|Year : 2020 | Volume
| Issue : 1 | Page : 23-27
Evaluation of growth factor independence 1 expression in patients with de novo acute myeloid leukemia
Fatemeh Salarpour1, Kourosh Goudarzipour2, Mohammad Hossein Mohammadi3, Ahmad Ahmadzadeh4, Sara Faraahi1, Atefeh Allahbakhshian5, Mehdi Allahbakhshian Farsani3
1 Laboratory Hematology and Blood Bank Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Science, Tehran, Iran
2 Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
3 Laboratory Hematology and Blood Bank Department, Faculty of Paramedical, Shahid Beheshti University of Medical Sciences; HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4 Research Center of Thalassemia and Hemoglobinopathy, Health Research Institute, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
5 Department of Medical Surgical, Nursing and Midwifery Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
|Date of Submission||05-Feb-2017|
|Date of Acceptance||26-Apr-2017|
|Date of Web Publication||19-Jul-2017|
Mehdi Allahbakhshian Farsani
Laboratory Hematology and Blood Bank Department, Faculty of Paramedical, Shahid Beheshti University of Medical Sciences, Tehran; and HSCT Research Center, Shahid Beheshti University of Medical Science, Tehran
Source of Support: None, Conflict of Interest: None
Objective: Growth factor independence 1 (GFI1), a transcriptional repressor, is required for hematopoietic stem cell maintenance and self-renewal in addition to controlling differentiation and proliferation of myeloid cells. As murine studies have demonstrated that this transcription factor has a notable role in the initiation and progression of acute myeloid leukemia (AML) disease, the aim of the current study was to investigate and review the influence of GFI1 in human AML cells.
Methods: GFI1 expression levels were measured by means of real-time polymerase chain reaction in 96 primary AML samples which were then compared to gene expression levels observed in 18 healthy subjects. Moreover, GFI1 expression patterns were analyzed based on specific AML subtypes including acute promyelocytic leukemia (APL). Finally, leukemic cells were stained to measure levels of myeloperoxidase (MPO) activity.
Results: This study reports that AML patients have significantly higher GFI1 mRNA levels in comparison to healthy subjects and that, when considering AML subtypes, patients with APL have higher GFI1 expression than non-APL patients.
Conclusion: It is also concluded that GFI1 overexpression in patients with high MPO levels, such as those of the APL subtype, is correlated with favorable disease prognosis as supported by other studies which demonstrate that increased peroxide activity and GFI1 are independently correlated with a favorable prognosis
Keywords: Acute myeloid leukemia, acute promyelocytic leukemia, growth factor independence 1
|How to cite this article:|
Salarpour F, Goudarzipour K, Mohammadi MH, Ahmadzadeh A, Faraahi S, Allahbakhshian A, Farsani MA. Evaluation of growth factor independence 1 expression in patients with de novo acute myeloid leukemia. J Can Res Ther 2020;16:23-7
|How to cite this URL:|
Salarpour F, Goudarzipour K, Mohammadi MH, Ahmadzadeh A, Faraahi S, Allahbakhshian A, Farsani MA. Evaluation of growth factor independence 1 expression in patients with de novo acute myeloid leukemia. J Can Res Ther [serial online] 2020 [cited 2020 Jun 6];16:23-7. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/23/208752
| > Introduction|| |
Many hematologic malignancies arise at the stem cell level, and so, identifying factors involved in hematopoietic stem cells (HSCs) self-renewal, quiescence, and differentiation are paramount in the understanding disease mechanisms. One suggested factor is growth factor independence 1 (GFI1) which several studies have demonstrated is involved in HSCs maintenance and development. GFI1 is a zinc finger protein which is highly expressed in hematopoietic cells and acts as a transcriptional repressor. It is required for the maintenance of hematopoietic stem and progenitor cells while also playing a role in the development of multiple hematopoietic lineages.,
The role of GFI1 in normal hematopoiesis has been exhibited by murine studies. GFI1 knockout mice have few HSCs, reduced lymphoid cells, myeloid/erythroid hyperplasia, and neutrophilic maturation arrest., Reduced levels of GFI1 expression may also contribute to deficiency of neutrophil-specific granules. During myeloid development, GFI1 is a component of a regulatory network that determines lineage fate decision between granulocytic and monocytic compartments and helps granulocytic maturation. Myeloid precursors from GFI1−/− mice cannot differentiate into mature neutrophils, instead they differentiate into atypical monocytes. In contrast, the myeloid precursors during GFI1 overexpression differentiate to mature neutrophils more than monocytes.
Correspondingly, the significance of GFI1 in the development of hematological disorders in humans has been identified, notably mutations in the zinc finger domain of GFI1 result in myeloid hyperplasia and severe congenital neutropenia (SCN) in humans, which is characterized by failure in the development of mature neutrophils., In the case of inherited mutations of GFI1, these are more commonly associated with SCN and nonimmune chronic idiopathic neutropenia in adults. SCN is accompanied with almost complete lack of neutrophils, a condition that leads to recurrent infection, and in some cases, the disease will eventually transform into myelodysplastic syndromes (MDS) and myeloid leukemia.
It has been proven that GFI1 defects are associated strongly with hematologic malignancies including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML)., In the case of AML, it has been reported that GFI1 defects, specifically low gene expression, can promote the development of malignancy. On the contrary, other studies have demonstrated that it is GFI1 overexpression that accelerates T-ALL-like disease in murine models and that a specific variant allele of GFI1 is associated with AML. In summary, these findings suggest that GFI1 is necessary for leukemic cell survival and GFI1 ablation is associated with tumor regression. To conclude, it is conceivable that the role of GFI1 in hematological malignancies may be one as an oncorequisite factor – a normal cellular protein on which malignant cells depend for their survival. Certainly, further study is necessary to incisively define a role for GFI1 in AML.
Identifying the specific function of GFI1 in AML allows GFI1 to be considered as a valuable therapeutic target and prognostic marker. In one particular study, Hönes et al . reported that low expression of GFI1 in patients with AML was associated with a significantly shorter survival and GFI1 overexpression was associated with a more favorable prognosis. In the present study, GFI1 expression levels are measured in AML patients and analyzed in relation to different AML subtypes in particular the distinct subtype, acute promyelocytic leukemia (APL). In addition to this, myeloperoxidase (MPO) activity, a marker of myeloid differentiation, is measured in AML patients and GFI1 expression is analyzed in terms of MPO grades. This study aims to identify a correlation between GFI1 expression and prognostic risk based on AML subtypes and MPO grades as variables.
| > Methods|| |
Ninety-six bone marrow (BM) and peripheral blood (PB) samples were obtained from newly diagnosed patients with de novo AML and 18 samples from healthy subjects (used as a normal control) between the years 2013 and 2015 and after receiving informed consent according to the institutional guidelines. The patients were referred to Mofid and Emam Khomeini Hospital, Tehran, Iran. The median age of individuals in this study was 47 years, with a range of 2–87 years and mean age of 45.39 years. Samples were taken from 44 female to 52 male subjects.
RNA isolation, cDNA synthesis, real-time polymerase chain reaction
Total cellular RNA was extracted from BM and PB using an RNeasy kit (Qiagen, Germany). Following extraction, the amount and quality of RNA were measured by a NanoDrop (Thermo Scientific, USA). All samples showed high purity (OD 260/280 nm ratio >1.8) and integrity. Subsequently, 2 μL (0.5 mg) RNA was transcribed into cDNA to a final volume of 20 μL using a Thermo Scientific kit (USA). An aliquot of 1/10th of the resulting cDNA (1 μL) was used as substrate for quantitative real-time polymerase chain reaction (qRT-PCR) amplification.
Primers specific to GFI1 and ABL (housekeeping gene) were designed through Oligo 7.56 software [Table 1] which subsequently allowed levels of GFI1 and ABL mRNA expression in patients and healthy subjects to be detected by qRT-PCR (Rotor-Gene 6000, Bosch). The components in the qRT-PCR reaction for each gene consisted of 1 μL of template cDNA, 1 μL forward and reverse primer, 7 μL of RealQ Plus 2x Master Mix Green-Low ROX (Ampliqon, Denmark), and 6 μL water for a total reaction volume of 15 μL. For each qRT-PCR reaction, a standard curve was produced, using five consecutive 1:10 dilutions cDNA sample (1, 0.1, 0.01, and 0.001). The thermal cycling conditions for each reaction included an initial hold at 95°C for 10 min followed by 40 cycles of primary denaturation at 95°C for 10 s and annealing/extension at 65°C for 15 s and a final extension at 72°C for 10 min. In addition, negative controls were included in the assay and the assay was performed in duplicate. The relative quantification of mRNA expression for each sample (fold change = FQ) was calculated using the Livak method (2−△△ct).,
|Table 1: Nucleotide sequences of primers used for ABL and GF11 quantitative real-time polymerase chain reaction reactions|
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Analysis of the data generated was performed using SPSS 16.0 and GraphPad Prism 6.01 software. The results were expressed as mean ± standard error of the mean. A P = 0.05 or less was considered statistically significant. Shapiro–Wilk and Kolmogorov–Smirnov tests were used to evaluate normal distribution of data. T -test and ANOVA were applied to determine significant differences between GFI1 expression in AML patients and normal control group and to assess differential distribution of gene expression based on patient/disease characteristics.
| > Results|| |
Growth factor independence 1 expression is significantly higher in acute myeloid leukemia patient samples in comparison to healthy subjects
Through means of real-time PCR, Ct values for ABL and GFI1 were obtained. The mean Ct values for the housekeeping gene ABL in AML patients and the normal control group were measured at 27.45 ± 0.33 and 29.1 ± 0.31, respectively, and for the target gene GFI1 at 25.75 ± 0.25 and 29.14 ± 0.22, respectively. The mean expression level detected for GFI1 in AML patients and the normal control group was 10.64 ± 2.42 and 2.20 ± 0.93, respectively. A GFI1 expression level in the range of 95% confidence interval was defined at 0.21–4.18 as a normal expression level for a healthy population. Accordingly, patients were categorized into three subtypes, those whose GFI1 expression levels fell within the normal range were considered to have an intermediate expression level, while those with levels above 4.18 were defined as having high GFI1 expression, and patients with expression levels under 0.21 were defined as having low expression. In the present study, the majority of patients were categorized as having intermediate and high GFI1 expression levels [Table 2].
|Table 2: Clinical characteristics of 96 de novo acute myeloid leukemia patients based on GFI1 expression level status (low, intermediate, high)|
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The resulting Ct values obtained from GFI1 were normalized against the internal reference gene ABL for both AML patients and the normal control group. The normalized GFI1 expression was subsequently compared between patient and normal control groups. The comparison of relative gene expression between patients and the normal control groups showed a 4.83-fold increase in AML patients [Figure 1]a. A statistical analysis using t -test determined that there was a significant difference ( P < 0.0001) in expression levels between these two groups [Figure 1]b.
|Figure 1: Relative expression of growth factor independence 1 in 96 acute myeloid leukemia patients and 18 healthy patients was measured from Ct values and normalized against a reference gene (ABL). (a) There is a 4.83-fold increase in growth factor independence 1 expression in acute myeloid leukemia patients in comparison to the normal control group. (b) A mean growth factor independence 1 expression level of 10.64 ± 2.42 (standard error of the mean) was measured in acute myeloid leukemia patients in comparison to a mean growth factor independence 1 expression level of 2.20 ± 0.93 in the normal control group. A significant difference ( P < 0.0001) between growth factor independence 1 expression in acute myeloid leukemia patients and healthy subjects was identified|
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Growth factor independence 1 expression is significantly higher in acute promyelocytic leukemia patients in comparison to healthy subjects
GFI1 expression levels in each French–American–British (FAB) subtype (M0–M5) were compared to the normal control group and a statistically significant difference was only observed in the M3 subtype ( P < 0.001) [Figure 2]a Within the M3 subtype, a marked overexpression of GFI1, with a value of 7.33, was observed in comparison to the normal control group. With regard to the other subtypes, despite observed increases and decreases in relative GFI1 expression level in comparison to the normal control group statistical analysis deemed these differences to be insignificant.
|Figure 2: Normalized relative expression of growth factor independence 1 in 96 acute myeloid leukemia patients and 18 healthy patients based on varying disease subtypes. (a) Growth factor independence 1 expression is analyzed in patients based on their French–American–British classification (M0-M5). With an expression value of 7.33, the only acute myeloid leukemia subtype to show a significant difference in expression level in comparison to the normal control group is M3 ( P < 0.0001). (b) Patients are classified into three disease subgroups based on differentiation status without differentiation (M0/M1/M2 subgroup), granulocytic differentiation (M3 subgroup), and monocytic differentiation (M4/M5 subgroup). Growth factor independence 1 expression in comparison to the normal control group was only significantly higher in the M3 subgroup ( P < 0.0001) and also significantly higher than the M01/M1/M2 ( P = 0.021) and M4/M5 ( P = 0.035) subgroups|
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Consequently, the patients in this study were classified by broader disease subgroups instead of the FAB classification they were initially assigned by. Patients were assigned to a subgroup based on three morphological differentiation statuses; without differentiation (M0/M1/M2 subgroup, 44 patients), granulocytic differentiation (M3 subgroup, 30 patients), and monocytic differentiation (M4/M5 subgroup, 21 patients). When GFI1 expression levels in these subgroups were compared to the normal control group, once again, it was observed that a significant gene overexpression was detected only in the M3 subgroup ( P < 0.001) [Figure 2]b. GFI1 expression levels in the M3 subgroup (granulocytic differentiation) were also significantly higher than subgroups with monocytic differentiation and those without differentiation ( P = 0.021 and P = 0.035, respectively).
Growth factor independence 1 is expressed at higher levels in patients with acute promyelocytic leukemia as compared to other acute myeloid leukemia subtypes
As previously mentioned, patients with the M3 subtype exhibit markedly higher levels of GFI1 in comparison to healthy patients than other FAB subtypes and broader morphological AML subgroups [Figure 2]a and [Figure 2]b. This implied correlation between APL and significantly increased levels of GFI1 expression was further supported as subsequent data analysis demonstrated that there is a 1.97-fold increase in expression and significant gene overexpression ( P = 0.008) in the M3 subgroup when compared to all other subtypes as a single subgroup (non-M3) [Figure 3]. Moreover, it is only when patients are grouped as M3 and non-M3 as a whole, that a significant increased ( P = 0.035) GFI1 expression level can be detected in the non-M3 subgroup in comparison to the normal control group.
|Figure 3: Normalized relative expression of growth factor independence 1 in 96 acute myeloid leukemia patients classified as M3 and non-M3 and 18 healthy patients as a normal control group. There is a 1.97-fold increase in gene expression levels in the M3 subgroup than the non-M3 subgroup. Patients with M3 disease have significantly higher ( P < 0.0001) growth factor independence 1 expression levels in comparison to normal control group and significantly higher ( P = 0.008) expression levels in comparison to non-M3 patients. Patients with non-M3 disease have significantly higher ( P = 0.035) growth factor independence 1 expression levels in comparison to the normal control group|
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Growth factor independence 1 expression is significantly higher in acute myeloid leukemia patients with strong myeloperoxidase activity
Patient samples were assessed for MPO activity by peroxidase staining and subsequently graded and sub-grouped based on the percentage of MPO positive cells: rare (<3%), few (10%), some (50%), most (80%), and strong (100%). GFI1 expression levels were evaluated based on the aforementioned MPO grades and compared. The ANOVA test was applied for normal distribution, and as a result, a significant correlation ( P = 0.01) of GFI1 expression between MPO subgroups was observed. The Tukey test was applied to reveal the relationship between GFI1 expression and specific MPO grade, and it was observed that it was the patients with a “strong” MPO grade which has significantly higher GFI1 expression levels ( P < 000.1) in comparison to the normal control group [Figure 4]. Analysis between MPO grades determined that GFI1 expression levels of the “strong” grade are significantly higher ( P = 0.024) than those of the “rare” grade and there is in fact a 5.03-fold increase in expression levels of the “strong” grade as compared to the “rare” grade.
|Figure 4: Normalized relative expression of growth factor independence 1 in 96 acute myeloid leukemia patients graded by myeloperoxidase activity and 18 healthy patients as a normal control group. Patients are graded “rare” to “strong” based on the percentage of myeloperoxidase positive cells. Patients graded with “strong” myeloperoxidase activity, those with the highest number of myeloperoxidase positive cells, had growth factor independence 1 expression levels which were significantly higher ( P < 0.0001) in comparison to the normal control group. A 5.03-fold increase in growth factor independence 1 expression levels is observed in the “strong” grade in comparison to the “rare” grade (lowest number of myeloperoxidase positive cells) and a significant difference ( P = 0.024) is determined between these two grades|
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| > Discussion|| |
The significance of GFI1 has not only been established in the normal hematopoiesis process, but growing evidence strongly advocates a significant role for this transcription factor in the leukemogenesis process. To date, literature has described an association between GFI1 and the malignancy process in AML, CML, ALL, and MDS. Although it is widely accepted that GFI1 has a role in the development of hematological malignancies such as AML, the mechanism by which it promotes malignancy is considered uncertain due to contradictory literature. In the current study, it is proposed that it is the overexpression of GFI1 that is associated with AML and overexpression of GFI1 is correlated with a favorable prognosis.
In the present study, the investigation of the significance of GFI1 in AML was undertaken in a number of experimental steps. First, we aimed to establish the relationship between AML and GFI1 expression levels and as a result characterize the nature of GFI1 in malignancy. GFI1 expression levels in AML patients were measured and compared with a normal control group, and it was found that GFI1 is markedly overexpressed in patients with AML ( P < 0.0001) with a 4.83-fold increase which strongly suggests that GFI1 has an oncogenic role in AML; however, on the other hand, as GFI1 has tumor suppressor effects as well, it is not unlikely to suppose that the increased GFI1 expression may be a response of the cell to resist against malignancy process.
In agreement with these findings, Wang et al . demonstrated that GFI1 expression levels are significantly higher in leukemia patients including cases with AML, CML, and ALL. In addition, murine model studies have also reported that GFI1 has overexpression in some cases with AML and CML. Zhao et al . reported a mechanism by which GFI1 is targeted by the MYB proto-oncogene and like MYB blocks myeloid differentiation in the AML scenario. GFI1 overexpression and its oncogenic behavior have been reported by Zörnig et al . where it was observed in mice that GFI1 acts as a dominant oncogene and cooperates closely with oncoproteins c-MYC and Pim-1 in lymphoma development. A further murine model study conducted by Khandanpour et al . has described an association between GFI1 overexpression and T-ALL-like disease progression. Specifically, it was observed that GFI1 is necessary for the growth and survival of leukemic cells and that withdrawal of GFI1 leads to tumor regression and improved survival. In summary, there is sufficient evidence pointing to increased expression of GFI1 with oncogenic behavior in AML.
However, other studies contradicted the aforementioned observations. In one study conducted by Hönes et al ., they reported that low expression levels of GFI1 were correlated with reduced AML patient survival and advanced stages of MDS. Moreover, a subsequent study in a murine model noted that in MDS, low levels of GFI1 expression were associated with an adverse prognosis. In regard to CML, low levels of GFI1 expression were related to the progression of chronic to accelerated phase in this malignancy. Hönes et al . proposed that low levels of GFI1 expression induce initiation and progression of leukemia through upregulation of genes involved in leukemogenesis.
The discrepancy in recent studies could be due to GFI1 possessing a different role, one as a tumor suppressor which influences prevention of leukemia formation. It is possible that in the situation where GFI1 gene expression is reduced, GFI1 loses its tumor suppressor activity and malignancy develops; however, in the situation where there is a pattern of GFI1 gene overexpression, GFI1 switches its function from a tumor suppressor to one of an oncogene. To put simply, it can be deduced that GFI1 may act as a double-edged sword; GFI1 is involved in malignancy acting as an oncogene in certain conditions and as a tumor suppressor in others.
Following validation of the association of GFI1 overexpression in AML, we aimed to investigate the significance of GFI1 expression in terms of AML subtypes, in particular APL. The expression level of GFI1 between different morphological FAB subtypes of AML (M0 to M5) was compared to the normal control group and it was observed that the AML-M3 subtype had significantly higher GFI1 expression levels. To analyze the significance of GFI1 expression in patients with the APL subtype in comparison to other AML subtypes, patients were classified by their morphological differentiation status, and thereafter, it was observed that patients with APL (M3 subtype) had significantly higher levels of GFI1 expression in comparison with the M0/M1/M2 and M4/M5 subtypes ( P = 0.021 and P = 0.035, respectively).
Further analyses performed on our data revealed that GFI1 overexpression was observed in 50% of total patients, 21.8% in patients with APL, 19.79% in patients without differentiation, and 8.33% in patients with monocyte differentiation. In addition, when GFI1 expression was evaluated in APL patients, of the 30 patients assessed, 21 patients (70%) presented with overexpression, while in AML patients without differentiation, of the 44 patients assessed, 19 patients (43.18%) presented with overexpression. Meanwhile, in patients with AML of the monocytic differentiation subtype, of the 21 patients assessed, 8 patients (38.09%) presented with overexpression. From these findings, it can be deduced that only half of patients had GFI1 overexpression but expression levels in these patients were high enough to shift average GFI1 expression levels of patients to be significantly higher than the normal control group. Moreover, the majority of patients that presented with GFI1 overexpression belonged to the M3 subtype with the M0/M1/M2 and M4/M5 subtypes having the second most and least number of patients with GFI1 overexpression, respectively.
The aforementioned data reveal interesting insights into the relationship between GFI1 expression and AML subtypes, principally that there is a close correlation between GFI1 overexpression and the APL subtype. APL, classified as AML-M3 by the traditional FAB system, is considered a distinct subtype in leukemias and is characterized by a translocation between chromosomes 15 and 17 resulting in the production of an abnormal fusion protein, promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA). Although early death is common due to the acute onset of the disease, the prognosis of this subtype is relatively good in comparison to other leukemias. The significance of the correlation between GFI1 overexpression and APL in this study lies in the observation that because patients with the APL subtype have a more favorable prognosis than other AML patients, overexpression of GFI1 in this subtype indicates that GFI1 overexpression is, in fact, correlated with a more favorable prognosis. Other studies have described another perspective of correlation where low levels of GFI1 expression are associated with an adverse prognosis.,
Finally, we evaluated the correlation between GFI1 expression and the extent of MPO positivity in leukemic cells. Peroxidase levels are routinely checked to determine whether cells have myeloid differentiation or not and are utilized as a powerful prognostic tool; Matsuo et al . have previously demonstrated that AML patients with higher levels of MPO-positive blast cells are associated with a favorable prognosis. Our findings demonstrated that there is a close and positive correlation between GFI1 overexpression and higher extent of MPO staining. As peroxidase is an essential component of promyelocytic cells, which are the prominent cells in APL, APL patients have the highest level of peroxidase staining between different subtypes of AML. This finding demonstrates that GFI1 has highest levels of expression in APL's promyelocytes.,,,,
In this regard, our observation of simultaneous GFI1 overexpression and high levels of MPO positivity in PML-RARA-positive APL patients advocates the use of GFI1 expression assessment as an alternative tool for determination of prognosis. Further research focusing on establishing the specific role of GFI1 in AML and its mechanism of action will advance understanding of the paramount events in leukemia formation and consequently designing new therapeutic approaches and monitoring methods.
| > Conclusion|| |
GFI1 overexpression was observed in 50% of AML cases, and so, it can be concluded that GFI1 is involved in the malignancy process and its role in disease in the current study is one of the oncogenes. This study also presents establishment of a significant correlation between the PML-RARA-positive APL subtype and high levels of GFI1 expression. GFI1 overexpression was significantly higher in the APL subtype and the strong MPO grade in comparison to other AML subtypes and the rare MPO grade, respectively. Independent studies have demonstrated that the APL subtypes as well as high MPO activity, a characteristic of APL, are variables which are associated with a favorable prognosis and improved patient survival. In this study, both these variables are correlated with high levels of GFI1 expression; therefore, it is reasonable to propose that it is GFI1 expression that is the variable that influences prognosis. This is supported by other studies which suggest that GFI1 overexpression is related to a favorable prognosis while its underexpression is related to an adverse prognosis. Further evaluation of GFI1 expression in AML patients, in particular APL patients, is necessary to substantiate its correlation with prognosis and patient survival. If there is extensive evidence of a correlation, then GFI1 can potentially be utilized as a prognostic biomarker in APL patients.
We strongly appreciate the staffs of Shahid beheshti paramedical research center, Tehran, Iran.
This work was supported in part by Shahid Beheshti University of Medical Science, Tehran, Iran, and Department of Medical Research.
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]
[Table 1], [Table 2]