Role of Backup NHEJ Repair in Creating Genomic Instability in CML. Addendum

摘要

The BCR-ABL1 fusion gene in Philadelphia (Ph)-+ve chronic myeloid leukemis (CML) encodes a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. BCR-ABL1 expression results in elevated levels of reactive oxygen species (ROS), an increased incidence of DNA double strand breaks (DSBs), error-prone repair and genomic instability. We recently demonstrated that an error-prone alternative (alt) NHEJ pathway involving DNA ligase IIIa/XRCC1 is upregulated in CML cells. 'Knockdown' of alt NHEJ proteins causes decreased DNA repair and an increased frequency of DSBs, indicating that this pathway is important for the survival of BCR-ABL1 positive cells, and so may be a specific therapeutic target (Blood publication, 2008). In the one year extension of the grant, we have shown that BCR-ABL modulates expression of alt NHEJ proteins. As an additional task, we have also examined the effect of recently identified alt NHEJ inhibitors in CML cells and show that they significantly decrease the survival of imatinib resistant BCR-ABL1+ve cells, compared with BCR-ABL1 cells that are imatinib sensitive and normal cells. These results suggest that alt NHEJ proteins may be therapeutic targets in CML that are sensitive to imatinib.