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.
Viale
Andrea
A
Department of Experimental Oncology at the IFOM-IEO Campus, European Institute of Oncology, IEO, 20141 Milan, Italy. andrea.viale@ifom-ieo-campus.it
De Franco
Francesca
F
Orleth
Annette
A
Cambiaghi
Valeria
V
Giuliani
Virginia
V
Bossi
Daniela
D
Ronchini
Chiara
C
Ronzoni
Simona
S
Muradore
Ivan
I
Monestiroli
Silvia
S
Gobbi
Alberto
A
Alcalay
Myriam
M
Minucci
Saverio
S
Pelicci
Pier Giuseppe
PG
D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D007938:Leukemia / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
C493957:Cdkn1a protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein