title: BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP.
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.
authors: 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.
authors: A
authors: A
authors: Morotti
authors: Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy.
authors: C
authors: C
authors: Panuzzo
authors: Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy.
authors: S
authors: S
authors: Crivellaro
authors: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors: B
authors: B
authors: Pergolizzi
authors: Division of Pathology, Department of Oncology, St Luigi Hospital, Torino, Italy.
authors: U
authors: U
authors: Familiari
authors: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors: A H
authors: AH
authors: Berger
authors: Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy.
authors: G
authors: G
authors: Saglio
authors: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors: P P
authors: PP
authors: Pandolfi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D016044:Fusion Proteins, bcr-abl; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7