Abstract
BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR-ABL. Here, we show that BCR-ABL stimulates the proteasome-dependent degradation of members of the forkhead family of tumor suppressors in vitro, in an in vivo animal model, and in samples from patients with BCR-ABL-positive CML or ALL. As several downstream mediators of BCR-ABL are regulated by the proteasome degradation pathway, we also show that inhibition of this pathway, using bortezomib, causes regression of CML-like disease. Bortezomib treatment led to inhibition of BCR-ABL-induced suppression of FoxO proteins and their proapoptotic targets, tumor necrosis factor-related apoptosis-inducing ligand and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy. We additionally show sensitivity of imatinib-resistant BCR-ABL T315I cells to bortezomib. Our data delineate the involvement of FoxO proteins in BCR-ABL-induced evasion of apoptosis and provide evidence that bortezomib is a candidate therapeutic in the treatment of BCR-ABL-induced leukemia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Apoptosis / genetics
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Benzamides
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Boronic Acids / pharmacology
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Boronic Acids / therapeutic use
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Bortezomib
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Cysteine Proteinase Inhibitors / pharmacology
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Cysteine Proteinase Inhibitors / therapeutic use*
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Female
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Forkhead Transcription Factors / metabolism*
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Forkhead Transcription Factors / physiology
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / physiology*
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Imatinib Mesylate
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Leukemia / drug therapy*
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Leukemia / genetics
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Leukemia / pathology
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Mice
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Mice, Nude
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Piperazines / pharmacology
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Proteasome Inhibitors
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Pyrazines / pharmacology
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Pyrazines / therapeutic use
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Pyrimidines / pharmacology
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Remission Induction
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / physiology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzamides
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Boronic Acids
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Cysteine Proteinase Inhibitors
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Forkhead Transcription Factors
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Piperazines
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Proteasome Inhibitors
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Pyrazines
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Pyrimidines
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Tumor Suppressor Proteins
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Bortezomib
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Imatinib Mesylate
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Fusion Proteins, bcr-abl