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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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

Leukemia volume 28, pages 1326–1333 (2014)Cite this article

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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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References

  1. Peng C, Chen Y, Yang Z, Zang H, Osterby L, Rosmarin AG et al. PTEN is a tumor suppressor in CML stem cells and Bcr-Abl induced leukemia in mice. Blood 2010; 115: 626–635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475–482.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006; 441: 518–522.

    Article  CAS  PubMed  Google Scholar 

  4. Salmena L, Carracedo A, Pandolfi PP . Tenets of PTEN tumor suppression. Cell 2008; 133: 403–414.

    Article  CAS  PubMed  Google Scholar 

  5. Song MS, Carracedo A, Salmena L, Song SJ, Egia A, Malumbres M et al. Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell 2011; 144: 187–199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Alice Berger H, Knudson AG, Pandolfi PP . A continuum model for tumour suppression. Nature 2011; 476: 163–169.

    Article  Google Scholar 

  7. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007; 128: 157–170.

    Article  CAS  PubMed  Google Scholar 

  8. Salmena L, Pandolfi PP . Changing venues for tumour suppression: balancing destruction and localization by monoubiquitylation. Nat Rev Cancer 2007; 7: 409–413.

    Article  CAS  PubMed  Google Scholar 

  9. Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network. Nature 2008; 455: 813–817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453: 1072–1078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ito K, Bernardi R, Pandolfi PP . A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell. Curr Opin Genet Dev 2009; 19: 51–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lim SK, Shin JM, Kim YS, Baek KH . Identification and characterization of murine mHAUSP encoding a deubiquitinating enzyme that regulates the status of p53 ubiquitination. Int J Oncology 2004; 24: 357–364.

    CAS  Google Scholar 

  13. Trotman LC, Wang Z, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 2007; 128: 141–156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ferretti R, Palumbo V, Di Savino A, Velasco S, Sbroggio M, Sportoletti P . Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis. Dev Cell 2010; 18: 486–495.

    Article  CAS  PubMed  Google Scholar 

  15. Faesen AC, Dirac AM, Shanmugham A, Ovaa H, Perrakis A, Sixma TK . Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase. Mol Cell 2011; 44: 147–159.

    Article  CAS  PubMed  Google Scholar 

  16. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker B . Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011; 121: 396–409.

    Article  CAS  PubMed  Google Scholar 

  17. Hamilton A, Helgason V, Schemionek M, Zhang B, Myssina S, Allan EK et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 2012; 119: 1501–1510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Perl A, Carroll M . BCR-ABL kinase is dead; long live the CML stem cell. J Clin Invest 2011; 121: 22–25.

    Article  CAS  PubMed  Google Scholar 

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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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Author notes

  1. A H Berger

    Present address: 5Current address: Cancer Program, Broad Institute, Cambridge, MA 02142, USA.,

Authors and Affiliations

  1. Department of Medicine and Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    A Morotti, A H Berger & P P Pandolfi

  2. Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy

    A Morotti, C Panuzzo, S Crivellaro & G Saglio

  3. Department of Clinical and Biological Sciences, University of Turin, Turin, Italy

    B Pergolizzi

  4. Division of Pathology, Department of Oncology, St Luigi Hospital, Torino, Italy

    U Familiari

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  1. A Morotti
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  2. C Panuzzo
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  3. S Crivellaro
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  7. G Saglio
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  8. P P Pandolfi
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Corresponding author

Correspondence to P P Pandolfi.

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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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