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Leukemia. 2014 Jun;28(6):1326-33. doi: 10.1038/leu.2013.370. Epub 2013 Dec 9.

BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP.

Author information

1
1] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA [2] Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy.
2
Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy.
3
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
4
Division of Pathology, Department of Oncology, St Luigi Hospital, Torino, Italy.
5
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Abstract

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.

PMID:
24317448
DOI:
10.1038/leu.2013.370
[Indexed for MEDLINE]

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