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- Title
BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP.
- Authors
Morotti, A; Panuzzo, C; Crivellaro, S; Pergolizzi, B; Familiari, U; Berger, A H; Saglio, G; Pandolfi, P P
- 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.
- Subjects
TREATMENT of chronic myeloid leukemia; PHOSPHORYLATION; CHIMERIC proteins; TUMOR suppressor proteins; PHOSPHATASES; TYROSINE; STEM cells
- Publication
Leukemia (08876924), 2014, Vol 28, Issue 6, p1326
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2013.370