title: Functional reprogramming of polyploidization in megakaryocytes.
abstract: Polyploidization is a natural process that frequently accompanies differentiation; its deregulation is linked to genomic instability and cancer. Despite its relevance, why cells select different polyploidization mechanisms is unknown. Here we report a systematic genetic analysis of endomitosis, a process in which megakaryocytes become polyploid by entering mitosis but aborting anaphase. Whereas ablation of the APC/C cofactor Cdc20 results in mitotic arrest and severe thrombocytopenia, lack of the kinases Aurora-B, Cdk1, or Cdk2 does not affect megakaryocyte polyploidization or platelet levels. Ablation of Cdk1 forces a switch to endocycles without mitosis, whereas polyploidization in the absence of Cdk1 and Cdk2 occurs in the presence of aberrant re-replication events. Importantly, ablation of these kinases rescues the defects in Cdc20 null megakaryocytes. These findings suggest that endomitosis can be functionally replaced by alternative polyploidization mechanisms in vivo and provide the cellular basis for therapeutic approaches aimed to discriminate mitotic and polyploid cells.
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
authors.forename: Marianna
authors.initials: M
authors.lastname: Trakala
authors.affiliation: DNA Replication Group, CNIO, 28029 Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez-Acebes
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Maroto
authors.affiliation: Experimental Oncology Group, CNIO, 28029 Madrid, Spain.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Symonds
authors.affiliation: Experimental Oncology Group, CNIO, 28029 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Santamaría
authors.affiliation: Transgenic Unit, CNIO, 28029 Madrid, Spain.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.affiliation: Experimental Oncology Group, CNIO, 28029 Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.affiliation: DNA Replication Group, CNIO, 28029 Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Méndez
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Electronic address: malumbres@cnio.es.
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
mesh_terms: D000705:Anaphase / Q000502:physiology; D000818:Animals; D064199:Cdc20 Proteins / Q000378:metabolism; D002478:Cells, Cultured; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D017346:Protein Serine-Threonine Kinases