title: Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice.
abstract: Polyploidization in megakaryocytes is achieved by endomitosis, a specialized cell cycle in which DNA replication is followed by aberrant mitosis. Typical mitotic regulators such as Aurora kinases or Cdk1 are dispensable for megakaryocyte maturation, and inhibition of mitotic kinases may in fact promote megakaryocyte maturation. However, we show here that Polo-like kinase 1 (Plk1) is required for endomitosis, and ablation of the Plk1 gene in megakaryocytes results in defective polyploidization accompanied by mitotic arrest and cell death. Lack of Plk1 results in defective centrosome maturation and aberrant spindle pole formation, thus impairing the formation of multiple poles typically found in megakaryocytes. In these conditions, megakaryocytes arrest for a long time in mitosis and frequently die. Mitotic arrest in wild-type megakaryocytes treated with Plk1 inhibitors or Plk1-null cells is triggered by the spindle assembly checkpoint (SAC), and can be rescued in the presence of SAC inhibitors. These data suggest that, despite the dispensability of proper chromosome segregation in megakaryocytes, an endomitotic SAC is activated in these cells upon Plk1 inhibition. SAC activation results in defective maturation of megakaryocytes and cell death, thus raising a note of caution in the use of Plk1 inhibitors in therapeutic strategies based on polyploidization regulators.
authors.affiliation: Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Marianna
authors.initials: M
authors.lastname: Trakala
authors.affiliation: Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Partida
authors.affiliation: Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Salazar-Roa
authors.affiliation: Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Maroto
authors.affiliation: Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Paulina
authors.initials: P
authors.lastname: Wachowicz
authors.affiliation: Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Guillermo
authors.identifier: http://orcid.org/0000-0002-3220-1785
authors.initials: G
authors.lastname: de Cárcer
authors.affiliation: Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Marcos
authors.identifier: http://orcid.org/0000-0002-0829-6315
authors.initials: M
authors.lastname: Malumbres
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency*; D002454:Cell Differentiation / Q000502:physiology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D008533:Megakaryocytes / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D011518:Proto-Oncogene Proteins / Q000172:deficiency*; D013921:Thrombocytopenia / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1