title: Aurora kinases in childhood acute leukemia: the promise of aurora B as therapeutic target.
abstract: 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). Aurora 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 (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) 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.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Hartsink-Segers
authors.forename: C M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: C
authors.initials: C
authors.lastname: Exalto
authors.forename: M W J
authors.initials: MW
authors.lastname: Luijendijk
authors.forename: V S
authors.initials: VS
authors.lastname: Calvert
authors.forename: E F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.forename: D
authors.initials: D
authors.lastname: Reinhardt
authors.forename: V
authors.initials: V
authors.lastname: de Haas
authors.forename: M
authors.initials: M
authors.lastname: Hedtjärn
authors.forename: B R
authors.initials: BR
authors.lastname: Hansen
authors.forename: T
authors.initials: T
authors.lastname: Koch
authors.forename: H N
authors.initials: HN
authors.lastname: Caron
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: M L
authors.initials: ML
authors.lastname: Den Boer
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000201:enzymology*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D009841:Oligonucleotides; D011799:Quinazolines; D012333:RNA, Messenger; C477371:locked nucleic acid; C531556:AZD 1152-HQPA; C576917:AURKA protein, human; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases