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Alachkar, H.* ; Mutonga, M.B.* ; Metzeler, K.H. ; Fulton, N.* ; Malnassy, G.* ; Herold, T. ; Spiekermann, K. ; Bohlander, S.K.* ; Hiddemann, W. ; Matsuo, Y.* ; Stock, W.* ; Nakamura, Y.*

Preclinical efficacy of Maternal Embryonic Leucine-zipper Kinase (MELK) inhibition in acute myeloid leukemia.

Oncotarget 5, 12371-12382 (2014)
Publ. Version/Full Text DOI PMC
Open Access Gold
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Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Melk ; Aml ; Ots167; Cancer Stem-cells; In-vivo; Expression; Foxm1; Proliferation; Phosphorylation; Glioblastoma; Progression; Regulator; Prognosis
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 1949-2553
e-ISSN 1949-2553
Journal OncoTarget
Quellenangaben Volume: 5, Issue: 23, Pages: 12371-12382 Article Number: , Supplement: ,
Publisher Impact Journals LLC
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-521000-001
PubMed ID 25365263
WOS ID WOS:000348037700045
Scopus ID 84920017381
DOI 10.18632/oncotarget.2642
Erfassungsdatum 2014-11-06
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