We investigated the effects of targeting the mitotic regulators aurora kinase A and B in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
protein expression levels in pediatric ALL and AML patient samples were
determined by western blot and reverse phase protein array. Both kinases were
overexpressed in ALL and AML patients (P<0.0002), especially in
E2A-PBX1-translocated ALL cases (P<0.002), compared with normal bone-marrow
mononuclear cells. Aurora
kinase expression was silenced in leukemic cell lines using short hairpin RNAs
and locked nucleic acid-based mRNA antagonists. Aurora B knockdown resulted in proliferation
arrest and apoptosis, whereas aurora A knockdown caused no or only minor growth
delay. Most tested cell lines were highly sensitive to the AURKB-selective
inhibitor barasertib-hydroxyquinazoline-pyrazol-anilide (AZD1152-HQPA) in the
nanomolar range, as tested with an MTS
assay. But most importantly, primary ALL cells with a high aurora B protein
expression, especially E2A-PBX1-positive cases, were sensitive as well. In
adult AML early clinical trials, clear responses are observed with barasertib.
Here we show that inhibition of aurora B, more than aurora A, has an
antiproliferative and pro-apoptotic effect on acute leukemia cells, indicating
that particularly targeting aurora B may offer a new strategy to treat
pediatric ALL and AML. Aurora
kinases in childhood acute leukemia: the promise of aurora B as therapeutic
target. Hartsink-Segers SA, Zwaan CM, Exalto C, Luijendijk MW, Calvert VS,
Petricoin EF, Evans WE, Reinhardt D, de Haas V, Hedtjärn M, Hansen BR, Koch T,
Caron HN, Pieters R, Den Boer ML (email@example.com).
Leukemia. 2012 Sep 3.
doi: 10.1038/leu.2012.256. Aurora
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