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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 627-633

Prognostic value of Prominin-1 Expression in Egyptian children with Acute Lymphoblastic Leukemia: Two centers Egyptian study


1 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Pediatric, Faculty of Medicine, Elmenofia University, Elsadat, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Web Publication25-Jul-2016

Correspondence Address:
Adel A Hagag
16 Elemam Moslem street branched from Elhelw Street, Tanta, Gharbia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148717

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 > Abstract 


Objectives: Acute lymphoblasstic leukemia (ALL) is the most common childhood malignancy. Prominin-1 is a cell-surface trans-membrane glycoprotein expressed on the stem cell surface and has potential role in diagnostic and prognostic work-up of several stem cell cancers.
Aim of this Work: To assess the prognostic value of Prominin-1 expression in Egyptian children with ALL.
Subjects and Methods: This study was conducted on 80 Egyptian children with newly diagnosed ALL and 30 healthy children of matched age and sex as a control group. Patient history, and clinical and laboratory examination results were taken, including complete blood count, serum LDH, bone marrow aspiration with cytochemistry, immunophenotyping, Fluorescent In Situ Hybridization technique for detection of t(9;22) and Flow cytometery for estimation of Prominin-1 expression on blast cells.
Results: No statistically significant differences were observed between Prominin-1 positive and negative patients regarding age, sex and clinical presentation at diagnosis. No statistically significant differences between Prominin-1 positive and negative patients were observed regarding white blood cells and platelet counts, peripheral blood and bone marrow blast cells percentage while there were significantly higher hemoglobin and LDH levels in Prominin-1 positive patients. There were no significant differences between Prominin-1 positive and negative patients regarding immunophenotyping and t(9;22). There were statistically significant differences in disease outcome between Prominin-1 positive and negative expression with higher rate of relapse and death and lower rate of complete remission in patients with Prominin-1 positive expression (14 cases with Prominin-1 positive relapsed versus 2 cases with Prominin-1 negative, 12 cases with Prominin-1 positive died versus 2 cases with Prominin-1 negative and complete remission occurred in 20 cases with Prominin-1 positive versus 30 cases with Prominin-1 negative) (P =0.017). There was statistically significant difference in disease-free survival (P = 0.0072) and overall survival (P = 0.0424) between ALL patients with Prominin-1 positive and Prominin--1 negative expression.
Conclusion: Prominin-1 is a helpful prognostic marker in patients with ALL; therefore, it should be routinely assessed at diagnosis in ALL patients for better prognostic assessment and should be taken in consideration in designing future therapeutic strategies based on patient-specific risk factors.

Keywords: Acute lymphoblastic leukemia, prominin-1 (CD133), stem cell markers


How to cite this article:
Hagag AA, Elmashad GM, Abd El-Bar ES. Prognostic value of Prominin-1 Expression in Egyptian children with Acute Lymphoblastic Leukemia: Two centers Egyptian study. J Can Res Ther 2016;12:627-33

How to cite this URL:
Hagag AA, Elmashad GM, Abd El-Bar ES. Prognostic value of Prominin-1 Expression in Egyptian children with Acute Lymphoblastic Leukemia: Two centers Egyptian study. J Can Res Ther [serial online] 2016 [cited 2019 Dec 8];12:627-33. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/627/148717




 > Introduction Top


Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, representing one-third of pediatric cancers. With aggressive multimodality therapy, it has become curable disease in more than 80% of patients; however, the treatment results in significant morbidity and mortality. The use of risk-adapted treatment protocols has improved cure rates while limiting the toxicity of therapy.[1]

The discovery of cancer stem cells (CSCs) has played a pivotal role in changing the view of carcinogenesis and chemotherapy.[2] Several markers have been identified for characterization of CSCs.[3] Prominin-1 is a cell-surface trans-membrane glycoprotein expressed on the surface of stem cells, including normal and CSCs.[4] Prominin-1 represents a marker of CSCs that has been shown to be more specific in hematopoietic malignancies than CD34[5] and may provide alternative to the usual CD34 monoclonal antibodies.[6] In contrast to CD34 antigen, Prominin-1 antigen is lost very early during the differentiation process.[7]

Prominin-1 positive cells are expressed in both acute and chronic myeloid and lymphoid leukemia of adult and pediatric patients.[8] High expression of Prominin-1 may be an adverse prognostic factor in patients with acute leukemia,[9] which is associated with

lower complete remission (CR) and overall survival (OS) rates.[10] Thus it seemed reasonable to undertake this study to assess the prognostic value of Prominin-1 (CD133) expression in Egyptian children with ALL.


 > Subjects and Methods Top


This study was done after approval from the ethics committee and written consent was obtained from parents of all children included. This study was conducted on 80 Egyptian children (52 males and 28 females) with newly diagnosed ALL in the period from January 2011 to June 2014 with their mean age at diagnosis of 8 ± 2.6 years (range, 3–11 years). Thirty healthy children (17 males and 13 females) were included in this study as a control group with main age of 8.75 ± 1.40 years (range, 4–12 years).

Diagnosis and classification of ALL were made on the basis of clinical presentation, morphological, cytochemical smears together with immunophenotyping. Immunophenotyping for diagnosis was done by Flow cytometry using the following markers: CD34, TdT and HLA-DR for hematopoietic progenitor cells, CD3 and CD7 for T-cell and CD10 and CD19 for B cell. Diagnosis was based on the presence of 20% or more blast cells in bone marrow (BM) according to WHO proposal and immunophenotyping results consistent with ALL.[11] The studied patients were treated according to ALL treatment protocol [12],[13],[14],[15],[16],[17],[18],[19] and were monitored during the period of follow up which lasted for 36 months.

For all patients the following were done at time of diagnosis

Patient history, and clinical and laboratory examination results were taken, including complete blood count, serum LDH levels, BM aspiration with morphological, cytochemistry and immunophenotypic classification: 1 ml BM and 2 ml venous blood were collected from each patient under complete aseptic conditions in EDTA tubes for complete blood count and BM morphologic, cytochemistry and immunophenotyping.[20] Follow-up of patients was carried out clinically and by blast count in BM on day 21 of induction chemotherapy. If BM blast cells is more than 5% on day 21, we add Etoposide 100 mg/m 2/dose IV (days 22, 25, 29), Cyclophosphamide 750 mg/m 2/dose IV infusion (days 22, 25, 29), Aracytine 100/m 2/dose IV (days 22, 25, 29), and high-dose methotrexate 5 g/m 2 over 4 h on day 28.[12]

Immunophenotyping for assessment of Prominin-1 expression in blast cells was done using Becton-Dickinson FAC Scan flow cytometer (BD FACS). Two milliliters of BM or peripheral blood samples were withdrawn into a sterile tube containing EDTA. Direct incubation with monoclonal antibodies (moAbs) followed by erythrocyte lysis was done. Monoclonal antibodies (AC141)-PE, anti-human reagent were used for identification of cells expressing Prominin-1 labeled with phycoerythrin (PE), commercially available by Miltenyi Biotec Inc, 2303 Lindbergh Street, Auburn, CA 95602, USA.[21] The percentage of Prominin-1 positive blast cells was determined as a percentage from the gated blast cells population. Samples were considered positive for Prominin-1 expression if ≥ 20% of the gated blast cells showed specific labeling with AC141 MoAb [21] [Figure 1].
Figure 1: Flow cytometric histogram showing positive CD133 (solid violet curve) vs. positive CD34 (red doted curve) and negative control (green colored curve) (to the left) and positive CD133 (solid violet curve) vs. negative CD34 (green colored curve) (to the right)

Click here to view


Fluorescent in situ hybridization (FISH) for detection of t(9;22): BM specimens were cultured for 72 hours at 37o C in RPMI medium supplemented with 10% fetal bovine serum without the addition of any mitogen (un-stimulated). Colcemid (0.02 µg/ml) was added to the cultures 30 minutes before harvest. After 30 minutes of hypotonic treatment with 0.075 M KCL, the cells were fixed with methanol and acetic acid (3:1) and made into slide preparations. Hybridization mixture (10 µl) was then applied to each slide, which was cover-slipped and sealed. Hybridization solution contained hybridization buffer, purified water, and the specific probe. Specific probe LSI BCR-ABL dual color DNA probe hybridizes to chromosome 9q34, and chromosome 22q11.2 for detection of t (9;22) (q 34, q 11.2) was used. FISH assay was performed according to manufacturer's (Vysis, Abbott # 32-190022) instructions. Analysis of cells was done under fluorescence microscope equipped with Quips spectra vision hardware and software [22][Figure 2].
Figure 2: FISH technique showing a case with BCR –ABL fusion gene

Click here to view


Protocol of treatment used in the studied ALL patients at diagnosis

Induction (6 weeks)

IV Vincristine 1.5 mg/kg/m 2/week (days 0, 7, 14, 21, 28, 35), Doxorubicin 25mg/m 2/week IV infusion (days 0, 7, 14, 21, 28, 35), asparaginase 6000 U/m 2 SC on alternate days (10 doses) and oral prednisone 40 mg/m 2/day for 6 weeks were given. On day 21, BM aspiration was done; If BM blast cells is more than 5%, we add Etoposide 100 mg/m 2/dose IV (days 22, 25, 29), Cyclophosphamide 750mg/m 2/dose IV infusion (days 22, 25, 29), Aracytine 100/m 2/dose IV (days 22, 25, 29), and methotrexate 5g/m 2 over 4 hours on day 28.[12]

Consolidation (9 weeks)

IV methotrexate 1g/m 2/dose over 24-hour infusion on days 0, 21, 42 and 63, oral mercaptopurine 60 mg/m 2 daily on days 0-13 and 28-41, IV vincristine 1.5 mg/m 2 on days 14, 21, 42 and 49, PEG asparaginase 2,500 units/m 2 IM on days 14 and 22, Cyclophosphamide 750 mg/m 2/dose IV infusion on days 0 and 28, Aracytine 100/m 2/dose IV on days 1-4, 8-11, 29-32 and 36-39 and age-adjusted intrathecal methotrexate on days 1, 8, 15 and 22.[13],[14]

Interim maintenance (6 weeks)

IV Vincristine 1.5 mg/m 2 on days 0, 10, 20, 30, 40, IV methotrexate starting dose of 100 mg/m 2/dose over 10-15 minutes on day 0 thereafter escalate by 50 mg/m 2/dose on days 10, 20, 30 and 40, PEG asparaginase 2,500 units/m 2 IM on days 1 and 21

and age-adjusted intrathecal methotrexate on days 0 and 30.[14]

Delayed –intensification (6 weeks)

Oral dexamethasone (10 mg/m 2/day on days 1-7 and 14-21, IV Vincristine 1.5 mg/m 2 on days 0, 7 and 14, IM or IV pegylated L-asparaginase 2500 U/m 2 on day 4, doxorubicin 25 mg/m 2 IV push on days 0, 7 and 14, IV Cyclophosphamide 1 g/m 2 over 30 minutes on day 28, oral 6-thioguanine 60 mg/m 2 on days 28-41, Aracytine 75 mg/m 2 on days 29-32 and 36–39 and age-adjusted intrathecal methotrexate on day 28.[15]

Maintenance (30 months)

Weekly IV methotrexate 20 mg/m 2, prednisone 120 mg/m 2/day for 5 days every 3 weeks, vincristine 2 mg/m 2 IV every 3 weeks, oral 6-mercaptopurine 50 mg/m 2/day for 14 days every 3 weeks and age-adjusted intrathecal methotrexate every 18 weeks.[16]

Imatinib therapy and BMT

In patients with t(9;22), Imatinib (Gleevic) was given in combination with chemotherapy in dose of 340 mg/m 2/day (not exceeding 600 mg) till CR [17] followed by

Allogeneic HSCT

after first remission in patients with t(9;22).[18]

Protocol of treatment used in patients at relapse

Induction and consolidation consisted of nine alternating short courses of intensive poly-chemotherapy (three each of R1, R2, and R3. R1 includes oral dexamethasone 20 mg/m 2/day on days 1-5, oral mercaptopurine 100 mg/m 2/day on days 1-5, IV vincristine 1.5 mg/m 2/day on days 1 and 6, methotrexate 5 g/m 2/ 24 hours IV infusion on day 1, IV cytarabine 2 × 2 g/m 2/day on day 5, L-asparaginase 25,000 U/m 2/day IM on day 6 and age-adjusted intrathecal methotrexate on day 1. R2 includes oral dexamethasone 20 mg/m 2/day on days 1-5, oral thioguanine 100 mg/m 2/day on days 1-5, Vindesine 3 mg/m 2/day IV on day 1, methotrexate 5 g/m 2/ 24 hours IV infusion on day 1, IV daunorubicin 50 mg/m 2/day on day 1, IV Ifosfamide 400 mg/m 2/day on days 1-5, L- asparaginase 25,000 U/m 2/day IM on day 6, and age-adjusted intrathecal methotrexate on day 1. R3 consisted of oral dexamethasone 20 mg/m 2/day on days 1-5, L-asparaginase 25,000 U/m 2/day IM on day 6, cytarabine (four rounds of 2 g/m 2 IV on day 1,2) and Etoposide (three rounds of 150 mg/m 2 IV on days 3-5), age-adjusted intrathecal methotrexate on day 5. All patients received maintenance therapy with daily thioguanine 50 mg/m 2 orally and Methotrexate 50 mg/m 2 IV every other week for 2 years.[19]

Definition of disease response and relapse

CR is defined as cellularity of more than 20% with fewer than 5% blasts in BM after induction chemotherapy.[23] Relapse is defined by appearance of more than 50% lymphoblasts in a single BM aspirate or more than 25% lymphoblasts in the BM and 2% or more circulating lymphoblasts or progressive repopulation of lymphoblasts in excess of 5% culminating in more than 25% on two or more BM samples separated by 1 week or more or leukemic cell infiltration in extramedullary organs as gonads or lymphoblasts in CSF with cell count greater than 5 WBCs/mm 3.[15]

Statistical analysis

The collected data were collected and statistically analyzed using SPSS software statistical computer package version 12. All Data were expressed as in terms of mean values ± SD. The difference between two means was statistically analyzed using the student (t) test. Chi-square test (χ2) and Fischer exact test was used as a test of significance. Log-rank test was used to assess survival. Significance was adopted at P < 0.05.


 > Results Top


There were no statistically significant differences between Prominin-1 positive and negative patients regarding age, sex and clinical presentation at time of diagnosis, including pallor, purpura, hepatomegaly, splenomegaly, lymphadenopathy and CNS infiltration [Table 1].
Table 1: Comparison between prominin-1 positive and prominin-1 negative expression in patients group regarding clinical and laboratory data

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There were no statistically significant differences between Prominin-1 positive and negative patients regarding white blood cells (WBCs) and platelet counts, peripheral blood and BM blast cell percentage, while there were significantly higher hemoglobin and LDH levels in Prominin-1 positive patients [Table 1].

There were no significant differences between Prominin-1 positive and negative patients regarding immunophenotyping with non-significant association between different studied immunophenotypic markers and Prominin-1 expression [Table 2].
Table 2: Comparison of immunophenotyping between prominin-1 positive and prominin-1 negative expression in studied patients

Click here to view


There were statistically significant differences in disease outcome between Prominin-1 positive and negative expression

with higher rate of relapse and death and lower rate of CR in patients with Prominin-1 positive expression (CR occurred in 20 cases with Prominin-1 positive versus 30 cases with Prominin-1 negative, relapse occurred in 14 cases with Prominin-1 positive versus 2 cases with Prominin-1 negative, death occurred in 12 cases with Prominin-1 positive versus 2 cases with Prominin-1 negative) (P value 0.017) [Table 3]. The causes of death in patients with Prominin-1 positive expression were meningitis (6 cases), febrile neutropenia (5 cases), intracranial hemorrhage (2 cases), and tumor lysis syndrome (1 case) while death in the 2 patients with Prominin-1 negative was due to septicemia.
Table 3: Outcome of studied patients in relation to prominin -1 expression

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There was statistically significant difference in disease-free survival (P = 0.0072) and OS (P = 0.0424) between

ALL patients with Prominin-1 positive and Prominin-1 negative expression. [Table 4] and [Figure 3] and [Figure 4].
Table 4: Log rank test of overall and disease-free survival

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Figure 3: Kaplan Meir curve showing overall survival (OAS) in Prominin-1 positive and negative ALL patients

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Figure 4: Kaplan-Meir curve showing disease-free survival (DFS) in Prominin-1 positive and negative ALL patients

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t(9,22) (Philadelphia chromosome positive ALL) was found in 3 cases with Prominin-1 positive and 1 case with Prominin-1 negative with no significant differences between Prominin-1 positive and negative patients regarding t(9,22) [Table 1].


 > Discussion Top


The current study was carried out on 80 Egyptian children with newly diagnosed ALL to assess the prognostic value of Prominin-1 expression in these patients.

In this study, positive Prominin-1 expression was found in 56/80 (70%) of studied patients. This is in agreement with Buhring et al. (2002)[24] who found nearly similar incidence (67%), while Guenova and Balatzenko (2008)[25] found positive Prominin-1 expression in only 30% and Elgendy et al. (2010)[26] reported Prominin-1 expression in 40% of patients with ALL.

In the present study, there were no statistically significant differences between Prominin-1 positive and negative patients regarding age, sex and clinical presentation at the time of diagnosis, including pallor, purpura, hepatomegaly, splenomegaly, lymphadenopathy and CNS infiltration. These results were in agreement with Zhou et al. (2005)[10] Guenova and Balatzenko (2008)[25] and Elgendy et al. (2010)[26] who found no significant differences between Prominin-1 positive and negative patients regarding age and sex and clinical presentation at the time of diagnosis.

In the present work, there were no significant differences between Prominin-1 positive and negative expression regarding initial WBCs and platelet counts, percentage of blast cells in peripheral blood and BM, but there was significantly higher Hb and LDH levels in Prominin-1 positive patients. These results were in agreement with Wang et al. (2007)[9] who found no significant association between Prominin-1 expression and any of the laboratory variables. Guenova and Balatzenko (2008)[25] and Elgendy et al. (2010)[26] found no correlation between Prominin-1 and laboratory variables, including WBCs count and Hb levels; however, they found significant association between Prominin-1 positive expression and percentage of peripheral blood blasts among ALL patients.

In the current study, there were no significant differences between Prominin-1 positive and negative expression regarding immunophenotyping with non-significant association between any of the studied immunophenotypic markers and Prominin-1. This is in concordance with Elgendy et al. (2010)[26] who found the same results and Guenova and Balatzenko (2008)[25] who reported that Prominin-1 expression could be detected in AML and B-cell and T-cell ALL and they concluded that Prominin-1 expression is not reliable for lineage distinction between AML and ALL while this is in disagreement with Zhou et al. (2004)[27] who found significant correlation between Prominin-1 and CD34 and HLA-DR expression.

In our study, there were statistically significant differences in disease outcome between Prominin-1 positive and negative expression with higher rate of relapse and death and lower rate of complete remission, disease free survival and overall survival in Prominin-1 positive expression compared with Prominin-1 negative expression. This is in agreement with Zhou et al. (2005)[10] who found lower CR and survival rates in Prominin-1 positive cases especially if co-expressed with CD34, Cox et al. (2009)[28] who found the same results and explained the poor clinical outcomes associated with positive Prominin-1 expression by increased resistance of Prominin-1 positive cells to chemotherapeutic agents especially dexamethasone and vincristine,[28] which in turn is attributed to higher expression of multidrug resistance gene, breast cancer resistance protein1 (BCRP1) as well as genes that inhibit apoptosis in the Prominin-1 expressing CSCs [29] and Mak et al. (2012)[30] who studied the functional role of Prominin-1 in the MLL-AF4–dependent ALL cells and found that Prominin-1 was required for leukemia cell survival and therefore may represent a bad prognostic factor in patients with ALL.

Also this was in agreement with some studies that were done to clarify the prognostic value of Prominin-1 expression in solid tumor, including Brugnoli et al. (2013)[31] who studied correlation between the levels of Prominin-1 expression and the biology of breast cancer and found that Prominin-1 high cells show higher invasive capability and increased expression of proteins involved in metastasis and drug-resistance of breast cancer, Qu et al. (2013)[32] who studied the prognostic value of Prominin-1 expression in 1,004 patients with non-small cell lung cancer and found that Prominin-1 expression had a significant worse 5-year OS and was associated with common clinicopathological poor prognostic factors and Zhang et al. (2014)[33] who studied the prognostic value of Prominin-1 expression in patients with lung adenocarcinoma and found that Prominin-1 positive cells expressed high levels of vascular endothelial growth factor and exhibited high migration and invasion capability.

Variation between the results of this work and the previous studies may be due to the different number of studied patients, different behavior of ALL in different localities, different age of studied patients, and different time and duration of these studies.


 > Conclusion Top


From the current study, we concluded that Prominin-1 positive expression

is a helpful prognostic marker in patients with ALL.


 > Recommendations Top


Prominin-1 should be routinely assessed at diagnosis in ALL patients for better prognostic assessment and should be taken in consideration in designing future therapeutic strategies based on patient-specific risk factors.

 
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[PUBMED]    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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