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

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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Figure 1: p21 maintains self-renewal of PML–RAR-expressing HSCs.
Figure 2: Fusion proteins induce DNA damage.
Figure 3: p21 upregulation and cell-cycle restriction in HSCs.
Figure 4: p21 limits DNA damage in LSCs and is indispensable for leukaemogenesis.
Figure 5: Effects of fusion proteins on progenitors and fibroblasts.

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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.

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Correspondence to Andrea Viale or Pier Giuseppe Pelicci.

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Viale, A., De Franco, F., Orleth, A. et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457, 51–56 (2009). https://doi.org/10.1038/nature07618

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