TY - JOUR
T1 - A non-redundant function of cyclin E1 in hematopoietic stem cells
AU - Campaner, Stefano
AU - Viale, Andrea
AU - De Fazio, Serena
AU - Doni, Mirko
AU - De Franco, Francesca
AU - D'Artista, Luana
AU - Sardella, Domenico
AU - Pelicci, Pier Giuseppe
AU - Amati, Bruno
N1 - Funding Information:
We thank Simona Ronzoni, Anna Sciullo for the technical help with FACS analysis. This work was supported by grants from the EU-FP7 Program EuroSyStem, the Italian health ministry and the Italian Association for Cancer Research (AIRC) to BA and a grant from the Italian Association for Cancer Research (AIRC) to SC.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - A precise balance between quiescence and proliferation is crucial for the lifelong function of hematopoietic stem cells (HSCs). Cyclins E1 and E2 regulate exit from quiescence in fibroblasts, but their role in HSCs remains unknown. Here, we report a non-redundant role for cyclin E1 in mouse HSCs. A long-term culture-initiating cell (LTC-IC) assay indicated that the loss of cyclin E1, but not E2, compromised the colony-forming activity of primitive hematopoietic progenitors. Ccne1-/- mice showed normal hematopoiesis in vivo under homeostatic conditions but a severe impairment following myeloablative stress induced by 5-fluorouracil (5-FU). Under these conditions, Ccne1 -/-HSCs were less efficient in entering the cell cycle, resulting in decreased hematopoiesis and reduced survival of mutant mice upon weekly 5-FU treatment. The role of cyclin E1 in homeostatic conditions became apparent in aged mice, where HSC quiescence was increased in Ccne1-/- animals. On the other hand, loss of cyclin E1 provided HSCs with a competitive advantage in bone marrow serial transplantation assays, suggesting that a partial impairment of cell cycle entry may exert a protective role by preventing premature depletion of the HSC compartment. Our data support a role for cyclin E1 in controlling the exit from quiescence in HSCs. This activity, depending on the physiological context, can either jeopardize or protect the maintenance of hematopoiesis.
AB - A precise balance between quiescence and proliferation is crucial for the lifelong function of hematopoietic stem cells (HSCs). Cyclins E1 and E2 regulate exit from quiescence in fibroblasts, but their role in HSCs remains unknown. Here, we report a non-redundant role for cyclin E1 in mouse HSCs. A long-term culture-initiating cell (LTC-IC) assay indicated that the loss of cyclin E1, but not E2, compromised the colony-forming activity of primitive hematopoietic progenitors. Ccne1-/- mice showed normal hematopoiesis in vivo under homeostatic conditions but a severe impairment following myeloablative stress induced by 5-fluorouracil (5-FU). Under these conditions, Ccne1 -/-HSCs were less efficient in entering the cell cycle, resulting in decreased hematopoiesis and reduced survival of mutant mice upon weekly 5-FU treatment. The role of cyclin E1 in homeostatic conditions became apparent in aged mice, where HSC quiescence was increased in Ccne1-/- animals. On the other hand, loss of cyclin E1 provided HSCs with a competitive advantage in bone marrow serial transplantation assays, suggesting that a partial impairment of cell cycle entry may exert a protective role by preventing premature depletion of the HSC compartment. Our data support a role for cyclin E1 in controlling the exit from quiescence in HSCs. This activity, depending on the physiological context, can either jeopardize or protect the maintenance of hematopoiesis.
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U2 - 10.4161/cc.26584
DO - 10.4161/cc.26584
M3 - Article
C2 - 24091730
AN - SCOPUS:84890266530
SN - 1538-4101
VL - 12
SP - 3663
EP - 3672
JO - Cell Cycle
JF - Cell Cycle
IS - 23
ER -