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

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. Cancer stem cell self renewal Haematopoietic stem cells in mammals are limited to about 80 to 200 replications in a lifetime, but leukaemia stem cells appear to retain an almost limitless capacity to self-renew. A clue to the origin of this significant difference comes with the discovery that the cell-cycle inhibitor p21 is necessary for self-renewal in leukaemia stem cells. The PML-RAR oncogene is activated in most patients with acute promyelocytic leukaemia. Experiments in a mouse model show that expression of PML-RAR in haematopoietic stem cells upregulates p21, leading to cell-cycle arrest and DNA repair. This maintains a pool of quiescent leukaemic stem cells and prevents their exhaustion by hyperproliferation. In the absence of p21, leukaemia-associated oncogenes neither initiate nor maintain leukaemogenesis. This work identifies p21 as a potential target for anticancer therapies based on the eradication of quiescent cancer stem cells. After expression of the PML–RAR oncogene in haematopoietic stem cells, p21 is necessary to limit cell cycle progression and thus limit the accumulation of DNA damage which would otherwise limit the self-renewal of leukaemic stem cells and prevent the development of leukaemia