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

Dennis J. Goussetis, Elias Gounaris, Edward J. Wu, Eliza Vakana, Bhumika Sharma, Matthew Bogyo, Jessica K. Altman, Leonidas C. Platanias

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3555-3562
Number of pages8
JournalBlood
Volume120
Issue number17
DOIs
StatePublished - Oct 25 2012
Externally publishedYes

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