Chronic myeloid leukemia (CML) accounts for 20% of adult leukemias, and is characterized by the presence of the constitutively active tyrosine kinase Bcr-Abl. Its presence is essential for CML blast survival even in advanced disease, and underlies the success that the Bcr-Abl kinase inhibitor imatinib has had. However, resistance to imatinib occurs in a significant number of accelerated phase or blast crisis patients. Instead of trying to inhibit Bcr-Abl signaling, we propose a previously unexplored approach to rewire signaling pathways to activate proteins that would not normally be activated by Bcr-Abl. We have previously shown that activation of Protein kinase C isoform βII (PKCβII) drives dendritic cell differentiation in normal and leukemic cells. We hypothesized that inserting the Abl kinase motif into a specific domain of PKCβII, would allow Bcr-Abl to activate PKCβII. Using molecular modeling techniques, we have shown that the modified PKCβII pseudosubstrate sequence is largely unchanged as a result of this mutation and still able to respond to traditional activating signals. Additionally, our modified PKCβII is activated in Bcr-Abl+ but not in Bcr-Abl- cells resulting in a decrease in viability and increase in apoptosis. Future experiments plan to characterize the immunogenic potential of these converted leukemic cells, and to fuse the protein transduction domain from HIV onto our modified PKCβII to test the efficacy of this modified protein in a murine model of CML.
- Copyright © 2011 by The American Association of Immunologists, Inc.