Chronic myeloid leukemia (CML) is the first malignant myeloproliferative disorder to be associated with a single acquired genetic hallmark: the Philadelphia chromosome (Ph) resulting from the t(9;22) (q34;q11) reciprocal translocation . The molecular consequence of this translocation is the formation of a chimeric BCR-ABL1 gene which is begotten by fusion of the ABL gene to the BCR gene on chromosome 22. This fusion gene is translated next to the BCR-ABL dysfunctional protein with constitutive tyrosine kinase activity that represents a critical to the improvement of CML .
The development of inhibitors specifically of the BCR-ABL tyrosine kinase activity, as a therapeutic agent has revolutionized the CML treatment [4,8,9]. Imatinib Mesylate (IM) is the 1st generation of Tyrosin Kinase Inhibitors (TKIs) that inhibit the activity of the BCR-ABL tyrosine kinase by the blocking of the ATP binding site and consequently inducts of apoptosis in the CML cells [5-7]. Notwithstanding the excellent results obtained with IM for the therapy of CML, a minority of CML patients acquired resistance to IM that has become an emerging problem that has been resolved only in part by second- and third-generation of TKIs [10,11]. The precise mechanisms underlying the resistance to IM therapy remain a debate point. These mechanisms have classically divided into BCR-ABL-dependent and BCR-ABL-independent mechanisms .
Previous observation demonstrated that the oxidation of redox-sensitive cysteine residues of BCR-ABL protein by Reactive Oxygen Species (ROS) can be lead to a change in the three-dimensional structure of the ABL kinase domain of this oncoprotein and exhibits constitutive kinase activity and resistance to IM (Zhang 2008). The implication of ROS in CML improvement is not clear, indeed, many studies show that the high level of ROS generation and the long-term of its accumulation may promote cell survival , migration and metastasis , proliferation and may contribute to oxidative DNA damage leading to genomic instability , as well as drug-resistance.
ROS are a heterogeneous group of free radicals that are generated naturally in cellular metabolism from diatomic oxygen . High levels of ROS are responsible for deoxyribonucleic acid (DNA), lipid and protein damage that can eventually lead to apoptosis of the normal hematopoietic cell . Cells mobilize an antioxidant defensive system founded mainly on enzymatic and non-enzymatic components to neutralize ROS and act as protective mechanisms. They consist of enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT); and antioxidant substrates like vitamin C and E . An excessive ROS production and/or a deficiency in their elimination by protective mechanisms result in oxidative stress.
Notwithstanding, the limitations of information about the association of ROS in CML open new horizons and offers different prospects for future research in an attempt to overcome these shortcomings. Therefore, a systemic analysis of the markers of oxidative stress in plasma of Tunisian patients with CML has undertaken. The aim of the present study was conducted to evaluate the markers of oxidative stress: (i) in CML patients and healthy subjects for understanding the association of ROS in CML (ii) as well as in CML patients IM-resistants and IM no-resistants for explaining the correlation between oxidative status and the resistance to IM in CML patients treated with TKI. To the best of our knowledge, this is the first case-control study to measure the variation of the markers of oxidative stress in CML patients from Tunisia.