TY - JOUR
T1 - Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis
AU - Sun, Hanshi
AU - Kapuria, Vaibhav
AU - Peterson, Luke F.
AU - Fang, Dexing
AU - Bornmann, William G.
AU - Bartholomeusz, Geoffrey
AU - Talpaz, Moshe
AU - Donato, Nicholas J.
PY - 2011/3/17
Y1 - 2011/3/17
N2 - Although chronic myelogenous leukemia (CML) is effectively controlled by Bcr-Abl kinase inhibitors, resistance to inhibitors, progressive disease, and incomplete eradication of Bcr-Abl-expressing cells are concerns for the long-term control and suppression of this disease. We describe a novel approach to targeting key proteins in CML cells with a ubiquitincycle inhibitor, WP1130. Bcr-Abl is rapidly modified with K63-linked ubiquitin polymers in WP1130-treated CML cells, resulting in its accumulation in aggresomes, where is it unable to conduct signal transduction. Induction of apoptosis because of aggresomal compartmentalization of Bcr-Abl was observed in both imatinib-sensitive and -resistant cells. WP1130, but not Bcr-Abl kinase inhibitors, directly inhibits Usp9x deubiquitinase activity, resulting in the down-regulation of the prosurvival protein Mcl-1 and facilitating apoptosis. These results demonstrate that ubiquitin-cycle inhibition represents a novel and effective approach to blocking Bcr-Abl kinase signaling and reducing Mcl-1 levels to engage CML cell apoptosis. This approach may be a therapeutic option for kinase inhibitor-resistant CML patients.
AB - Although chronic myelogenous leukemia (CML) is effectively controlled by Bcr-Abl kinase inhibitors, resistance to inhibitors, progressive disease, and incomplete eradication of Bcr-Abl-expressing cells are concerns for the long-term control and suppression of this disease. We describe a novel approach to targeting key proteins in CML cells with a ubiquitincycle inhibitor, WP1130. Bcr-Abl is rapidly modified with K63-linked ubiquitin polymers in WP1130-treated CML cells, resulting in its accumulation in aggresomes, where is it unable to conduct signal transduction. Induction of apoptosis because of aggresomal compartmentalization of Bcr-Abl was observed in both imatinib-sensitive and -resistant cells. WP1130, but not Bcr-Abl kinase inhibitors, directly inhibits Usp9x deubiquitinase activity, resulting in the down-regulation of the prosurvival protein Mcl-1 and facilitating apoptosis. These results demonstrate that ubiquitin-cycle inhibition represents a novel and effective approach to blocking Bcr-Abl kinase signaling and reducing Mcl-1 levels to engage CML cell apoptosis. This approach may be a therapeutic option for kinase inhibitor-resistant CML patients.
UR - http://www.scopus.com/inward/record.url?scp=79953072934&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953072934&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-03-276477
DO - 10.1182/blood-2010-03-276477
M3 - Article
C2 - 21248063
AN - SCOPUS:79953072934
SN - 0006-4971
VL - 117
SP - 3151
EP - 3162
JO - Blood
JF - Blood
IS - 11
ER -