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oai:repisalud.isciii.es:20.500.12105/105432024-11-29T14:58:51Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Trakala, Marianna author Partida, David author Salazar-Roa, Maria author Maroto, María author Wachowicz, Paulina author de Carcer Diez, Guillermo author Malumbres Martinez, Marcos author 2015-10-01 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. Blood . 2015;126(14):1707-14. 10.1182/blood-2015-03-634402 1528-0020 Blood 26185128 http://hdl.handle.net/20.500.12105/10543 POLO-LIKE KINASES VOLASERTIB BI 6727 CELL-CYCLE AURORA-B MEGAKARYOCYTE ENDOMITOSIS INHIBITOR VOLASERTIB PHASE-2 TRIAL IN-VIVO POLYPLOIDIZATION MITOSIS Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice.