BCR-ABL down-regulates the DNA repair protein DNA-PKcs

This study demonstrates in both stable and inducible BCR-ABL-expressing hem atopoietic cells a down-regulation of the major mammalian DNA repair protei n DNA-PKcs by BCR-ABL. Similar results were found in BCR-ABL CD34(+) cells from patients with chronic myelogenous leukemia (CML), DNA-PKcs down-regula tion is a proteasome-dependent degradation that requires tyrosine kinase ac tivity and is associated with a marked DNA repair deficiency along with inc reased sensitivity to ionizing radiation, The conjunction of a major DNA re pair deficiency and a resistance to apoptosis, both induced by BCR-ABL, pro vides a new mechanism to explain how secondary genetic alterations can accu mulate in CML, eventually leading to blast crisis. The down-regulation of D NA-PKcs was reversible in CD34(+) CML cells suggesting that this approach m ight offer a novel and powerful therapeutic strategy in this disease, espec ially to delay the blast crisis.