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The Role of Backup NHEJ Repair in Creating Genomic Instability in CML. Addendum
Final rept. (addendum) 1 Mar 2007-28 Feb 2009
MARYLAND UNIV BALTIMORE SCHOOL OF MEDICINE
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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 IIIaXRCC1 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-ABL1ve 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.
APPROVED FOR PUBLIC RELEASE