الفهرس 
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Abstract
Chronic myeloid leukemia is the most common type of myeloproliferative neoplasms accounting for 15-20% of all leukemias. Its resistance to treatment increases the probability of progression into more advanced stages (accelerated phase and blast crisis) which are lethal.
Imatinib methylate, has improved the prognosis for CML patients. However, the presence of some drug-resistance mechanisms appears to be responsible for the therapeutic failure of IM in CML patients. This elucidates the importance of the predictive biomarkers for response of IM chemotherapy.
The aim of current thesis was to study the role of SH2-containing tyrosine phosphatase-1 (SHP-1) mRNA expression & its promoter methylation in imatinib response in Egyptian chronic myeloid leukemia patients.
In order to achieve this goal, CML patients were recruited from the Hematology Unit of Alexandria Main University Hospital and divided into two groups; imatinib resistant group and imatinib responder group. A control group matched in sex and age was added to the study. The diagnosis and response were based upon clinical evaluation, CBC and the determination of BCR-ABL gene expression level. Determination of expression levels of SHP-1 was done using mRNA Quantitative reverse transcriptase polymerase chain reaction using Taqman assay (qRT-PCR). Determination of promoter methylation of SHP-1 gene was done by methylation- specific polymerase chain reaction (SYBR green-based quantitative MSP).
Statistical analysis of the studied parameters showed the following results:
- The expression level of SHP-1 mRNA was significantly higher in the responder group than the resistant group and also significantly higher in the control group than the resistant group but no significant difference was found between the responder and the control group.
- Another point of interest was that the methylation state of SHP-1 gene was significantly higher in the resistant group than the responder group.
- Furthermore, it was found that there was a significant relation between SHP-1 mRNA expression level and the methylation state of its gene in both groups.
- However, it was found that there was no significant relation between BCR-ABL transcript levels and neither SHP-1 mRNA expression level nor methylation state of SHP-1 gene in each group.
- By plotting a ROC curve, the sensitivity and specificity of SHP-1 mRNA expression level as predictor for response to treatment were 90% and 90 % respectively. While SHP-1 methylation ratio had a sensitivity of 65% and a specificity of 90%.
- Combined together SHP-1 mRNA expression level and its methylation ratio had a sensitivity of 80% and a specificity of 90% in predicting the response to imatinib treatment in CML patients.
Consequently, SHP-1 mRNA expression level is more sensitive biomarker in predicting imatinib methylate response than both SHP-1 methylation state or combining them together. Therefore, SHP-1 mRNA expression level could be a promising biomarker for prediction of response to IM in CML patients and SHP-1 gene hypermethylation could be the reason for decreased SHP-1 gene expression in IM-resistant CML patients.