الفهرس 
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Abstract
Chronic myeloid leukemia is a clonal myeloproliferative disorder, originated from mutated pluripotent hematopoietic stem cell. Philadelphia chromosome is the cytogenetic hallmark of CML which results from the balanced reciprocal translocation (9; 22) (q34; q11). The result of this translocation is the generation of chimeric BCR-ABL protein with uncontrolled tyrosine kinase activity which known to be essential for the growth, proliferation and survival of CML cells.
Imatinib is the 1st line target therapy capable of selectively inhibiting the tyrosine kinase activity of aberrant BCR-ABL1 protein by competing with ATP for binding to the BCR-ABL1 kinase domain, thus preventing phosphorylation of tyrosine residues on its substrates. Interruption of the oncogenic signal in this way is effective for control of the disease, particularly when used early in CP.
Unfortunately, imatinib resistance has considered as a major problem in the CML treatment by many mechanisms including amplification or mutation of the BCR/ABL1 gene, aberrant expression of drug transporters, dysregulation of anti-apoptotic proteins and recently, dysregulated micro RNAs expression.
MiRNAs are small non-coding RNAs regulating the expression of coding genes in biological cells at the post-transcriptional level. Among these miRNAs, miR-451 was claimed to play a vital role in the pathogenesis of CML and could be involved in IM resistance. Many studies have demonstrated that miR-451 could inhibit cell growth and induce apoptosis. Additionally, growing evidence has established that miR-451 is dysregulated in human malignancies, including leukemia.
Summary
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The aim of this study was to measure the expression levels of miR-451 in chronic myeloid leukemia patients and to correlate miR-451 expression levels with response to imatinib mesylate based therapeutic protocol.
The present study was carried on 40 CP CML patients who were selected from Clinical Oncology department, Menoufia University and National Cancer Institute, Cairo University during the period from August 2017 to December 2018. We retrospectively analyzed 30 CP CML patients who were classified according to the European Leukemia Net recommended response criteria. Twelve patients were characterized as IM-responders while 18 were IM-resistant patients. In addition; samples from 10 newly diagnosed CP CML patients were prospectively collected and analyzed. All studied patients received imatinib as first-line therapy and received at least 12 months of TKI therapy. All IM-resistant patients received second-generation TKI drug. As a control group, 10 apparent healthy adult persons with matched age and gender were included.
For diagnosis and follow up of newly diagnosed patients; complete blood count, peripheral blood smear, bone marrow aspiration and molecular analysis of BCR-ABL1 by Real-time quantitative PCR (qPCR) were done. The plasma miR-451 relative expression levels were studied in all participants by real time polymerase chain reaction (qPCR) using RNU6 as an internal control.
No statistically significant differences were detected between different CML groups regarding age, gender, spleen size, hemoglobin concentration, leucocytes count, platelets count, peripheral blood basophils %, bone marrow blasts % and BCR-ABL1% at diagnosis.
Summary
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Statistically significant differences between the studied groups were found with respect to serum LDH levels, uric acid levels, BCR-ABL1% at 12 months and miR-451 expression levels.
MiR-451 expression levels was compared between IM-responder group, IM-resistant group and control group. MiR-451 expression was significantly up-regulated in IM-responder group when compared with the IM-resistant group. Furthermore, miR-451 was significantly down-regulated in IM-resistant in comparison with the healthy control group while no significant difference was detected between IM-responder group and healthy controls.
MiR-451 expression levels of newly diagnosed CP CML was compared with imatinib treated CP CML patients who accomplished major molecular response (MMR). MiR-451 expression levels were found to be up-regulated in imatinib treated CP CML as compared to newly diagnosed CP CML patients.