|Year : 2017 | Volume
| Issue : 3 | Page : 88-94
CD135 expression in childhood acute lymphoblastic leukemia: association with chromosomal aberrations and survival
Deena M.M Habashy
Hematology Unit, Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||16-Jul-2017|
|Date of Acceptance||16-Jul-2017|
|Date of Web Publication||9-Nov-2017|
Deena M.M Habashy
Clinical Pathology Department, Hematology Unit, Faculty of Medicine, Ain Shams University, Cairo - 11759
Source of Support: None, Conflict of Interest: None
Background Building strategies for targeted therapy in acute lymphoblastic leukemia (ALL) patients has been a challenge over the past few years; this raised the importance of revealing new prognostic markers of which CD135, an fms-like tyrosine kinase 3 (FLT3), expression may play a role in patients’ survival and prognosis.
Objective This study aimed at detecting the expression of CD135 in childhood ALL, searching for a possible association with chromosomal aberrations and overall survival (OS).
Patients and methods Forty newly diagnosed pediatric ALL patients and 20 age-matched and sex-matched controls were studied for the expression of CD135 by flow cytometry.
Results Medians of total leukocytic count and CD135 expression [percentage and mean fluorescence intensity (MFI)] were higher in the patient group compared with controls, whereas medians of hemoglobin and platelet count were higher in controls compared with the patient group (P<0.001). Median of CD135 MFI was higher in the patient group with unfavorable chromosomal aberrations, CD33+ and those with poor outcome than those with favorable chromosomal aberrations, CD33− and those with good outcome (P<0.001). CD135 MFI was inversely correlated to OS in the patient group (P<0.001). Patients with MFI values more than or equal to 2.25 had median survival of 13 months, whereas patients with values less than 2.25 had a median survival of 30 months (P<0.001).
Conclusion CD135 is expressed in ALL pediatric patients. High CD135 MFI is associated with unfavorable chromosomal aberrations, poor outcome, and is correlated with shorter OS in those patients, which highlights its possible role in follow-up of ALL patients and disease outcome.
Keywords: acute lymphoblastic leukemia, CD135, prognosis
|How to cite this article:|
Habashy DM. CD135 expression in childhood acute lymphoblastic leukemia: association with chromosomal aberrations and survival. Egypt J Haematol 2017;42:88-94
|How to cite this URL:|
Habashy DM. CD135 expression in childhood acute lymphoblastic leukemia: association with chromosomal aberrations and survival. Egypt J Haematol [serial online] 2017 [cited 2018 Jan 17];42:88-94. Available from: http://www.ehj.eg.net/text.asp?2017/42/3/88/217881
| Introduction|| |
Acute lymphoblastic leukemia (ALL) remains a major cause of mortality in children and is considered the most common childhood cancer . A progress has been made throughout the years regarding the implementation of therapeutic approaches based on cytogenetic and molecular lesions .
Complete remission (CR) in ALL is met by most of the patients. Survival is linked to a group of risk factors that succeed in stratifying risk groups with survival probabilities . These risk factors include clinical, biological, genetic, and molecular features that play a crucial role in patients’ outcome .
Cluster of differentiation antigen 135 (CD135), also known as fms-like tyrosine kinase 3 (FLT3), is a class III receptor tyrosine kinase. When this receptor binds to FLT3 ligand (FLT3L), a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L . The formation of such a complex results in bringing the two intracellular domains in close proximity to each other, eliciting initial transphosphorylation of each kinase domain, which in turn activates the intrinsic tyrosine kinase activity, leading to phosphorylation and activation of signal transduction molecules that propagate the signal in the cell . Human FLT3 is a 160-kDa, type I transmembrane glycoprotein originally cloned from a CD34+ stem cell library. FLT3L is expressed by marrow stromal cells and synergize with other growth factors to stimulate proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells . Signaling through CD135 plays a role in cell survival, proliferation, differentiation, and is important for lymphocyte (B cell and T cell) development .
FLT3 is highly expressed in acute myeloid leukemia . In addition, high expression is noticed in a spectrum of hematologic malignancies including B-cell precursor ALL, a fraction of T-cell ALL, and chronic myelogenous leukemia in lymphoid blast crisis .
This work aimed to study the expression of CD135 in childhood ALL patients and to investigate its possible role in disease prognosis and its correlation with chromosomal aberrations encountered in those patients and their overall survival (OS).
| Patients and methods|| |
This study was carried out on 40 ALL pediatric patients newly diagnosed according to the American Society of Hematology Clinical Practice Guidelines . The patients were attending the Hematology Oncology Unit of Ain Shams University Hospitals. There were 28 male and 12 female patients with a male-to-female ratio of 2.3 : 1, with a median age of 7 years. Immunophenotypic analysis revealed 30 pre-B ALL (75%) and 10 B-ALL cases (25%). Twenty healthy age-matched individuals were studied as the control group. They were 12 male and eight female individuals, with a male-to-female ratio of 1.5 : 1, with a median age of 8 years. Thorough clinical and laboratory investigations were performed for all participants, including complete blood count (CBC), erythrocyte sedimentation rate (ESR), and immunophenotyping (IPT). The 40 ALL cases underwent bone marrow (BM) aspirate smear film examination, karyotyping, and fluorescence in-situ hybridization (FISH) analysis. The procedures applied in this study were approved by the Ethical Committee of Human Experimentation of Ain Shams University and are in accordance with the Helsinki Declaration of 1975. All participants and their caregivers were informed about the objectives and procedures of the study and written consents were obtained before enrollment.
Children with ALL were risk-stratified based on recognized prognostic features (including cytogenetics) , and received risk-adapted therapeutic protocol of the European Society of Medical Oncology .
CR was defined by clinical and morphological criteria; the presence of 5% or less blasts in a normocellular or hypercellular BM, with granulocytes more than 1.0×109/l and platelets (PLT) more than 100×109/l . Unfavorable day 14 response was defined as more than 5% leukemic blasts on the BM aspirate on day 14, the presence of a leukemic cell cluster on the BM tissue section on day 14, or a persistence of circulating leukemic blasts in the peripheral blood (PB) on day 14 . Relapse after CR was defined as the reappearance of leukemic blasts in PB or more than 5% blasts in BM not attributable to any other cause (e.g. BM regeneration after consolidation therapy) . OS was measured from the day of diagnosis until death from any cause.
A volume of 2 ml of PB was obtained on potassium EDTA for CBC. Another 1 ml of PB or BM aspirate on sterile potassium EDTA was collected for flow cytometric studies. A measure of 1 ml of BM aspirate was collected in a sterile preservative-free heparin-coated vacutainer tube for karyotyping and FISH analysis.
Flow cytometric analysis
The panel of monoclonal antibodies used for the immunophenotypic diagnosis of acute leukemia included phycoerythrin (PE)-conjugated monoclonal CD135 in addition to routine panel of acute leukemia:
- B lineage markers: CD19, CD20, and CD79a.
- T lineage markers: CD2, CD5, CD7, surface CD3, T-cell receptor α-β, T-cell receptor δ-γ, CD4, CD8, and cytoplasmic CD3.
- Myeloid markers: CD33, CD13, CD117, and myeloperoxidase.
- Other markers: CD34, human leukocyte antigen–antigen D related, CD10, terminal deoxynucleotidyl transferase, and CD38.
All monoclonal antibodies were provided by Immunotech, a Beckman Coulter company (Coulter Electronics Inc., Hialeah, Florida, USA). The IPT staining procedure used was the standard ‘whole-blood lysis’ technique, in which 50 ml of whole blood or BM sample (with leukocytic count adjusted to 5–10×103 cells/ml) was placed into polystyrene tubes and simultaneously stained with 5 ml of one fluorescein isothiocyanate-labeled and one PE-conjugated anti-human monoclonal antibody or with their corresponding isotypic controls. After 15 min of incubation in the dark, at room temperature, 1.0 ml of laboratory-prepared ammonium chloride-based lysing solution was added and RBC lysis was allowed for 10 min at room temperature. Samples were washed once and resuspended in 0.5 ml of PBS. Staining with isotypic controls was performed to distinguish positive staining from autofluorescence and nonspecific antibody binding. Cells were analyzed on a Coulter EPICS XL flow cytometer using System II software (Beckman Coulter). The flow cytometer acquired a minimum of 10 000 cellular events; an electronic gate was set in a linear forward scatter/log side scatter histogram to determine the lymphoid cell population. A CD19 PE-cy5 conjugate was used in control samples only to separate B lymphocytes from total PB lymphocytes. Cells were considered positive for a marker when more than 20% of cells expressed that marker (≥10% for CD34). The percentage of positive cells was defined as cells in the electronic gate that had fluorescein isothiocyanate and/or PE fluorescence falling in the positive region determined by the corresponding isotypic control . A histogram for a case with positive CD135 expression is shown in [Figure 1]. A cutoff of 1.3 was calculated for mean fluorescence intensity (MFI) for CD135 using the receiver operating characteristic curve, which discriminated patients from controls with a sensitivity of 95%, specificity of 100%, and efficacy of 96.7% ([Figure 2]).
|Figure 2 Receiver operating characteristic curve analysis showing the diagnostic performance of MFI for discriminating patients from controls.|
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Conventional karyotyping and fluorescence in-situ hybridization analysis
Conventional cytogenetic analysis and molecular cytogenetics using FISH probes for conventional cytogenetic analysis failed cases on PB or BM samples were performed . Cytogenetics were performed according to Schoch et al. . In all cases, 15–20 metaphases were analyzed and classified according to the International System for Human Cytogenetic Nomenclature . FISH analysis of PB/BM samples using routine panel of probes for ALL; ETV6-RUNX1 fusion for t(12;21); mixed-lineage leukemia (MLL) rearrangement for 11q23 rearrangements; and BCR/ABL for t(9;22) were performed.
IBM SPSS statistics (V. 24.0; IBM Corp., New York, NY, USA) was used for data analysis. Data were expressed as median and percentiles for quantitative nonparametric measures in addition to both number and percentage for categorized data. The following tests were done:
Comparison between two independent groups for nonparametric data was done using Wilcoxon rank sum test (Z). Ranked Spearman’s correlation test (r) was performed to study the possible association between each two variables among each group for nonparametric data and χ2-test to study the association between each two variables or comparison between two independent groups as regards the categorized data. Diagnostic validity test was done and receiver operating characteristic curve was constructed to obtain the most sensitive and specific cutoff for CD135 MFI. To evaluate the most discriminating cutoff between the compared groups, area under curve was also calculated. Survival analysis (Kaplan–Meier Curve) was done to compare the survival rate between two groups. Log-rank (Mantel–Cox) test was run to determine the difference in survival between studied groups. The probability of error at 0.05 was considered significant, whereas at 0.01 and 0.001 they are highly significant.
| Results|| |
Demographic, clinical, and laboratory data of studied groups are shown in [Table 1]. All ALL patients expressed CD135 (100%), whereas none of the controls expressed CD135. Medians of total leukocytic count (TLC) and CD135 expression (percentage and MFI) were higher in the patient group compared with controls, whereas medians of hemoglobin (Hb) and PLT count were higher in controls compared with the patient group (P<0.001) ([Table 2]). Median of CD135 MFI was higher in the patient group with unfavorable chromosomal aberrations, CD33+ and those with poor outcome than patients’ group with favorable chromosomal aberrations, CD33− and those with good outcome (P<0.001) ([Table 3]). CD135 MFI was inversely correlated to survival in the patient group (P<0.001) ([Table 4]).
|Table 2 Comparison between the control group and the patient group regarding all studied parameters|
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|Table 3 Comparison between studied groups regarding median of CD135 mean fluorescence intensity|
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|Table 4 Correlation between CD135 mean fluorescence intensity and studied parameters in the patient group|
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Overall median survival of studied patients was 24 months [95% confidence interval (CI), 16.562–31.438]. Patients with MFI values more than or equal to 2.25 had a median survival of 13 months (95% CI, 8.617–17.383), whereas patients with values less than 2.25 had a median survival of 30 months (95% CI, 28.91–31.09). Log-rank test for equality of survival distribution of both studied groups showed highly significant difference (χ2=13.918; P<0.001) ([Figure 3]).
|Figure 3 Receiver operating characteristic curve analysis showing the diagnostic performance of mean fluorescence intensity for discriminating patients from controls.|
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| Discussion|| |
Although significant progress has been made in the treatment of ALL, prognosis following relapse is still poor. Trials for more intensive treatment have been offered for high-risk patients at the time of diagnosis to improve leukemia-free survival . However, intensive therapeutic strategies are also associated with increased treatment-related morbidity and mortality, which raised the need for accurate assignment of relapse risk at diagnosis aiming at the optimal treatment of ALL .
It was suggested that most of the patients experiencing disease relapse cannot be adequately assessed for their chance of experiencing relapse at diagnosis . Over the past few years, the use of uniform criteria (including age, TLC count at presentation, early response to therapy, cytogenetics, central nervous system status, and IPT) to assign risk-based therapy for patients with pediatric ALL has been advocated .
FLT3 (CD135) is a highly expressed cell surface receptor in a majority of acute leukemias with near universal expression in acute myeloid leukemia ,. This study investigated the expression of CD135 in pediatric ALL patients aiming at proving its possible role in disease prognosis and its correlation with chromosomal aberrations encountered in those patients and their OS, which could help in building new therapeutic strategies for high-risk patients.
In the present work, all 40 patients expressed CD135 compared with studied controls. It was previously reported that CD135 was expressed in ALL ,. Strong surface CD135 expression was detected before in CD117/KIT+ T-ALL and CD117/KIT expression in T-ALL lymphoblasts identified a subset of patients in whom FLT3 gene mutations play a crucial role in the multistep mutational pathway to oncogenesis .
Regarding CBC parameters in this work, median of TLC was higher in the patient group compared with controls, whereas medians of hemoglobin and PLT count were higher in controls compared with the patient group (P<0.001). In accordance, it was proven before that newly diagnosed ALL patients experience anemia , and thrombocytopenia. Regarding TLC, it may be normal, high, or low with usual neutropenia . Presentation with pancytopenia reflecting marrow failure can also be detected .
In the present work, investigating chromosomal aberrations encountered in ALL patients showed presence of hyperdiploidy in 30% of cases; a percentage similar to that detected before ,, t(12;21) in 22.5% of cases; it was shown previously that it occurs in 25% of children with B-ALL and confers an excellent prognosis ,, hypodiploidy in 7.5% of cases; as detected previously ,, t(9;22) in 7.5% of cases; 3–5% in other studies  and t(4;11) in 32.5% of cases; it was shown previously that. MLL gene rearrangements at 11q23 are present in 80% of all infant B-ALL cases and 10% of all childhood B-ALL ,. Median of CD135 MFI was higher in the patient group with unfavorable chromosomal aberrations (P<0.001). Previously, it was reported that significant differences existed between the immunophenotypic features of t(12;21)+, a translocation harboring good outcome and t(12;21)− precursor B-ALL patients, the former being associated with higher levels of expression of CD10, human leukocyte antigen–antigen D related, and lower expression of CD20, CD135, and CD45 . Additionally, CD135 was highly expressed in t(4;11)+ ALL, which is characterized by poor outcome ,,.
In the present work, median of CD135 MFI was higher in the patient group with CD33+ expression compared with CD33− expression (P<0.001). It was shown earlier that pre-B ALL expressing myeloid antigens (CD13, CD33) had poorer outcome compared with those without myeloid antigens .
This study detected a higher median of CD135 MFI in the patient group with poor outcome. Patients with MFI values more than or equal to 2.25 had shorter median survival than those with MFI values less than 2.25 (P<0.001). It has been suggested that FLT3 internal tandem duplication (FLT3-ITD) markedly worsens patient survival . In contrast, several authors even reported no deterioration of OS for FL3-ITD-positive standard-risk ALL patients ,,,,. It has been proposed earlier that the prognosis might be correlated with high levels of FLT3 on leukemic blasts rather than with FLT3-ITD in ALL patients .
Association of high CD135 (P<0.01) with FLT3-ITD was observed before. Investigators concluded that the addition of CD135 to the diagnosis can predict molecular aberrations in T-ALL cases, mainly segregating patients with FLT3-ITD, who would benefit from treatment with inhibitors of tyrosine . No previous studies investigated the association between CD135 MFI in ALL and disease outcome.
| Conclusion|| |
CD135 is expressed in ALL pediatric patients. High CD135 MFI is associated with unfavorable chromosomal aberrations, poor outcome, and is correlated with shorter OS in those patients, which highlights its possible role in follow-up of ALL patients and disease outcome. Targeted therapy using CD135 inhibitors should be suggested for treatment of high-risk ALL patients and relapsed cases. The study of FLT3 mutations in ALL is crucial to elucidate its effect on the oncogenesis process in those patients.
The facilities offered by the Hematology Unit, Clinical and Chemical Pathology Department of Ain Shams University Hospitals, Cairo, Egypt, which enabled me to carry out this work, are greatly appreciated.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]