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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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.

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Acknowledgements

We thank all members of the Pandolfi laboratory for comments and discussion and Thomas Garvey for critical editing of the manuscript. We appreciate the help of Dr Enrico Bracco, from the Department of Clinical and Biological Sciences at the University of Turin, for spectrometry analysis. AM was supported by postdoctoral fellowship for research abroad. AHB is supported by NIH grant R01CA142787. This work was supported by NIH grants to PPP and AIRC grant to GS.

Author contributions

The experiments were conceived and designed by AM, CP, SC, AHB, GS and PPP. Mass Spectrometry analysis was performed in collaboration with BP. Experiments were performed by AM, CP, SC, UF and BP. The paper was written by AM, AHB and PPP.

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Correspondence to P P Pandolfi.

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The authors declare no conflict of interest.

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Morotti, A., Panuzzo, C., Crivellaro, S. et al. BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP. Leukemia 28, 1326–1333 (2014). https://doi.org/10.1038/leu.2013.370

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Keywords

  • chronic myeloid leukemia
  • BCR-ABL
  • HAUSP
  • PTEN
  • PML

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