Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid and/or arsenic trioxide represents a paradigm in targeted cancer therapy because these drugs cause clinical remission by affecting the stability of the fusion oncoprotein promyelocytic leukemia (PML)/retinoic acid receptor...

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Bibliographic Details
Published inBlood Vol. 116; no. 13; pp. 2324 - 2331
Main Authors Isakson, Pauline, Bjørås, Magnar, Bøe, Stig Ove, Simonsen, Anne
Format Journal Article
LanguageEnglish
Published Washington, DC Elsevier Inc 30.09.2010
Americain Society of Hematology
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Summary:Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid and/or arsenic trioxide represents a paradigm in targeted cancer therapy because these drugs cause clinical remission by affecting the stability of the fusion oncoprotein promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARA). The authors of previous studies have implicated the ubiquitin-proteasome pathway as the main mechanism involved in therapy-induced PML/RARA degradation. Here we have investigated a role of autophagy, a protein degradation pathway that involves proteolysis of intracellular material within lysosomes. We found that both all-trans retinoic acid and arsenic trioxide induce autophagy via the mammalian target of rapamycin pathway in APL cells and that autophagic degradation contributes significantly both to the basal turnover as well as the therapy-induced proteolysis of PML/RARA. In addition, we observed a correlation between autophagy and therapy-induced differentiation of APL cells. Given the central role of the PML/RARA oncoprotein in APL pathogenesis, this study highlights an important role of autophagy in the development and treatment of this disease.
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ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2010-01-261040