Pathogenic Mechanism of Malignant Progression in Chronic Myelogenous Leukemia
Final rept. 30Aug 2004-29 Aug 2005
CALIFORNIA UNIV SAN DIEGO LA JOLLA
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Chronic myelogenous leukemia CML is a progressive disease of the hematopoietic stem cell HSC. It has long been postulated that BCR-ABL causes genomic instability, which then drives the malignant progression of CML. We propose that BCR-ABL causes a chronic instability through a congruence of events that are accidentally combined to place the genome at risk. In particular, we focus on three events production of reactive oxygen species ROS, reduction in the repair of oxidized DNA, and defect in oxidative stress-induced apoptosis. We propose the following three lines of exploratory experiments 1 Determine the effect of BCR- ABL kinase on the steady-state levels of reactive oxygen species ROS . 2 Examine the effect of BCR-ABL kinase on the expression and the function of MYH repair pathway. 3 Examine the effect of BCR-ABL kinase on the p53-family of transcription factors. The proposed research may elucidate a pathway for oxidative damage to propel malignant progression in CML and thus identifies specific use of antioxidants to combat CML blast crisis.
- Medicine and Medical Research