title: 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.
authors.affiliation: Department of Experimental Oncology at the IFOM-IEO Campus, European Institute of Oncology, IEO, 20141 Milan, Italy. andrea.viale@ifom-ieo-campus.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Viale
authors.forename: Francesca
authors.initials: F
authors.lastname: De Franco
authors.forename: Annette
authors.initials: A
authors.lastname: Orleth
authors.forename: Valeria
authors.initials: V
authors.lastname: Cambiaghi
authors.forename: Virginia
authors.initials: V
authors.lastname: Giuliani
authors.forename: Daniela
authors.initials: D
authors.lastname: Bossi
authors.forename: Chiara
authors.initials: C
authors.lastname: Ronchini
authors.forename: Simona
authors.initials: S
authors.lastname: Ronzoni
authors.forename: Ivan
authors.initials: I
authors.lastname: Muradore
authors.forename: Silvia
authors.initials: S
authors.lastname: Monestiroli
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.forename: Myriam
authors.initials: M
authors.lastname: Alcalay
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: 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
chemical_list: 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