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

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 and Pier Giuseppe Pelicci ()
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Andrea Viale: European Institute of Oncology, IEO, 20141 Milan, Italy
Francesca De Franco: European Institute of Oncology, IEO, 20141 Milan, Italy
Annette Orleth: European Institute of Oncology, IEO, 20141 Milan, Italy
Valeria Cambiaghi: European Institute of Oncology, IEO, 20141 Milan, Italy
Virginia Giuliani: European Institute of Oncology, IEO, 20141 Milan, Italy
Daniela Bossi: European Institute of Oncology, IEO, 20141 Milan, Italy
Chiara Ronchini: European Institute of Oncology, IEO, 20141 Milan, Italy
Simona Ronzoni: European Institute of Oncology, IEO, 20141 Milan, Italy
Ivan Muradore: European Institute of Oncology, IEO, 20141 Milan, Italy
Silvia Monestiroli: European Institute of Oncology, IEO, 20141 Milan, Italy
Alberto Gobbi: European Institute of Oncology, IEO, 20141 Milan, Italy
Myriam Alcalay: European Institute of Oncology, IEO, 20141 Milan, Italy
Saverio Minucci: European Institute of Oncology, IEO, 20141 Milan, Italy
Pier Giuseppe Pelicci: European Institute of Oncology, IEO, 20141 Milan, Italy

Nature, 2009, vol. 457, issue 7225, 51-56

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature07618

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