Toggle Main Menu Toggle Search

Open Access padlockePrints

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

Lookup NU author(s): Dr Matthew Allen, Dr Daniel Williamson, Professor Steven Clifford

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels.


Publication metadata

Author(s): Hartsink-Segers SA, Exalto C, Allen M, Williamson D, Clifford SC, Horstmann M, Caron HN, Pieters R, Den Boer ML

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2013

Volume: 98

Issue: 10

Pages: 1539-1546

Print publication date: 10/06/2013

ISSN (print): 0390-6078

ISSN (electronic): 1592-8721

Publisher: Fondazione Ferrata Storti

URL: http://dx.doi.org/10.3324/haematol.2013.084434

DOI: 10.3324/haematol.2013.084434


Altmetrics

Altmetrics provided by Altmetric


Share