title: Cdk4 and Cdk6 cooperate in counteracting the INK4 family of inhibitors during murine leukemogenesis.
abstract: Cdk4 and Cdk6 are related protein kinases that bind d-type cyclins and regulate cell-cycle progression. Cdk4/6 inhibitors are currently being used in advanced clinical trials and show great promise against many types of tumors. Cdk4 and Cdk6 are inhibited by INK4 proteins, which exert tumor-suppressing functions. To test the significance of this inhibitory mechanism, we generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6(R/R) mice display altered development of the hematopoietic system without enhanced tumor susceptibility, either in the presence or absence of p53. Unexpectedly, Cdk6 R31C impairs the potential of hematopoietic progenitors to repopulate upon adoptive transfer or after 5-fluorouracil-induced damage. The defects are overcome by eliminating sensitivity of cells to INK4 inhibitors by introducing the INK4-insensitive Cdk4 R24C allele, and INK4-resistant mice are more susceptible to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, Cdk6 R31C causes increased binding of p16(INK4a) to wild-type Cdk4, whereas cells harboring Cdk4 R24C and Cdk6 R31C are fully insensitive to INK4 inhibitors, resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in hematopoietic tumor development and suggest a role for Cdk6 in sequestering INK4 proteins away from Cdk4.
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;
authors.forename: Esther
authors.initials: E
authors.lastname: Rodríguez-Díez
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;
authors.forename: Victor
authors.initials: V
authors.lastname: Quereda
authors.affiliation: Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Vienna, Austria;
authors.forename: Florian
authors.initials: F
authors.lastname: Bellutti
authors.affiliation: Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Vienna, Austria;
authors.forename: Michaela
authors.initials: M
authors.lastname: Prchal-Murphy
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;
authors.forename: David
authors.initials: D
authors.lastname: Partida
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Eguren
authors.affiliation: Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Vienna, Austria;
authors.forename: Karoline
authors.initials: K
authors.lastname: Kollmann
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;
authors.forename: Marta
authors.initials: M
authors.lastname: Gómez de Cedrón
authors.affiliation: EA2406 University of Bordeaux, Bordeaux, France; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.affiliation: Histopathology Unit, and.
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Flow Cytometry Unit, CNIO, Madrid, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Martínez
authors.affiliation: Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Vienna, Austria;
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
mesh_terms: D000483:Alleles; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D063990:Gene Ontology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050505:Mutant Proteins; D016044:Fusion Proteins, bcr-abl; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6