Inducing Apoptosis in Bcr/Abl-Expressing Cells
Abstract
With the emergence of CMLs that are resistant to Bcr-Abl tyrosine kinase inhibitors it becomes imperative that we identify other effective agents to eliminate these cells. In recent years it has become evident that most successful chemotherapeutics work by inducing apoptosis. Unfortunately high levels of Bcr-Abl can preclude the successful use of many agents by dampening the apoptotic response. In this proposal we developed a strategy that relies on indeed exploits the high tyrosine kinase activity of Bcr-Abl to induce cell killing. We have designed and engineered constructs to fuse the catalytic domains of caspases (the apoptotic proteases) to either an SH2 domain or to sites well-phosphorylated by Bcr-Abl. We have made variants based on the Ork SH2 domain as well as phosphorylation sites from Stat 5 Bor-AbI and Ork itself (this is the sequence to which the Ork SH2 domain would bind intramolecularly). These have now been used to infect cells. Initial results suggest that the relevant fusion proteins are being produced and that there may be selective killing of Bcr-Abl-expressing cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2006
- Accession Number
- ADA462025
Entities
People
- Sally Kornbluth
Organizations
- Duke University