Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

We provide evidence that arsenic trioxide (As2O3) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autop...

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Bibliographic Details
Published in:Blood 2012-10, Vol.120 (17), p.3555-3562
Main Authors: Goussetis, Dennis J., Gounaris, Elias, Wu, Edward J., Vakana, Eliza, Sharma, Bhumika, Bogyo, Matthew, Altman, Jessica K., Platanias, Leonidas C.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - antagonists & inhibitors
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Antineoplastic Agents - pharmacology
Arsenic Trioxide
Arsenicals - pharmacology
Autophagy - drug effects
Autophagy - genetics
Autophagy-Related Protein 7
Biological and medical sciences
Cathepsin B - antagonists & inhibitors
Cathepsin B - genetics
Cathepsin B - metabolism
Chromosome aberrations
Enzyme Inhibitors - pharmacology
Fusion Proteins, bcr-abl - genetics
Fusion Proteins, bcr-abl - metabolism
Gene Expression Regulation, Neoplastic - drug effects
Hematologic and hematopoietic diseases
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism
Lysosomes - drug effects
Lysosomes - metabolism
Medical genetics
Medical sciences
Myeloid Neoplasia
Oxides - pharmacology
Phosphorylation
Plasmids
Primary Cell Culture
Proteolysis - drug effects
Sequestosome-1 Protein
Signal Transduction - drug effects
Signal Transduction - genetics
Transfection
Ubiquitin-Activating Enzymes - antagonists & inhibitors
Ubiquitin-Activating Enzymes - genetics
Ubiquitin-Activating Enzymes - metabolism
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Summary:We provide evidence that arsenic trioxide (As2O3) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or cathepsin B activity and/or molecular targeting of p62/SQSTM1, Atg7, or cathepsin B result in partial reversal of the suppressive effects of AS2O3 on BCR-ABL expressing leukemic progenitors, including primitive leukemic precursors from chronic myelogenous leukemia (CML) patients. Altogether, these findings indicate that autophagic degradation of BCR-ABL is critical for the induction of the antileukemic effects of As2O3 and raise the potential for future therapeutic approaches to target BCR-ABL expressing cells by modulating elements of the autophagic machinery to promote BCR-ABL degradation.
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2012-01-402578