor coupling lead to multiple biological responses in a variety of cells, including mitogenic, motogenic (enhancement of cell motility), morphogenic, neurite extension, antiapoptotic activity, and enhancement of hematopoiesis. HGF has also an organotrophic role in the regeneration and protection of various organs, including the liver, lung, stomach, pancreas, heart, brain, and kidney. Cells shown to express HGF mRNA include megakaryocytes, monocytes, platelets, fibroblasts, smooth muscle cells, mast cells, and endothelial cells but not epithelial cells. Various types of human leukemia cells also secrete HGF. Expression of HGF receptor in vitro and in vivo in epithelial cells suggests that HGF acts in a paracrine manner to mediate interactions between epithelial and stromal cells during development and in normal tissue maintenance [19],[20] . HGF is a potent inducer of angiogenesis, a process necessary for the continued growth of tumors. In vitro, HGF stimulates endothelial cell proliferation, chemotaxis, and chemokinesis; it promotes migration of endothelial cells from carrier beads to flat surfaces, and it induces capillary-like tube formation. It has also been reported that HGF induces endothelial cell expression of plasminogen activators. In-vivo studies also indicated that HGF-induced neovascularization exceeds that achieved with vascular endothelial growth factor (VEGF). HGF has been shown to be induced in skeletal muscle after ischemic injury, and it has been implicated in capillary endothelial cell regeneration in ischemically injured myocardium. The receptor for HGF, the c-Met proto-oncogene product, is expressed by endothelial cells and pericytes of blood vessel walls. Because HGF is apparently produced by stromal cells located outside the vessel wall, it has been suggested that it may act as a paracrine mediator in the angiogenic cascade [20],[21] .

Bone marrow stromal cells, which include macrophages, fibroblasts, endothelial cells, and adipocytes, have been shown to produce several factors that modulate the growth of bone marrow progenitors as HGF, which is fibroblast derived. Bone marrow cells were found to express both c-Met mRNA and its protein; c-Met mRNA has also been detected in several murine hematopoietic progenitor cell lines, suggesting that HGF and c-Met might function during hematopoiesis. HGF was shown to synergize with interleukin-3 and granulocyte macrophage colony-stimulating factor to stimulate colony formation of hematopoietic progenitors cells. In vitro, HGF may be a regulatory protein for the proliferation and differentiation of hematopoietic progenitors and considered as a new member of the functionally related group of factors that modulate hematopoiesis [22] . HGF expression was detected in various types of leukemia/lymphoma cell lines, particularly in plasma cell and myeloid malignancies [23] . It has a mitogenic activity on myeloid leukemia cell lines. A high level of HGF is found in blood and bone marrow plasma from patients with various types of leukemia [24] . The aim of this study was estimation of the plasma concentration of HGF as an angiogenic factor in acute leukemia.


  Patients and methods Top


This study included three groups: group I comprised 30 newly diagnosed ALL cases; group II comprised 30 patients with newly diagnosed AML; and group III comprised 30 apparently healthy individuals as controls. The patients were selected from the main hospital of South Valley University. All participants were subjected to the following: thorough history taking and clinical examination, with special stress on the presence of extramedullary infiltration such as gum hypertrophy, lymphadenopathy, hepatomegaly, central nervous system involvement, and skin infiltration, as well as complete blood count, bone marrow examination (for patients), liver and kidney function tests, and radiological study (chest radiograph and abdominal ultrasound). A volume of 5 ml of venous blood was collected into a disposable tube containing ethylenediaminetetraaceticacid 5% as an anticoagulant; centrifugation was carried out immediately. After centrifuging at 1000g for 10 min, the recovered plasma was stored at −70°C until the time of assay of HGF. Estimation of plasma concentration of HGF was carried out using the ELISA technique [25] . The kit was supplied by R&D Systems Inc. (Minneapolis, Minneapolis, USA.

Patients with ALL were treated with a combination of intravenous push of daunorubicin 50 mg/m 2 for the first 3 days of therapy, 2 mg intravenous bolus of vincristine at days 1, 8, 15, and 22, and prednisone 60 mg/m 2 daily for 28 days. They were considered in complete remission (CR) when they had less than 5% blasts in a cellular bone marrow recovery of peripheral neutrophils and platelets and absence of detectable extramedullary leukemia [26] .

AML patients were treated with 7 and 3 regimen. AML patients were considered in CR when they had a morphologically normal bone marrow containing less than 5% blasts and no  Auer rods More Details, absence of extramedullary leukemia, and normalization of neutrophil counts (≥1.5 × 10 9 /l) and platelet counts (>100 × 10 9 /l). These criteria should be maintained for at least 4 weeks or until initiation of intensification therapy. Partial remission (PR) was defined by 5-25% bone marrow blasts [27] . All patients were followed up for response to chemotherapy for at least 6 months.

Statistical analysis

The study data were statistically analyzed using statistical package for the social sciences program (SPSS program, version 10.0; SPSS Inc., Chicago, Illinois, USA). The differences between cases and controls as regards quantitative variables was ascertained using ANOVA, F test, and Kruskal-Wallis test. For testing the association between categorized variables, the χ2 -test and Monte Carlo test were used. Pearson's correlation test was carried out to study the possible correlation between quantitative variables. Statistical significance was assessed at P less than 0.05. All calculated P values were two-tailed.


  Results Top


The study was conducted on 60 patients suffering from acute leukemias. Thirty patients had ALL [(4) L 1 , (12) L 2 , (14) L 3 ]; of them, 18 were male patients. Their ages ranged between 3 and 18 years, with a X̄ ± SD of 19.2 ± 17 years. Thirty patients had AML [(8) M 1 , (4) M 2 , (4) M 3 , (4) M 4 , (6) M 5 , (2) M 6 , (2) M 7 ]; of them, 12 were male patients and their ages ranged between 24 and 42 years, and the X̄ ± SD was 31.3 ± 5.8 years. The patients were age-matched and sex-matched with 30 controls. The age of controls ranged from 5 to 18 years, with X̄ ± SD of 21.9 ± 13 years and comprised 14 male and 16 female patients. Among ALL patients, 26 (86.7%) presented with pallor, whereas among AML patients, 24 (80%) presented with pallor. However, the difference between the two groups was not statistically significant (χ2 = 0.000, P > 0.05). Twenty (66.7%) patients with ALL and AML presented with hemorrhage, and the difference between the two groups was not statistically significant (χ2 = 0.000, P > 0.05).

Among ALL patients, 20 (66.7%) presented with fever, whereas among AML patients, six (20%) presented with fever, and this was statistically significant (χ2 = 6.652, P < 0.05). Among ALL patients, two (6.7%) presented with hepatosplenomegaly, eight (26.7%) with lymphadenopathy, and 12 (40%) with hepatosplenomegaly plus lymphadenopathy.

Among AML patients, 10 (33.3%) presented with hepatosplenomegaly, two (6.7%) with hepatosplenomegaly plus lymphadenopathy, four (13.3%) with hepatosplenomegaly plus gum hypertrophy, and four (13.3%) with splenomegaly; this was statistically significant (Monte Carlo, P > 0.000).

Among ALL patients, 22 (73.3%) entered into remission, four (13.3%) entered into partial remission, and four (13.3%) died. Among AML patients, 14 (46.7%) were in remission, two (6.7%) were in partial remission, eight (26.7%) were resistant to therapy, and six (20%) died, and this was not statistically significant (P > 0.05).

Haematological data

In ALL patients, hemoglobin (Hb) values ranged from 3 to 9.5 g/dl, with a X̄ ± SD of 6.506 ± 1.931 g/dl, whereas in AML patients Hb values ranged from 3.5 to 12 g/dl, with a X̄ ± SD of 7.72 ± 2.275 g/dl. In the control group, Hb values ranged from 12.7 to 14.5 g/dl, with a X̄ ± SD of 13.68 ± 0.578 g/dl. There was significant difference between ALL, AML, and control groups (F = 71.796, P ≤ 0.000). This difference using least significant difference (LSD) was significant between ALL patients and controls and AML patients and controls.

In ALL patients, RBC counts ranged from 0.94 to 3.5 × 10 12 /l, with a X̄ ± SD of 2.398 ± 0.762 × 10 12 /l. In AML patients, the RBC counts ranged from 1 to 4.1 × 10 12 /l, with a X̄ ± SD of 2.793 ± 0.859 × 10 12 /l, whereas in the control group, it ranged from 4.39 to 4.84 × 10 12 /l, with a X̄ ± SD of 4.642 ± 0.187 × 10 12 /l. There was significant difference between ALL, AML, and control groups (F = 52.027, P ≤ 0.000), and this difference using LSD was significant between ALL patients and controls and AML patients and controls.

In ALL patients, white blood cell (WBC) counts ranged from 5.1 to 200 × 10 9 /l, with a X̄ ± SD of 40.16 ± 55.141 × 10 9 /l. In AML patients, it ranged from 2 to 92.5 × 10 9 /l, with a X̄ ± SD of 22.08 ± 25.81 × 10 9 /l, whereas in the control group, it ranged from 4.2 to 6.7 × 10 9 /l, with a X̄ ± SD of 5.281 ± 0.791 × 10 9 /l. This was statistically significant between ALL patients and controls and AML patients and controls.

In ALL patients the platelet count ranged from 12 to 130 × 10 9 /l, with a X̄ ± SD of 72.033 ± 67.127 × 10 9 /l. In AML patients it ranged from 15 to 138 × 10 9 /l, with a X̄ ± SD of 61.2 ± 41.167 × 10 9 /l, whereas in the control group it ranged from 220 to 332 × 10 9 /l, with a X̄ ± SD of 254.467 ± 28.65 × 10 9 /l. There was significant difference between ALL, AML, and control groups (F = 75.57, P = 0.000). Using the LSD the difference was significant between ALL patients and controls and between AML patients and controls.

The peripheral blood blasts ranged from 20 to 85% in ALL patients, with a X̄ ± SD of 56.2 ± 20.73%, whereas it ranged from 5 to 80% in AML patients, with a X̄ ± SD of 46.333 ± 24.025%, and this was not significant (t = 0.699, P = 0.506). The bone marrow blasts ranged from 60 to 93% in ALL patients, with a X̄ ± SD of 83.2 ± 11.194%, whereas it ranged from 60 to 93%, with a X̄ ± SD of 62.066 ± 21.819%, and this was not significant between the two groups (t = 5.37, P = 0.07) ([Table 1] and [Table 2] and O [Figure 1]).
Figure 1 Mean levels of hepatocyte growth factor (HGF) in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and control group.

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Table 1 Comparison between the three studied groups as regards hematological data

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Table 2 Statistical comparison between acute lymphoblastic leukemia, acute myeloid leukemia and control group as regards hepatocyte growth factor

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Results of hepatocyte growth factor as regards the extramedullary infiltration

HGF was significantly higher in patients who presented with hepatosplenomegaly plus gum hypertrophy (four patients), with a mean value of 5.5 ± 1.1 pg/ml, followed by those who presented with hepatosplenomegaly plus lymphadenopathy (two patients) (2.03 pg/ml), those who presented with splenomegaly (four patients), with a mean value of 1.68 ± 0.85, those who presented with hepatosplenomegaly (10 patients), with a mean value of 1.6 ± 1.13, and those patients with no extramedullary infiltration (eight patients), with a mean value of 1.8 ± 1.07 ng/ml (F = 5.05, P = 0.017). As regards the response to therapy, there was no significant relation between HGF plasma levels and the response to therapy in ALL and AML patients (F = 0.941, P = 0.417).

The results of the correlation between plasma levels of hepatocyte growth factor and age and hematological parameters in acute lymphoblastic leukemia and acute myeloid leukemia patients

There was no significant correlation between plasma levels of HGF and age and hematological parameters in ALL patients. In AML patients, it was found that HGF positively correlated with Hb values (r = 0.569, P = 0.027), RBC counts (r = 0.556, P = 0.032), and WBC counts (r = 0.936, P = 0.000).

There was no significant correlation between the studied angiogenic and apoptotic factors, neither the hematological parameter nor with the age.


  Discussion Top


Acute leukemia is a malignant disease, which is characterized by three different features: hematopoietic cell arrest at a certain level of differentiation, continued progenitor cell proliferation in a way that displaces normal hematopoiesis, and immature cells prematurely leaving the bone marrow to reach peripheral tissues [28] .

It is well known that the growth of solid tumor is angiogenic dependent. However, the role of angiogenesis in the growth and survival of leukemias and other hematological malignancies has been clarified since 1994 in a series of demonstrations showing that the progression of several leukemias is closely related to their degree of angiogenesis [28] . This evidence was reported in patients with acute leukemia in which the increased angiogenesis disappeared in complete hematological remission [29] .

Recently it has been reported that there is an close correlation between the increased vessel density found in AML and VEGF expression [30] , which is a main angiogenic factor; therefore, it is of interest to investigate the role of other angiogenic factors such as HGF in acute leukemia.

HGF is known as a powerful angiogenic factor and is believed to increase angiogenesis in multistep process including an effect on the proliferation, motility, adhesion of endothelial cells, and the morphogenesis of new blood vessels [19] .

Our data proved that the plasma concentration of HGF was significantly higher in ALL and AML patients compared with controls.

This finding was in agreement with other studies [31],[32],[33],[34],[35],[36] , suggesting that the source of elevated HGF to be from blast cells, as it is demonstrated that a variety of human leukemia cell lines in culture produce a significant amount of HGF and these include T, B, myeloid, and erythroid cell lines. Moreover, a high level of HGF was detected in blood and bone marrow plasma of leukemia patients [33] .

In support of this hypothesis, the eradication of leukemic blast cells with successful treatment was observed to be accompanied by significant diminution of HGF level in bone marrow [31] . In contrast, other workers suggested that the source of HGF may be stromal cells, endothelial cells, and other cells [37] .

This HGF that is originated from blast cells was suggested to promote the growth of leukemic blast cells. Isolated AML blast cells overexpress HGF and HGF receptors. Thus, the HGF/HGFR pathways can promote the growth of leukemic blasts in an autocrine and paracrine manner [38] .

HGF is considered a very aggressive factor as it helps in the formation of extramedullary infiltrate and affects patient survival. The first effect was verified in our study as it has been revealed that there is a significant increase of HGF in AML patients with extramedullary infiltrate compared with those without extramedullary infiltrate. This is in agreement with the result of Aref et al. [36] , who found that HGF was significantly elevated in AML patients with extramedullary infiltrate compared with those without extramedullary infiltrate. This could be explained according to Fiedler et al. [39] , who stated that paracrine stimulation may not only be restricted to the bone marrow microenvironment but may also take place at extramedullary sites. Circulating AML blast may profit from paracrine provision of growth factors in various capillary bed; this may result in their expansion in peripheral blood under favorable conditions. Therefore, extramedullary manifestations of AML, such as gingival hyperplasia or organ infiltration may be initiated by similar a mechanism [39] .

As regards the second effect of HGF on patient's survival, it has been found in our study that there was a nonsignificant increase in the mean level of HGF in AML patients who died compared with those who survived and entered in CR.

In agreement with our results, Kim et al. [31] found that plasma HGF level was increased in AML patients and is considered as a strongly predictive parameter for CR. Furthermore, he stated that AML patients with lower HGF tended to have better leukemia-free survival compared with those with higher levels.

An explanation to the observed association between high HGF and a significant lower survival in newly diagnosed AML patients may be due to augmentation of angiogenesis induced by cytokines and other angiogenic factors [40] . HGF may exert a potent combination of direct and indirect effect, including direct effect on endothelial cells and indirect effect through an increase in the production of VEGF [21] . In contrast, Hjorth-Hansen et al. [34] reported no significant correlation between HGF levels in AML patients and patient survival. This controversy was attributed to the usage of serum rather than plasma samples. Sakon et al. [41] compared the measurement of HGF in serum and plasma samples and concluded that HGF plasma levels yield more valid and precise measurement compared with HGF serum levels. Blood clotting induces the release of angiogenic factors from platelets into the serum during serum isolation [41] . In addition, HGF was initially isolated from normal rat platelet, and removal of platelets greatly reduced the HGF activity of normal rat serum [42] .

In AML patients, HGF of this study was directly correlated to peripheral total WBC counts but inversely correlated to Hb and RBC counts. This finding suggests that HGF as an angiogenic factor correlated with tumor cell mass [31] .

This finding was in agreement with that of other investigators [31],[34],[35] who reported that HGF levels in AML were correlated significantly with WBC and monocytic count. HGF promotes proliferation and migration of blood mononuclear cells in AML patients with elevated blasts, and it was found that a neutralizing antibody directed against HGF reduced AML blast migration significantly [23],[43] .

Given these observations, HGF could be used as a marker for disease activity in acute leukemia cases and may add to the risk stratification of AML.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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