title: CDK6 levels regulate quiescence exit in human hematopoietic stem cells.
abstract: Regulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. The molecular mechanisms underlying this variability in HSC division kinetics are unknown. We report here that quiescence exit kinetics are differentially regulated within human HSC subsets through the expression level of CDK6. LT-HSCs lack CDK6 protein. Short-term (ST)-HSCs are also quiescent but contain high CDK6 protein levels that permit rapid cell cycle entry upon mitogenic stimulation. Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impacting function. Computational modeling suggests that this independent control of quiescence exit kinetics inherently limits LT-HSC divisions and preserves the HSC pool to ensure lifelong hematopoiesis. Thus, differential expression of CDK6 underlies heterogeneity in stem cell quiescence states that functionally regulates this highly regenerative system.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: el422@cam.ac.uk.
authors.forename: Elisa
authors.initials: E
authors.lastname: Laurenti
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Frelin
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Xie
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Ecole Normale Supérieure de Cachan, Département de Biologie, Cachan, 94235, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, LMC, Station 12, Lausanne, CH-1015, Switzerland.
authors.forename: Cyrille F
authors.initials: CF
authors.lastname: Dunant
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Neumann
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Plumb
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Doulatov
authors.affiliation: Illumina, San Diego, CA 92121, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Illumina, San Diego, CA 92121, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: April
authors.affiliation: Illumina, San Diego, CA 92121, USA.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Norman
authors.initials: N
authors.lastname: Iscove
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jdick@uhnresearch.ca.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D002455:Cell Division / Q000502:physiology*; D003198:Computer Simulation; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D008954:Models, Biological
chemical_list: C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6