2026-06-14T03:29:46Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/105432024-11-29T14:58:51Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Trakala, Marianna
author
Partida, David
author
Salazar-Roa, Maria
author
Maroto, María
author
Wachowicz, Paulina
author
de Carcer Diez, Guillermo
author
Malumbres Martinez, Marcos
funder
Fundación La Caixa
funder
Ministerio de Economía y Competitividad (España)
funder
Comunidad de Madrid (España)
funder
Worldwide Cancer Research
funder
Unión Europea
funder
Consolider-Ingenio Programme
2020-06-23T16:30:53Z
2020-06-23T16:30:53Z
2015-10-01
Blood . 2015;126(14):1707-14.
10.1182/blood-2015-03-634402
1528-0020
Blood
26185128
http://hdl.handle.net/20.500.12105/10543
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.
eng
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.
journal article
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