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Type: Journal article
Title: Proteasome proteolytic profile is linked to Bcr-Abl expression
Author: Crawford, L.
Windrum, P.
Magill, L.
Vaz de Melo, J.
McCallum, L.
McMullin, M.
Ovaa, H.
Walker, B.
Irvine, A.
Citation: Experimental Hematology, 2009; 37(3):257-266
Publisher: Elsevier Science Inc
Issue Date: 2009
ISSN: 0301-472X
Statement of
Lisa J. Crawford, Phlip Windrum, Laura Magill, Junia V. Melo, Lynn McCallum, Mary F. McMullin, Huib Ovaa, Brian Walker, and Alexandra E. Irvine
Abstract: <h4>Objective</h4>We have previously demonstrated that proteasome activity is higher in bone marrow from patients with chronic myeloid leukemia (CML) than normal controls. This study investigates whether there is any relationship between Bcr-Abl expression and proteasome activity.<h4>Materials and methods</h4>Fluorogenic substrate assays and an activity-based probe were used to profile proteasome activity in CML cell-line models and the effect of the proteasome inhibitor BzLLLCOCHO on these cell-line models and primary CML cells was investigated.<h4>Results</h4>We have demonstrated that oncogenic transformation by BCR-ABL is associated with an increase in proteasome proteolytic activity. Furthermore, small interfering RNA targeted against BCR-ABL reduces proteasome activity. In addition, we have found that Bcr-Abl-positive cells are more sensitive than Bcr-Abl-negative cells to induction of apoptosis by the proteasome inhibitor BzLLLCOCHO, and that sequential addition of imatinib followed by BzLLLCOCHO has an additive effect on the induction of apoptosis in Bcr-Abl-positive cells. Finally, we demonstrate that cell lines that become resistant to imatinib remain sensitive to proteasome inhibition.<h4>Conclusion</h4>This is the first time that a direct relationship has been demonstrated between BCR-ABL transformation and the enzymatic activity of the proteasome. Our results suggest that the proteasome might provide a useful therapeutic target in CML, particularly in those patients who have developed resistance to conventional treatment.
Keywords: K562 Cells
Tumor Cells, Cultured
Cell Transformation, Neoplastic
Proteasome Endopeptidase Complex
Fusion Proteins, bcr-abl
Protease Inhibitors
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Imatinib Mesylate
Rights: Copyright 2009 ISEH - Society for Hematology and Stem Cells
DOI: 10.1016/j.exphem.2008.11.004
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