Journal
LEUKEMIA
Volume 28, Issue 6, Pages 1326-1333Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.370
Keywords
chronic myeloid leukemia; BCR-ABL; HAUSP; PTEN; PML
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Funding
- postdoctoral fellowship for research abroad
- NIH [R01CA142787]
- AIRC
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Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the t(9; 22) translocation coding for the chimeric protein p210 BCR-ABL. The tumor suppressor phosphatase and tensin homolog (PTEN) has recently been shown to have a critical role in the pathogenesis of CML. Nuclear localization and proper nuclear-cytoplasmic shuttling are crucial for PTEN's tumor suppressive function. In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity. Importantly, we also find that PTEN delocalization induced by BCR-ABL does not occur in the leukemic stem cell compartment due to high levels of PML, a potent inhibitor of HAUSP activity toward PTEN. We therefore identify a new proto-oncogenic mechanism whereby BCR-ABL antagonizes the nuclear function of the PTEN tumor suppressor, with important therapeutic implications for the eradication of CML minimal residual disease.
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