الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Acute lymphoblastic leukemia (ALL) is a disease characterized by the production of large number of Immature lymphocytes (lymphoblasts) by the bone marrow and represent 25% of all childhood leukemias.
cytogenetic and molecular genetic findings are involved in the risk of development and predict the prognosis for the disease. In case of absence of cytogenetic and molecular genetic alterations, gene polymorphism has shown to play an influential role in childhood ALL risk and treatment response. In addition, the expression behavior of the leukemic blasts can be used to predict the disease prognosis.
Macrophage inhibitory factor is pro-inflammatory cytokine modulating monocyte motility and pleiotropic regulator of different biological and cellular processes and plays an important role in the pathogenesis of many diseases, such as autoimmune diseases and cancers.
The MIF - 173G/C polymorphism is found in the promoter region of the gene and affect its activity.
Our study is designed to investigate the MIF polymorphism as a risk factor for acute lymphoblastic leukemia development in the Egyptian children and the prognostic impact of its expression. Furthermore, we investigate the relation between MIF polymorphism and its expression pattern.
To study the MIF - 173G/C polymorphism as a risk factor for ALL development, we recruited 180 ALL cases from the oncology center Mansoura University(OCMU) Hospital and 150 healthy control. The patients and the control were matched in age, sex.
The cases being diagnosed by bone marrow aspiration and classified regarding immunophenotyping to B-cell and T-cell ALL patients. the Patients chosen didn’t have previous history of cancer, chemotherapy or even hematological disorder. we asked for parental smoking as potential risk factor for ALL.
To study MIF gene expression and its prognostic impact, we take sixty patients from the studied 180 cases, treated, and had been followed up until death or for periods up to 36 months (between 2014 and 2017) in oncology center Mansoura University(OCMU) Hospital.
We analyzed MIF polymorphism by amplification of the gene using Polymerase chain reaction followed by restriction endonuclease digestion and running on agarose gel then visualization for the product. The MIF expression was analyzed using quantitative real-time (QRT) PCR.
The main results of the present study are:
• No statistically significant difference was found between cases and controls as age and sex
• Statistically significant differences of all clinical presentation in patients in comparison to control group. Actually, control group was negative for all clinical presentations. (Pallor, bleeding tendency, Splenomegaly, Hepatomegaly, LAD and fever.
• There was statistically significant decrease in RBCs count, hemoglobin concentration, and platelets count, while WBCs count increased in patients’ group in comparison to control group
• The majority of the studied ALL cases (78.3%) were classified with B-Cell ALL
• No statistically significant difference was found between patients and control groups as regard parental smoking and patients with other ALL risk factors, that would make results confliction, like Previous Cancer, DS or MDS excluded from the study.
• MIF polymorphism was significantly common in patients than control group for the homozygous polymorphic (CC) genotype and the combined (GC+CC) genotype, while the wild-type (GG) genotype more common in healthy control than patients which give the potential for the MIF polymorphism as ALL risk factor.
• The heterozygous (GC) genotype shows no significant difference between patients and control groups.
• Multivariate logistic regression analysis adjustment, for MIF different genotypes and other potential risk factors like age, sex, and parental smoking, indicated that the homozygous polymorphic (CC) genotype is the only significant risk factor for the test
• Comparison between MIF different genotypes in ALL group show no significant prevalence for any of the studied risk factors (age, sex, parental smoking)
• There was no significant difference in clinical and hematological findings has been found between MIF different genotypes in patients group except for the total leukocytic count that found to be a significantly higher in patients with the homozygous polymorphic genotype (CC) than other genotypes.
• There were 51.7% of patients with high MIF expression in comparison to 48.3% patients with low expression.
• No statistical differences were observed between patients with low and high MIF expression with respect to age, gender, clinical findings, or hematological findings.
• There was no significant prevalence in one of each ALL phenotypes (B-cell &T-cell ALL) among both expression classes.
• Patients with high MIF expression were associated with low CR rate achieved after induction therapy (25.8% Vs 72.4%), high mortality rate (54.8%Vs 20.7%), and high refractory rate (51.6% Vs 24.1%) consequently shorter disease-free survival (12.48Months Vs 25.11Months) and overall survival (20.61Months Vs 29.29 Months) than patients with low MIF expression.
• Multivariate cox-regression analysis, adjusted for the studied ALL prognostic markers like MIF expression, age WBCS, Hb concentration and immunophenotyping, confirmed that; MIF expression was the only independent prognostic factor in ALL patients for OS and DFS in our study
• By studying the relation between MIF polymorphism and its expression pattern we found that, high expression pattern is significantly linked to MIF polymorphic genotypes while the low expression is linked to the wild-type genotype.
Based on these findings, we concluded that the MIF-173 G/C polymorphism in the promoter area increases the risk of acute lymphocytic leukemia development in children and increases the expression level of the MIF gene, which found to have bad prognostic impact. The incorporation of these findings into a new therapeutic strategy will improve the remission rates for this group of patients.
1. Recommendations
1- Studies that illustrate weather the MIF protein has different concentration levels in different MIF genotypes or not.
Studies that illustrate the specific mechanism by which the polymorphic base (C) increases the activity of the promotor, consequently, the gene expression.