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Proteasome proteolytic profile is linked to Bcr-Abl expression

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dc.contributor.authorCrawford, L.
dc.contributor.authorWindrum, P.
dc.contributor.authorMagill, L.
dc.contributor.authorVaz de Melo, J.
dc.contributor.authorMcCallum, L.
dc.contributor.authorMcMullin, M.
dc.contributor.authorOvaa, H.
dc.contributor.authorWalker, B.
dc.contributor.authorIrvine, A.
dc.date.issued2009
dc.description.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.
dc.description.statementofresponsibilityLisa J. Crawford, Phlip Windrum, Laura Magill, Junia V. Melo, Lynn McCallum, Mary F. McMullin, Huib Ovaa, Brian Walker, and Alexandra E. Irvine
dc.description.urihttp://www.elsevier.com/wps/find/journaldescription.cws_home/601451/description#description
dc.identifier.citationExperimental Hematology, 2009; 37(3):257-266
dc.identifier.doi10.1016/j.exphem.2008.11.004
dc.identifier.issn0301-472X
dc.identifier.issn1873-2399
dc.identifier.orcidVaz de Melo, J. [0009-0009-5343-4893]
dc.identifier.urihttp://hdl.handle.net/2440/58516
dc.language.isoen
dc.publisherElsevier Science Inc
dc.rightsCopyright 2009 ISEH - Society for Hematology and Stem Cells
dc.source.urihttps://doi.org/10.1016/j.exphem.2008.11.004
dc.subjectK562 Cells
dc.subjectTumor Cells, Cultured
dc.subjectHumans
dc.subjectCell Transformation, Neoplastic
dc.subjectBenzamides
dc.subjectPiperazines
dc.subjectPyrimidines
dc.subjectProteasome Endopeptidase Complex
dc.subjectFusion Proteins, bcr-abl
dc.subjectProtease Inhibitors
dc.subjectApoptosis
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDrug Resistance, Neoplasm
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectImatinib Mesylate
dc.titleProteasome proteolytic profile is linked to Bcr-Abl expression
dc.typeJournal article
pubs.publication-statusPublished

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