Cdk-inhibitors and exit from quiescence in primitive haematopoietic cell subsets.
Prolonged quiescence of haematopoietic stem cells has been proposed to support durable haematopoiesis through clonal succession. Genetic experiments in mice have implicated the cyclin-dependent kinase inhibitor (cdki) p21Waf1 in sustaining stem cell quiescence, and the cdki p27Kip1 in inhibiting the expansion of more mature progenitor cells. The expression of these inhibitory proteins in human haematopoietic stem cell candidates has not hitherto been studied. We describe a rare subpopulation (3 x 10-7 umbilical cord mononuclear cells) of lineage-negative cells that exhibited sustained resistance over months to cytokine-induced cycling, and characterized the expression of p21Waf1 and p27Kip1 proteins in these cells. Whereas p27Kip1 was uniformly expressed in these cells, the expression of p21Waf1 in this population and in lineage-negative CD34+ cells was variable. For this rare subset of cells exhibiting prolonged quiescence, p21Waf1 may be dispensable and p27Kip1 necessary for growth arrest.
Steinman
Richard
R
Suite 2.19 Hillman Cancer Center, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. steinman@pitt.edu
Yaroslavskiy
Beatrice
B
Goff
Julie P
JP
Alber
Sean M
SM
Watkins
Simon C
SC
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000032:analysis; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000032:analysis / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D018613:Microscopy, Confocal; D019089:Stem Cell Factor / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000032:analysis
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016207:Cytokines; D007166:Immunosuppressive Agents; D007377:Interleukin-3; D019089:Stem Cell Factor; D025521:Tumor Suppressor Proteins; D016179:Granulocyte Colony-Stimulating Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D005472:Fluorouracil