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العنوان
Evaluation of FOXP3 Gene Expression Level in Childhood Acute Lymphoblastic Leukemia \
المؤلف
Abdelhafeez, Hossam El Din Ahmed.
هيئة الاعداد
باحث / حسام الدين أحمد عبد الحفيظ
مشرف / فاطمة فرج عبد الحميد
مشرف / ماجدة محمود أحمد عاصم
مشرف / أحمد فتحى سليمان
تاريخ النشر
2021.
عدد الصفحات
140 p. :
اللغة
الإنجليزية
الدرجة
ماجستير
التخصص
Biochemistry
تاريخ الإجازة
1/1/2021
مكان الإجازة
جامعة عين شمس - كلية العلوم - الكيمياء الحيوية
الفهرس
Only 14 pages are availabe for public view

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Abstract

ALL is the most commonly diagnosed malignancy in children. Globally, 3 in 100,000 individuals may acquire the disease, mostly at ages under six years with the highest likelihood of developing the disease occurring between the ages of 2 and 4 years.
Survival in pediatric patients with ALL has significantly improved over time with almost 90% of children being cured.
Nonetheless, there are still challenges to overcome, as patients are sometimes over-treated, increasing toxicity phenomena or present resistance to anti-leukemic agents. This highlights the need for the clinical evaluation of novel prognostic markers and therapeutic tools either to mitigate the risk for acute toxic and late side effects or to predict more effectively patients’ response to therapy and the risk for disease relapse.
Therefore, the present study was conducted to evaluate the expression of FOXP3 in newly diagnosed children with ALL, relate its expression level with clinical and laboratory data and treatment response, and evaluate its role as a biomarker for predicting outcome in childhood ALL patients in the form of OS and DFS.
This was an observational prospective study in which 112 eligible children with newly diagnosed B-ALL were enrolled. Patients were treated according to the St. Jude Children’s Research Hospital Total Therapy XV protocol at National Cancer Institute (NCI), Cairo University, Cairo, Egypt in the period between July 2016 and May 2020. Additionally, 27 sex- and age-matched children not suffering from any hematologic or other types of malignancy were included in the study as a control group.
Written informed consent was obtained from the legal guardians of each subject before the start of the study. This work was carried out per The Declaration of Helsinki and approved by the institutional review board of NCI (Organization no. IORG0003381) under IRB number of IRB00004025 with a Federal Wide Assurance (FWA) number of FWA00007284 and approval number of 201617024.4.
All subjects were subjected to
• Full clinical and family history.
• Patients were subjected to
I. Clinical examinations including
a) Diagnosis
 Date of first complaints.
 Date of the diagnosis.
 Age at diagnosis.
b) Symptomatic findings (Fever, bleeding, bone pain, frequent infections).
c) Clinical findings (splenomegaly, lymphadenopathy, hepatomegaly, tender bones).
II. Hematological analysis including
a) Complete blood count (CBC).
b) Bone marrow aspiration.
III. Biochemical analysis
a) Flow cytometric analysis to identify and classify leukemic cases by Immunophenotyping (IPT).
b) Cytogenetic analysis for chromosomal abnormalities.
IV. Response to chemotherapeutic treatment at days 15 and 42
• Determination of relative FOXP3 expression levels in all subjects at the beginning of the study.
The results of the study can be summarized as follows
• Compared to the control group, FOXP3 was over-expressed in the bone marrow of patients with childhood ALL.
• The ability of bone marrow FOXP3 relative expression to discriminate childhood ALL from the healthy control group was highlighted by ROC analysis showing AUC of 0.687.
• Among the clinical features of patients, only low WBCs count showed a borderline significant association with high FOXP3 expression level.
• Kaplan-Meier analysis and Log-Rank test were examined to determine the prognostic value of relative FOXP3 expression level for childhood B-ALL. The results showed that patients with elevated FOXP3 expression at disease diagnosis suffered from a significantly shorter DFS and OS compared to patients with reduced levels suggesting the association between high FOXP3 and poor prognosis of childhood ALL.
• Univariate Cox regression analysis confirmed the higher risk for disease relapse and death of patients with over-expressed FOXP3 at disease diagnosis in comparison with those with low FOXP3 expression.
• Multivariate Cox analysis revealed the independent prognostic value of FOXP3 relative expression level for childhood ALL at diagnosis both for disease relapse and death.
• The ability of FOXP3 relative expression in improving the prediction strength of the established and clinically used prognostic markers (WBCs count ≥50000 cells/μl, M2/M3 bone marrow response at day 15, positive MRD, and standard/high-risk patients’ cohort) was examined.
 The results revealed that patients who over-expressed FOXP3 at disease diagnosis present significantly shorter OS even if they have WBCs count <50000 cells/μl, or M1 bone marrow response.
 The percentage of relapsed patients with high FOXP3 expression levels and M1 bone marrow response was higher than those with low FOXP3 expression level although the latter had shorter DFS.
 Further, the predicting ability of MRD at day 15 as well as that of the current total therapy XV-risk stratification system were significantly ameliorated by the implementation of the high FOXP3 expression level at diagnosis as the relative expression of FOXP3 can identify patients with even more aggressive disease among the MRD positive patients’ group or standard/high-risk patients’ cohorts with shorter DFS and OS.
 This indicates that the relative expression level of FOXP3 enhances significantly the prognostic value of the clinically established biomarkers for disease progression and the patients’ survival outcome.
In summary, the present study revealed that FOXP3 relative expression was up-regulated in childhood B-ALL patients at diagnosis, and its high expression level was associated with adverse outcomes, with a stronger risk for relapse and inferior survival. Surprisingly, the combination of FOXP3 relative expression with the clinically used disease prognostic markers clearly enhanced treatment stratification.