Chronic myelogenous leukemia (CML) is initiated by expression of the BCR-ABL fusion gene product which results from the Philadelphia chromosome translocation in self-renewing, hematopoietic stem cells. Imatinib mesylate (IM) is an inhibitor of the BCR...
Chronic myelogenous leukemia (CML) is initiated by expression of the BCR-ABL fusion gene product which results from the Philadelphia chromosome translocation in self-renewing, hematopoietic stem cells. Imatinib mesylate (IM) is an inhibitor of the BCR-ABL tyrosine kinase and has continued to show remarkable clinical benefits. But, the IM-based therapy has two major obstacles that resistance to IM and relapse of the disease. Therefore it is a very important issue that minimal residual disease detection by molecular or cytogenetic method. Several investigators have recently shown that the BCR-ABL kinase induces production of reactive oxygen species (ROS) and inhibition of ROS decrease the mutagenesis rate of IM resistance. We report here that mononuclear cells (MNCs) from CML patients' bone marrow show decreased expression levels of antioxidant enzymes including PrxⅠ, PrxⅡ, PrxⅥ and GpxⅠwhile the increased level of catalase. Interestingly, the expression level of these enzymes is restored to the level in a normal individual as the result of IM therapy. In addition, it is shown that the expression pattern of antioxidant enzymes in several hematopoietic stem cell lineages changes during maturation in a healthy individual. To examine the cause of alteration in a CML patient, we have tried to develop the method to study the changes of antioxidant enzymes at the single cell level using immunocytochemistry with monoclonal antibodies. Using this method we confirmed that the intracellular expression levels of antioxidant enzymes are various in different hematopoietic lineages. It also has shown that amounts of PrxⅡ and catalase changes in MNCs of CML patients not because the cell population changes. In bone marrow MNCs, regulation of ROS by antioxidant enzymes might be related to the change of BCR-ABL kinase pathway during IM treatment. Understanding the molecular mechanism of changes in antioxidants at the single cell level might be a potent tool to develop more effective new drugs in CML.