Article | Published:

Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells

Nature volume 457, pages 5156 (01 January 2009) | Download Citation

Abstract

Rare cells with the properties of stem cells are integral to the development and perpetuation of leukaemias. A defining characteristic of stem cells is their capacity to self-renew, which is markedly extended in leukaemia stem cells. The underlying molecular mechanisms, however, are largely unknown. Here we demonstrate that expression of the cell-cycle inhibitor p21 is indispensable for maintaining self-renewal of leukaemia stem cells. Expression of leukaemia-associated oncogenes in mouse haematopoietic stem cells (HSCs) induces DNA damage and activates a p21-dependent cellular response, which leads to reversible cell-cycle arrest and DNA repair. Activated p21 is critical in preventing excess DNA-damage accumulation and functional exhaustion of leukaemic stem cells. These data unravel the oncogenic potential of p21 and suggest that inhibition of DNA repair mechanisms might function as potent strategy for the eradication of the slowly proliferating leukaemia stem cells.

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Acknowledgements

We thank L. Luzi, D. Shing and M. Faretta for discussions and suggestions; M. Capillo, M. Stendardo and D. Sardella for assistance in maintenance of mouse colonies and for mouse genotyping; B. Amati, G. McVie, P. P. Di Fiore and C. Basilico for reviewing the manuscript; and P. Dalton for editing the manuscript. This study was supported by grants from the Italian Association on Cancer Research (AIRC), Ministero Italiano della Salute, Cariplo and the European Community (FP6: EPITRON and GENICA) to P.G.P. A.V. is a fellow of the Vollaro Foundation.

Author information

Author notes

    • Andrea Viale
    • , Francesca De Franco
    •  & Annette Orleth

    These authors contributed equally to this work.

Affiliations

  1. Department of Experimental Oncology at the IFOM-IEO Campus, European Institute of Oncology, IEO, 20141 Milan, Italy

    • Andrea Viale
    • , Francesca De Franco
    • , Annette Orleth
    • , Valeria Cambiaghi
    • , Virginia Giuliani
    • , Daniela Bossi
    • , Chiara Ronchini
    • , Simona Ronzoni
    • , Ivan Muradore
    • , Silvia Monestiroli
    • , Alberto Gobbi
    • , Myriam Alcalay
    • , Saverio Minucci
    •  & Pier Giuseppe Pelicci
  2. Dipartimento di Medicina Clinica e Sperimentale, Policlinico Monteluce, University of Perugia, 06100 Perugia, Italy

    • Francesca De Franco
    •  & Annette Orleth
  3. Dipartimento di Scienze Biomolecolari e Biotecnologie, University of Milano 20100, Milano, Italy

    • Saverio Minucci
  4. Dipartimento di Medicina, Chirurgia e Odontoiatria, University of Milano, Milano 20100, Italy

    • Myriam Alcalay
    •  & Pier Giuseppe Pelicci

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Correspondence to Andrea Viale or Pier Giuseppe Pelicci.

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DOI

https://doi.org/10.1038/nature07618

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