|Year : 2015 | Volume
| Issue : 4 | Page : 166-174
Prognostic significance of intracellular survivin in myeloid blast cells as an inhibitor of apoptosis in Egyptian adult acute myeloid leukemia patients
Mohamed Azzazi, Soha Ezz El-Arab, Hany M Hegab MD , Walaa Elsalakawy, Rasha Ibrahim, Mohammad Shazly
Department of Internal Medicine, Clinical Hematology and SCT Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||21-Aug-2015|
|Date of Acceptance||13-Sep-2015|
|Date of Web Publication||23-Nov-2015|
Hany M Hegab
Clinical Hematology and SCT Unit, Department of Internal Medicine, Faculty of Medicine, University of Ain Shams, 11321 Cairo
Source of Support: None, Conflict of Interest: None
Context Abnormalities in the control of apoptosis play an important role in tumorigenesis. Survivin is one of eight members of the inhibitor of apoptosis protein family that regulates and integrates cell division and suppresses apoptosis.
Aim The aim of this study was to assess intracellular expression of survivin on malignant myeloid blast cells and its correlation with clinical outcome, overall survival (OS), and other prognostic factors among adult Egyptian patients with acute myeloid leukemia (AML).
Settings and design A total of 120 patients with de-novo AML were treated and followed up in Ain Shams University Hospitals Hematology Units and compared with 60 age-matched and sex-matched normal healthy controls.
Patients and methods All patients received induction chemotherapy under a 3 + 7 regime, whereas AML-M3 patients received an all-transretinoic acid-based regime. Detection of intracellular survivin antigen in myeloid blast cells was done by flow cytometry on bone marrow samples at diagnosis and after chemotherapy.
Results Survivin expression was higher in AML patients at day 0 compared with healthy controls (P = 0.001). The highest survivin level was seen in AML French American British subtypes M5 and M4. A significant positive correlation was found between patients' age, CD15, CD14, and CD11c expression, whereas negative correlation was found between survivin level and the control group, which included 60 age-matched and sex-matched normal healthy volunteers under complete remission, and event-free survival. Patients with a positive survivin expression have shorter OS compared with patients with a negative survivin expression (log-rank = 3.940, P = 0.047).
Conclusion Higher survivin levels at diagnosis predict poor response to chemotherapy and shorter OS (P = 0.016).
Keywords: acute myeloid leukemia, apoptosis, chemotherapy, prognosis, survival, survivin
|How to cite this article:|
Azzazi M, El-Arab SE, Hegab HM, Elsalakawy W, Ibrahim R, Shazly M. Prognostic significance of intracellular survivin in myeloid blast cells as an inhibitor of apoptosis in Egyptian adult acute myeloid leukemia patients. Egypt J Haematol 2015;40:166-74
|How to cite this URL:|
Azzazi M, El-Arab SE, Hegab HM, Elsalakawy W, Ibrahim R, Shazly M. Prognostic significance of intracellular survivin in myeloid blast cells as an inhibitor of apoptosis in Egyptian adult acute myeloid leukemia patients. Egypt J Haematol [serial online] 2015 [cited 2020 Jan 18];40:166-74. Available from: http://www.ehj.eg.net/text.asp?2015/40/4/166/170199
| Introduction|| |
Acute myeloid leukemia (AML) is a malignant stem cell disorder characterized by a disruption in hematopoiesis resulting in accumulation of immature or blast cells in the bone marrow and the peripheral blood (PB). This leads to bone marrow failure, severe cytopenia, and death if left untreated  .
The incidence of AML increases with age, with the majority of patients older than 60 years. Elderly patients with AML have a particularly poor prognosis  .
Apoptosis is a highly evolutionarily conserved mechanism of cell death triggered by a large range of extracellular or intracellular stimuli, including developmental signals and environmental and intracellular stress. This is a genetically controlled process, playing a major role in normal development and tissue homeostasis. It is considered a potent mechanism of tumor protection  .
Survivin (Birc5) is a member of the family of inhibitors of apoptosis proteins (IAPs)  of which eight members are known, including X-linked inhibitor of apoptosis (XIAP), cIAP1, cIAP2, NAIP (NLR family, apoptosis inhibitory protein), livin, IAP-like protein 2 (ILP2), BRUCE, and survivin , .
It is expressed during embryonic and fetal development and by many different cancer cell types: survivin is expressed in lung cancer (85.5%), esophageal cancer (80%), breast cancer (70.7-90.2%), colorectal cancer (63.5%), AML (54.8%), and acute lymphocytic leukemia (68.8%)  . Unlike other IAPs, survivin is not expressed in differentiated normal tissue , .
Survivin, the smallest family member, is a 142 amino acid, 16.5 kDa protein encoded by a single gene located on the human 17q25 chromosome 8; it consists of three introns and four exons  and exists physiologically as a functional homodimer , .
Alternative splicing of survivin pre-mRNA produces five different mRNAs with the potential to encode up to five distinct proteins: survivin, survivin 2B, survivin ΔEx3, survivin 3B, and survivin 2a  .
Survivin has been implicated in both control of cell survival and regulation of mitosis in cancer  .
Survivin is upregulated during cell division and is closely associated with centrosomes and mitotic spindle microtubules. It controls chromosome spindle-checkpoint assembly, thereby ensuring normal cell division. Survivin is maximally expressed during the G2M phase of the cell cycle and exists predominantly as a multiprotein complex, known as the chromosomal passenger complex  . By functioning in this complex survivin can facilitate accurate sister chromatid segregation and stabilization of the microtubules in late mitosis , .
In addition to its direct role in carcinogenesis, survivin may also play a key role in tumor angiogenesis as it is strongly expressed in endothelial cells during the proliferative phase of angiogenesis  .
Results of in-vitro and in-vivo studies have shown that survivin downmodulation reduces tumor growth and sensitizes tumor cells to chemotherapeutic agents such as taxanes, platinum agents, etoposide, g irradiation, and immunotherapy  .
| Patients and methods|| |
The current study included 120 patients with untreated de-novo AML (52 females and 68 males), of a mean age of 42.2 ± 13.07 years (range: 18-59 years), who were treated and followed up for 2 years in Ain Shams University Hospitals Hematology Unit. They had been stratified according to French American British (FAB) classification of AML. The study was carried out from January 2012 until February 2014.
Sixteen patients had AML-M0, 32 had AML-M1, 32 had AML-M2, 12 had AML-M3, 16 had AML-M4, and 12 had AML-M5. The control group included 60 age-matched and sex-matched normal healthy volunteers.
All patients were treated according to our unit's ongoing induction and consolidation regimens. Patients were followed up for 1 year, and outcome was designated as either favorable or unfavorable.
Apart from AML-M3, patients received induction chemotherapy under a 3 + 7 regime: daunorubicin at 25 mg/m 2 /day for 3 days and cytarabine (Ara-c) at 200 mg/m 2 /day for 7 days continuous intravenous infusion.
Patients received a consolidation regime consisting of 1.5-3.0 g Ara-c/12 h intravenous infusion over 3 h on days 1, 3, and 5 in 4-monthly courses.
Patients with AML-M3 received induction with all-trans retinoic acid (ATRA) at 45 mg/m 2 daily and idarubicin at 12 mg/m 2 intravenous on days 2, 4, 6, and 8.
Patients received consolidation therapy consisting of ATRA at 45 mg/m 2 /day for 15 days together with idarubicin at 5 mg/day on days 1-4 (consolidation 1), mitoxantrone at 10 mg/m 2 /day on day 1 (consolidation 2), and idarubicin at 12 mg/m 2 /day on day 1 (consolidation 3).
Patients received maintenance treatment consisting of ATRA at 45 mg/m 2 /day for 15 days every 3 months plus 6-mercaptopurine at 90-100 mg/m 2 /day plus methotrexate at 15 mg/m 2 /week, all for 2 years.
Favorable outcome was considered when complete remission (CR) was achieved. CR status was determined 4 weeks after induction chemotherapy. It is defined by neutrophil count of at least 1.5 × 103/μl, platelet (PLT) count of more than 100 × 103/μl, bone marrow aspiration and biopsy that demonstrates at least 20% cellularity, less than 5% blasts and no Auer rods More Details, as well as absence of extramedullary infiltration.
Unfavorable outcome was considered with death. Informed consent was obtained from each participant after complete description of the study.
Patients with AML in relapse and patients younger than 18 years or older than 60 were excluded from the study.
Detection of intracellular survivin antigen in myeloid blast cells was done by flow cytometry on bone marrow samples at day 0 (D0) and D28 and then every 6 months or at each patient endpoint.
Detection of intracellular survivin antigen
Under complete aseptic conditions malignant myeloid blast cells were obtained by bone marrow aspiration and determination of the expression of human survivin was carried out using flow cytometry.
Immunophenotyping was carried out by flow cytometry using diagnostic kits supplied by Beckman Coulter (Fullerton, California, USA).
- PBS (1×): 0.137 mol/l NaCl, 0.05 mol/l NaH 2 PO 4 (pH 7.4) or Hank's Balanced Salt Solution (1×).
- Flow cytometry fixation buffer (R&D Systems, Minneapolis, Minnesota, USA), or an equivalent solution containing 1-4% paraformaldehyde.
- Flow cytometry permeabilization buffer/wash buffer I (1×; R&D Systems), or an equivalent solution containing a permeabilization agent such as saponin or Triton X-100.
- Detection antibodies.
- Isotype control antibodies.
- FACS tubes (5 ml round-bottomed polystyrene tubes), pipette tips and pipettes, centrifuge, and vortex.
- Harvest the cells and wash two times by adding 2 ml of PBS, centrifuging at 300g for 5 min, and then decanting buffer from pelleted cells.
- Aliquot up to 1 × 10 6 cells/100 μl into FACS tubes. Add 0.5 ml of cold flow cytometry fixation buffer and vortex. Incubate at room temperature for 10 min. Vortex the cells intermittently to maintain a single cell suspension.
- Centrifuge cells and decant the fixation buffer. Wash the cells two times with PBS as in step 1. Resuspend the cell pellet in 100-200 μl of flow cytometry permeabilization/wash buffer I.
- Add 10 μl of conjugated antibody (or a previously titrated amount) and vortex. Incubate cells for 30 min at room temperature in the dark.
- Wash cells two times with flow cytometry permeabilization/wash buffer I as in step 3.
- Resuspend the cells in 200-400 μl PBS for flow cytometric analysis.
For negative control, a separate set of cells were stained with an isotype control antibody. Survivin expression was considered positive when more than 20% of cells were positive.
Statistical presentation and analysis of the present study was conducted using mean, standard error, the Student t-test, the χ2 -test, and analysis of variance with SPSS (version 17; IBM corporation, New York, USA). Survival analysis was carried out using the KaplanMeier test, and comparison of survival between groups was made with the log-rank test. The P-value was then obtained from all these tests: P-value more than 0.05 was considered NS, P-value 0.05 or less was considered significant, and P-value 0.001 or less was considered highly significant.
| Results|| |
The characteristics of patients and controls are summarized in [Table 1].
The current prospective study included 120 adult patients with newly diagnosed AML with a mean age of 42.07 ± 12.55 years (range: 20-59 years). Among controls the mean age was 40.13 ± 7.73 years (range: 19.00-56.00 years). There was no statistical difference between patients and controls as regards age (P = 0.281) ([Table 1]).
The study included 52 (43.33%) female and 68 male patients. Of 120 adult patients with AML, 78 (63.33%) patients had positive survivin expression and 42 (36.67%) patients had negative survivin expression.
Survivin expression in patients and controls
Patients with AML had statistically higher mean survivin expression (40.0 ± 31.77) as compared with mean survivin expression in healthy controls (4.76 ± 2.95) on D0 ([Table 1]). Highest survivin level was seen in AML-M5 (FAB subtypes) followed by M4, M1, M0, M3, and M2 subtype. However, there was no statistically significant difference in mean survivin expression among different FAB subtypes (z = 12.033, P = 0.074) ([Table 2]).
|Table 2 Comparison among patients with different French American British subtypes as regards survivin expression |
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The mean age among AML patients with negative survivin expression was 35.27 ± 11.88 years and the mean age among AML patients with positive survivin expression was 47.00 ± 13.19 years, which showed a statistically significant difference (P = 0.0218) ([Table 3]).
|Table 3 Comparisons between acute myeloid leukemia patients as regards survivin expression according to sex, cytogenetic risk, age, postinduction chemotherapy, and follow-up |
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Among the 21 patients with unfavorable cytogenetics, eight (72.73%) were negative for survivin expression and 13 (68.42%) were positive for survivin expression. Among the nine patients with favorable cytogenetics, three (27.27%) were negative for survivin expression and six (31.58%) were positive for survivin expression.
Unfavorable cytogenetics (21 patients, 70%) was assigned if the patients were negative for t (8;21), t (15;17), and inversion 16. Favorable cytogenetics (nine patients, 30%) was assigned if the patients were positive for t(8;21), t (15;17), and inversion 16.
The mean survivin level in the unfavorable cytogenetics group was 32.78 ± 30.53, whereas the mean survivin level in the favorable cytogenetics group was 26.00 ± 20.43%. When compared with the mean survivin level at diagnosis (D0) according to cytogenetics risk analysis, the difference was statistically NS (P = 0.55) ([Table 2]).
Survivin expression in relation to response to therapy
With respect to response to induction chemotherapy, patients with unfavorable response had statistically significantly higher mean survivin expression at time D0 (56.67 ± 33.07), compared with mean survivin expression in patients with favorable response (CR; 25.501 ± 22.791) (P = 0.005) ([Table 3]).
After 1 year of follow-up, survivin expression was still higher in patients with unfavorable response (52.079 ± 34.340) compared with mean survivin expression of 24.308 ± 19.816 (P = 0.015) ([Table 3]).
A statistically significant positive correlation was detected between survivin level and age in AML patients (r = 0.544, P = 0.04) ([Table 4]).
|Table 4 Correlation analysis between survivin levels in acute myeloid leukemia patients at the time of diagnosis (day 0) and age, complete blood count, flow cytometry, and event-free survival of the patients |
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A statistically significant positive correlation was detected between survivin level in AML patients at diagnosis and level of CD14 (P = 0.04), CD15 (P = 0.00), and CD11c (P = 0.01) ([Table 4]).
Survivin expression and patients' survival
A negative correlation was found between survivin expression and event-free survival (r = –0.485, P = 0.040) ([Table 4]).
The difference in mean overall survival (OS) between AML patients with positive survivin expression (mean: 15 days) and AML patients with negative survivin expression (mean: 222.2 days) was statistically significant (log-rank: 3.940, P = 0.047) ([Table 5] and [Figure 1]).
|Figure 1 Kaplan-Meier curve for overall survival of acute myeloid leukemia (AML) patients with positive survivin expression and AML patients with negative survivin expression.|
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|Table 5 Comparison between the overall survival in acute myeloid leukemia patients with positive survivin expression and in acute myeloid leukemia patients with negative survivin expression using the log-rank test |
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| Discussion|| |
AML is an aggressive, clonal myeloid neoplasm with maturation arrest of myelopoiesis, leading to an accumulation of myeloblasts in the bone marrow and/or blood  .
Survivin has been implicated in the regulation of apoptosis, cell division, and cell cycle both in cancer cells and normal tissues, through caspase-dependent and independent mechanisms  .
In the present study, a higher statistically significant difference in survivin expression was found in AML patients (40.05 ± 31.77) when compared with survivin expression in the control group (4.76 ± 2.95) (P < 0.001); this is in concordance with data reported by Sun et al.  , who showed that the expression of survivin in newly diagnosed AML patients was higher than that of normal controls (P < 0.01).
The mean age of AML patients with positive survivin expression (47 ± 13.191 years) and the mean age of AML patients with negative survivin expression (35.273 ± 11.875 years) showed a statistically significant difference (P = 0.0218) and this is supported by data reported by Adida et al.  that survivin-positive patients had more advanced median age when compared with the survivin-negative group (43 vs. 35 years; P = 0.09).
In contrast, Sun et al.  reported that the expression of survivin did not correlate with the age of patients.
When comparing the mean survivin level in male AML patient (47.26 ± 32.94) with the mean survivin level in female AML patients (34.53 ± 30.67), the result was statistically NS (P = 0.284), which is in agreement with data reported by Sun et al.  that survivin did not correlate with sex of the patients.
The results obtained from complete blood count, bone marrow aspiration, and blood chemistry revealed no significant correlation between survivin level and white blood cell (WBC), hemoglobin, PLT, PB blasts, bone marrow blasts, lactate dehydrogenase, and uric acid (UA) with P-values of 0.532, 0.889, 0.704, 0.314, 0.500, 0.734, and 0.952, respectively. These results are in accordance with data reported by Sun et al.  that expression of survivin did not correlate with WBC.
In contrast, data reported by Sadek et al.  showed a statistically negative correlation between survivin expression and red blood cell count, hemoglobin level, and PLT count, with P = 0.01, 0.01, and 0.001, respectively, and positive correlations between survivin and total leukocyte count, PB blasts, bone marrow malignant cells, lactate dehydrogenase, alkaline phosphatase (ALK), and uric acid (P = 0.0001, 0.0001, 0.03,0.0001, 0.006, and 0.001, respectively). Also, Adida et al.  showed that survivin expression correlated with lower WBC count (P = 0.008).
Comparison of the flow cytometry results with the results of survivin expression showed that there was no statistically significant correlation between CD34 expression and survivin level (P = 0.204), which is concordant with data reported by Cartier et al.  that survivin levels were significantly higher in CD34+ CD38- AML stem/progenitor cells than in bulk blasts and total CD34+ AML cells (P < 0.05). However, Fukuda and Pelus  have reported the expression of survivin in umbilical cord blood and adult bone marrow CD34+ cells.
We did not find any significant correlation between survivin expression and expressions of CD33, HLADR, myeloperoxidase, CD13, CD117, CD64, CD7, CD5, and CD19 (P = 0.585, 0.073, 0.741, 0.842, 0.241, 0.150, 0.725, 0.969, and 0.269, respectively).
Positive correlation was found between survivin expression and CD15 (P = 0.004), which was in agreement with the study by Read et al.  for identification of CD15 as a marker for tumor propagating cells in a mouse model of medulloblastoma. Their results showed that expression of proapoptotic genes (including those encoding the ubiquitin ligase Fbxo7, the Bcl-2-interacting protein harakiri, and the apoptosis-inducing factor Aifm3) was markedly lower in CD15-positive cells compared with CD15-negative cells, whereas the antiapoptotic protein Birc5/survivin was higher and CD15 was the only marker tested that consistently enriched for tumor propagation.
Data reported by Altznauer et al.  showed that immature neutrophils express large amounts of survivin protein compared with terminally differentiated cells, which express no or little survivin; further, elevated survivin levels in mature neutrophils are observed in active inflammatory diseases such as acute appendicitis, ulcerative colitis, and cystic fibrosis, and these infiltrating neutrophils were identified using an anti-CD15 mAb.
CD15 mediates phagocytosis and chemotaxis found on neutrophils  . It is expressed in patients with Hodgkin's disease, some B-cell chronic lymphocytic leukemias, acute lymphoblastic leukemias, and most acute nonlymphocytic leukemias. It is also called Lewis X and stage-specific embryonic antigen 1 (SSEA-1) and represents a marker for murine pluripotent stem cells, in which it plays an important role in adhesion and migration of cells in the preimplantation embryo. It is synthesized by fucosyltransferase 4 (FUT4) and FUT9  .
Positive correlation was found between survivin and CD11c (P = 0.019). This is in accordance with data reported by Mera et al.  that extracellular survivin possesses immunomodulatory properties. It binds to the surface of the majority of granulocytes and a significant part of lymphocytes and monocytes, inducing the activation of α-chains of β-integrins and their ligand ICAM-1. In vivo, high circulating survivin levels are associated with an increased expression of CD11c on monocytes and granulocytes in patients with rheumatoid arthritis.
CD11c, a member of the leukocyte function associated family of molecules, is a 150 kDa type I transmembrane glycoprotein, which is also known as integrin  .
Expression of CD11c by monocyte progenitors is useful for the subclassification of AML. Up to 50% of AML cases with monocytoid differentiation (acute monoblastic leukemia, acute monocytic leukemia, and acute myelomonocytic leukemia) are CD11c positive, as demonstrated by immunophenotyping of cell smears and by flow cytometry  .
Positive correlation was found between survivin and CD14 (P = 0.0461). CD14 exists in two forms, one anchored to the membrane by a glycosylphosphatidylinositol tail (mCD14), the other a soluble form (sCD14). Soluble CD14 either appears after shedding of mCD14 (48 kDa) or is directly secreted from intracellular vesicles (56 kDa)  .
CD14 is expressed mainly by macrophages and neutrophils. It is also expressed by dendritic cells. The soluble form of the receptor (sCD14) is secreted by the liver and monocytes  .
Concerning the outcome of our studied patients, difference in survivin expression level during the postinduction period between patients who achieved CR (favorable response) and those who did not achieve CR (unfavorable response) was statistically significant (P = 0.005). At 1-year follow-up, leukemic patients who achieved CR (favorable response) showed significant change of expression of survivin when compared with those who did not achieve CR (unfavorable response) (P = 0.015).
These results are in accordance with data reported by Zhu et al.  that showed that CR rate in the survivin-positive AML patients receiving chemotherapy was significantly less than that in the survivin-negative AML ones (P = 0.018).
Further data reported by Ibrahim et al.  showed that 81.2% of patients with survivin expression had unfavorable response to chemotherapy and that 100% of patients with expression of both survivin and XIAP had unfavorable response to induction therapy as well as the shortest median survival (30 days).
Sun et al.  showed that survivin-positive patients had lower CR and higher relative relapse rates; however, this was not statistically significant.
The difference in OS between AML patients with positive survivin expression and AML patients with negative survivin expression was statistically significant (P = 0.047) and there was significant negative correlation between survivin and date of death (P = 0.040).
Netterwald  had reported that higher survivin levels predicted shorter OS (P = 0.016). However, Adida et al.  showed no significant difference in CR rate or OS between survivin-positive and survivin-negative AML patients (P = 0.15 by the log-rank test).
Survivin was expressed in 63.33% (19 patients) of 30 AML patients. Also Mori et al.  reported survivin expression in 17 of 31 (54.8%) AML patients.
The comparison of survivin level in AML patients with the results of cytogenetic studies revealed no significant difference between the two groups (P = 0.648).
This result is in agreement with that reported by Wagner et al.  that neither expression of survivin nor of any splice variant correlated with cytogenetic risk groups. However, the results were not in agreement with the results reported by Adida et al.  that survivin expression was significantly associated with favorable/intermediate cytogenetics (P = 0.03).
We also found no significant difference between survivin expression and AML FAB subtypes (maturation stage) (P = 0.063). This is in agreement with the results reported by Wagner et al.  that neither expression of survivin nor of any splice variant correlated with AML FAB subtypes.
| Conclusion|| |
Our results provide further evidence that survivin plays a role in the pathophysiology of AML. Survivin is an important factor involved in the control of apoptosis in malignant cells. In the present study survivin expression was higher in AML patients than in controls, and in older AML patients compared with younger patients; however, there was no statistically significant correlation between survivin expression and sex. There was a positive correlation between survivin expression and CD15, CD14, and CD11c. Higher survivin levels at diagnosis predicted shorter OS (P = 0.016). A statistically significant negative correlation was found between survivin level at D0 and CR, OS, event-free survival, and progression-free survival. CR was achieved in patients with negative survivin expression more than in patients with positive survivin expression, after induction chemotherapy and at 2 years of follow-up.
Being preferentially and highly expressed in cancer cells, with little expression in normal tissues, makes it an attractive therapeutic target for inhibiting cancer growth by inhibiting extrinsic and intrinsic apoptotic pathways and conferring resistance to apoptosis by directly suppressing caspase activity.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]