Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

Houda Alachkar; Martin B.G. Mutonga; Klaus H. Metzeler; Noreen Fulton; Gregory Malnassy; Tobias Herold; Karsten Spiekermann; Stefan K. Bohlander; Wolfgang Hiddemann; Yo Matsuo; Wendy Stock; Yusuke Nakamura

doi:10.18632/oncotarget.2642

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Research Papers:

Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

Houda Alachkar, Martin B.G. Mutonga, Klaus H. Metzeler, Noreen Fulton, Gregory Malnassy, Tobias Herold, Karsten Spiekermann, Stefan K. Bohlander, Wolfgang Hiddemann, Yo Matsuo, Wendy Stock and Yusuke Nakamura _

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Oncotarget. 2014; 5:12371-12382. https://doi.org/10.18632/oncotarget.2642

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Abstract

Houda Alachkar1, Martin B.G. Mutonga1, Klaus H. Metzeler2,3, Noreen Fulton1, Gregory Malnassy1, Tobias Herold2,3, Karsten Spiekermann2,3, Stefan K. Bohlander4, Wolfgang Hiddemann2,3, Yo Matsuo5, Wendy Stock1 and Yusuke Nakamura1

1 Department of Medicine, University of Chicago, Chicago, IL

2 Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), München, Germany

3 Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany

4 Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand

5 OncoTherapy Science, Inc., Kanagawa, Japan

Correspondence:

Yusuke Nakamura, email:

Keywords: MELK, AML, OTS167

Received: September 17, 2014 Accepted: October 28, 2014 Published: October 28, 2014

Abstract

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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Research Papers:

Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

Abstract