Pathogenic Mechanism of Malignant Progression in Chronic Myelogenous Leukemia

摘要

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.