Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

• Published in: Blood 2011-03, Vol.117 (11), p.3151-3162
• Main Authors: Sun, Hanshi, Kapuria, Vaibhav, Peterson, Luke F., Fang, Dexing, Bornmann, William G., Bartholomeusz, Geoffrey, Talpaz, Moshe, Donato, Nicholas J.
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Benzamides; Biological and medical sciences; Cell Line, Tumor; Chromosome aberrations; Cyanoacrylates; Drug Resistance, Neoplasm - drug effects; Endopeptidases - metabolism; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - metabolism; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Models, Biological; Nitriles - pharmacology; Phosphorylation - drug effects; Piperazines - pharmacology; Protein Transport - drug effects; Pyridines - pharmacology; Pyrimidines - pharmacology; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Substrate Specificity - drug effects; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - metabolism; Ubiquitination - drug effects
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-03-276477

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 ubiquitin-cycle 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.