1. Department of Experimental Oncology at the IFOM-IEO Campus, European Institute of Oncology, IEO, 20141 Milan, Italy
2. Dipartimento di Medicina Clinica e Sperimentale, Policlinico Monteluce, University of Perugia, 06100 Perugia, Italy
3. Dipartimento di Scienze Biomolecolari e Biotecnologie, University of Milano 20100, Milano, Italy
4. Dipartimento di Medicina, Chirurgia e Odontoiatria, University of Milano, Milano 20100, Italy
5. These authors contributed equally to this work.

Correspondence to: Andrea Viale^1,5Pier Giuseppe Pelicci^1,4 Correspondence and requests for materials should be addressed to A.V. (Email: andrea.viale@ifom-ieo-campus.it) or P.G.P. (Email: piergiuseppe.pelicci@ifom-ieo-campus.it).

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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