Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cell (Nature, 2009, 457:51-56)

報告日期: 2009/03/13
報告時間: 17:10/18:00
報告學生: 洪君樺(英文報告)
講評老師: 賴明德


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


Nature 457, 51-57 (2009)


Presenter: Hung Chun- Hwa 洪君樺

Commentator: Prof. Lai Ming-Derg 賴明德教授

Date: 13 March, 2009 (17:10-18:00)

Place: Room 602, College of Medicine



The number of times a single haematopoietic stem cells (HSCs) replicates during a lifespan in mammals is limited (about 80-200 times), suggesting that self-renewal of HSCs is intrinsically restricted. This limit becomes experimentally evident as exhaustion of their regenerative potential when HSCs are induced to proliferate rapidly in response to environmental stress, such as in serial transplantation or myelosuppressive chemotherapy. Under these conditions, cell-cycle restriction of HSCs might become critical, because HSCs proliferate more and are rapidly consumed in p21-/- mice. Like normal blood cells, leukaemic cells are maintained by a small population of stem cells (termed leukaemia stem cells, LSCs), which is indispensable to the development and perpetuation of leukaemias. In contrast to HSCs, self-renewal of LSCs is unlimited, as inferred by their ability to support continuous expansion of the leukaemia clone and to be propagated inexhaustibly in mice during serial bone marrow transplantation. However, it is largely unknown whether specific mechanisms are selected during leuaemogenesis to prevent hyper-proliferating LSCs from exhaustion. The authors investigate the role of p21 in the regulation of LSC self-renewal in mice, using PML-RAR (promyelotic leukaemia- retinoic acid receptor), the initiating oncogene of human acute promyelocytic leukaemia (APL), one subtype of acute myeloid leukaemia (AML). The cell-cycle inhibitor p21 is integral to maintaining self-renewal of LSCs. Either PML-RAR expression or p21 loss induces a moderate degree of DNA-damage in PML-RAR-expressing HSCs, suggesting that p21 might limit DNA-damage accumulation (indicated by the intension of g-H2AX foci) in those cells. Expression of another leukaemia-associated oncogene, AML1-ETO (acute myeloid leukemia- eight twenty one), in mouse HSCs also induces DNA damage and activates a p21-dependent cellular response, which leads to reversible cell-cycle arrest and DNA repair. Once more, activated p21 shows a critical role in preventing excess DNA-damage accumulation and functional exhaustion of LSCs. In conclusion, these data unravel the oncogenic potential of p21 and suggest that inhibition of DNA repair mechanisms might function as potent strategy for eradicating the slowly proliferating LSCs.