期刊
BLOOD
卷 120, 期 17, 页码 3555-3562出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-01-402578
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资金
- National Institutes of Health [CA121192, CA77816, CA155566]
- Department of Veterans affairs
- Leukemia and Lymphoma Society of America [LLS-6166-09]
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 AS(2)O(3) 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. (Blood. 2012;120(17):3555-3562)
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