title: CDK6 as a key regulator of hematopoietic and leukemic stem cell activation.
abstract: The cyclin-dependent kinase 6 (CDK6) and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (hematopoietic stem cells [HSCs] and leukemic stem cells [LSCs]) that exceeds its function as a cell-cycle regulator. Although hematopoiesis appears normal under steady-state conditions, Cdk6(-/-) HSCs do not efficiently repopulate upon competitive transplantation, and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil treatment. We find that activation of HSCs requires CDK6, which interferes with the transcription of key regulators, including Egr1. Transcriptional profiling of HSCs is consistent with the central role of Egr1. The impaired repopulation capacity extends to BCR-ABL(p210+) LSCs. Transplantation with BCR-ABL(p210+)-infected bone marrow from Cdk6(-/-) mice fails to induce disease, although recipient mice do harbor LSCs. Egr1 knock-down in Cdk6(-/-) BCR-ABL(p210+) LSKs significantly enhances the potential to form colonies, underlining the importance of the CDK6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Ruth
authors.initials: R
authors.lastname: Scheicher
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoelbl-Kovacic
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Florian
authors.initials: F
authors.lastname: Bellutti
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Anca-Sarmiza
authors.initials: AS
authors.lastname: Tigan
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Michaela
authors.initials: M
authors.lastname: Prchal-Murphy
authors.affiliation: Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;
authors.forename: Gerwin
authors.initials: G
authors.lastname: Heller
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Christine
authors.initials: C
authors.lastname: Schneckenleithner
authors.affiliation: Cell Division and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain; and.
authors.forename: María
authors.initials: M
authors.lastname: Salazar-Roa
authors.affiliation: Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;
authors.forename: Sabine
authors.initials: S
authors.lastname: Zöchbauer-Müller
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Cell Division and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain; and.
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Karoline
authors.initials: K
authors.lastname: Kollmann
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D000818:Animals; D002453:Cell Cycle; D017690:Cell Transplantation; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011070:Poly I-C / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D014158:Transcription, Genetic
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016044:Fusion Proteins, bcr-abl; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D011070:Poly I-C